Surgical

Infections
 Surgical
Infections

Edited by
Donald E. Fry, MD
Adjunct Professor of Surgery
Northwestern University Feinberg School of Medicine
Chicago, Illinois
Emeritus Professor of Surgery
University of New Mexico School of Medicine
Albuquerque, New Mexico
USA

London • St Louis • Panama City • New Delhi

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Preface

The management of infection has a long history and continues conceptually different from the Pasteur and Metchnikoff idea of
to be a major challenge for surgeons in all specialties, for host enhancement through vaccines.
whom infectious disease had its earliest major relevance in the The discovery of penicillin and the development of sulfa
management of battlefield casualties. Ambroise Paré identified compounds in the late 1920 and 1930s resulted in specific
that the topical treatment of traumatic wounds influenced chemotherapy (Ehrlich’s term) becoming the mainstay for the
the outcome. His substitution of a turpentine-based topical treatment of infection. Thus, after World War II, antibiotics
treatment, as opposed to the boiled oil and cauterization were widely deployed for the treatment of infection, with
method, was a beginning for antisepsis at the injury site. In the different antibiotics used against different organisms. Microbial
17th century, Leewenhoek first observed bacteria and became resistance patterns developed for specific pathogens and this
the ‘Father of Microbiology’. Bacteria were not viewed as being required the development of newer drugs, or the re-engineering
of pathologic significance at that time. In the 18th century, of older ones.
the Scottish surgeon John Hunter observed the value of open The treatment of clinical infections largely became the purview
management and delay closure of battlefield wounds, an of internal medicine practitioners. It was William Altemeier who
observation that should be remembered today. pioneered interest in the treatment and prevention of infectious
The 19th century saw significant progress in understanding problems that were unique to the surgical patient. In the 1950s,
and managing infections of the surgical patient. The Hungarian Altemeier and others began to look at antibiotics as a potential
Semmelweis, working at the Vienna General Hospital, identified avenue not only to treat infection, but to prevent infections in the
the role of obstetricians in potentially introducing a toxin patient undergoing invasive procedures. However, early clinical
or poison into birthing women with the pre-partum pelvic trials failed to show any clinical benefit. The shortcomings
examination. He studied the benefits of hand-washing with of these early trials were due to very heterogeneous patient
sodium hypochlorite solution and demonstrated a reduction in populations, but more importantly to the fact that the antibiotics
the rate of what was called ‘child bed fever’. Of course, the germ were not initiated until the postoperative period. Ashley Miles at
theory of disease was not yet formulated and an infectious agent the Lister Institute in London became the father of preventive
(Streptococcus pyogenes as it turned out) was not suspected. antibiotics in surgery, by conducting basic experimental studies
Despite clinical evidence of benefit, the work of Semmelweis was in 1957 with John Burke from Boston, which demonstrated
not accepted at the time. that the antibiotics needed to be given before the insult to
It was Louis Pasteur who developed the germ theory of achieve benefit. In 1969 Hiram Polk provided the critically
disease, which largely originated in his work on the bacterial stratified, prospective, randomized clinical trial to provide
contamination of French wine and his studies of silkworm proof of concept. Thus, the use of antibiotics and the evolution
infections. He proposed microbes as infectious pathogens in of preventive strategies became commonplace in surgical care.
man but unfortunately a stroke prevented him from claiming the The work of all of these international investigators led to the
scientific achievement of proving his theory. Nevertheless, his establishment of the Surgical Infection Society of North America,
contributions subsequently led to the development of the rabies The Musculoskeletal Infection Society, The Surgical Infection
and anthrax vaccines. Perhaps his ultimate contribution was Society of Europe, and the Japan Society for Surgical Infection.
the Pasteur Institute, which prospers to this day, with original The management of the infectious disease problems covered
research into infection and the host response. Elie Metchnikoff in this book form an integral part of surgeons’ clinical duties.
was one of the first appointees at the Pasteur Institute, and First, there is the patient who presents with a community-
is generally credited with being the father of immunology. acquired infection. These infections commonly include soft
Metchnikoff earned the Nobel Prize in 1908 for the discovery of tissue infections following traumatic injury (chapter 5) or intra-
phagocytic cells. abdominal infections after perforation of a viscus (chapter 6).
Robert Koch, a German physician, developed the scientific They may include brain abscess (chapter 22), empyema from
evidence to prove the germ theory and the internationally pneumonia (chapter 15), or osteomyelitis (chapter 19). In
recognized Koch postulates. His early research with anthrax in the community-acquired infection, treatments require combinations
1870s was conducted in a home laboratory using a microscope of surgical management of the primary focus of infection,
given to him by his wife. He discovered Mycobacterium tuberculosis antimicrobial therapy for the offending micro-organisms, and
in 1882, for which he received the Nobel Prize in 1905. supportive care to manage physiologic perturbations created by
With the dawn of the 20th century came the hope that specific the infectious event.
treatments could be developed to treat specific infections. Second, surgical site infection (SSI) continues to be a
Paul Ehrlich discovered salvarsan as a treatment for syphilis. complication of care that has defied control (chapter 4). SSI rates
With this first treatment for an established bacterial infection, have dramatically improved since the times of Ambroise Paré
Ehrlich’s work led to the concept of the ‘magic bullet’ that and Joseph Lister. However, the design of surgical interventions
would be microbe specific and eradicate infection. This was has become more innovative with transplantation procedures,

v
 extensive surgical oncology efforts, and the general deployment of will a text on surgical infections change over the next decade?
prosthetic materials to replace effete tissues. The surgical host has Many of the following may occur, with some being more likely
clearly become more susceptible, with increasing age at the time than others:
of intervention, more advanced diseases at the time of operation,
and immunosuppression either associated with therapeutic ⦁⦁ Bacterial resistance will continue and the need for ad-
interventions (e.g. corticosteroids) or loss of homestasis (e.g. ditional antibiotics will continue. Staphylococcus aureus
trauma, shock, resuscitation). While progress has been made in will become progressively more resistant and additional
the prevention of SSI, newer methods and strategies are needed. mechanisms of resistance will likely be seen among Gram-
Third, nosocomial infections of the surgical patient at negative pathogens.
anatomic sites remote from the operation have continued to ⦁⦁ Will a post-antibiotic era of preventing and treating infections
complicate surgical care. The surgical intensive care unit (ICU) emerge? It can be anticipated that there may be increased
has provided dramatic support for critically ill patients, but investigation to develop vaccines and passive immunity with
has become a reservoir of increasingly resistant pathogens. antitoxins and immunoglobulins. In surgery, topical agents to
Support technology has yielded endotracheal tubes (chapter 8), prevent or treat infections that modulate microbial virulence
intravenous infusion sites and arterial lines (chapter 10), drainage such as phosphates or siderophores will be developed.
catheters (chapter 9), and many other invasive devices that serve ⦁⦁ Immune enhancement of the host has been explored in the
an important support function but which have become portals past with levamasole and muramyl dipeptide. Will non-specific
for microbial access to the host. Not only has our invasive support enhancement of the host before major operations be desirable,
technology created the opportunity for infection, but systemic and what will be the consequences for the enhanced host if a
antibiotic treatment has changed the ecology of the host to one systemic inflammatory response emerges?
where resistant bacteria are the rule and not the exception. Thus, ⦁⦁ Hospital-acquired infections with unusual pathogens are
meticillin-resistant Staphylococcus aureus, extended-spectrum likely to increase as support technology maintains the patient
β-lactamase Gram-negative bacteria, and Clostridium difficile through critical illness in the intensive care unit. It is likely
have become common problems of hospital-acquired infection that more fungal infections will be identified and that viruses
for surgical patients. may emerge as a new group of pathogens for postoperative
The prevention and management of surgical infection has surgical patients.
become a part of the management for every patient that has a ⦁⦁ What will be the influence of new diagnostic methods upon the
surgical procedure, and justifies books that, like this one, attempt recognition and treatment of surgically-associated infections?
to address all of these contemporary issues. The role of infection Amplification of microbial DNA has already become a com-
and surgery is a dynamic one that is constantly changing. Who mon method in the diagnosis of Clostridium difficile infection.
would have believed 40 years ago that peptic ulcer disease was Some studies have found increased sensitivity to the detection
an infection of the gastric mucosa with Helicobacter pylori? Over of blood-borne DNA where conventional cultures have not
the last 40 years, community-acquired staphylococcal infections identified pathogens. Will enhanced molecular detection be
have been transformed from being penicillin-sensitive to being overly sensitive in the detection of microbes that have long
meticillin-resistant. Bacterial infections in the ICU are now since been extinguished but have left residual genetic material
commonly pan-resistant to virtually all available antibiotics. within the host?
Fungal infections are all too common in severely ill surgical ⦁⦁ Will other infectious proteins similar to prions be uncovered to
patients but were barely identified 40 years ago. The future of explain other neurodegenerative diseases, and will infectious
head and neck cancer is likely to be more commonly associated protein be yet another source for nosocomial transmission in
with human papilloma virus infection and not tobacco- patient care?
associated. Finally, contagious disease has now been associated
with misfolded neuroproteins (new-variant Creutzfeldt–Jakob It is certain that prevention and management of infection in the
disease) rather than nucleotide-bearing pathogens such as surgical patient will remain a challenge. We trust that the many
bacteria, fungi, or viruses. Indeed, the germ theory of disease contributions to Surgical Infections will have a useful role as we
may be returning to theory status. all move forward from this point in time.
Reflections on changes in infectious diseases within a surgical
setting over the last 40 years can only beg the question: ‘What Donald E. Fry
will happen in the next 10 or so years as we go forward?’ How

vi
Contents

Preface iv

Contributors ix

Chapter 1
Microbiology of surgical pathogens 1
Donald E. Fry

Chapter 2
Antimicrobial agents 11
Lena M. Napolitano

Chapter 3
Surgical immunology 27
William G. Cheadle, Ziad Kanaan, Adrian T. Billeter,
Rebecca E. Barnett

Chapter 4
Surgical site infections 49
Donald E. Fry

Chapter 5
Skin, skin structure, and soft tissue infections 63
Donald E. Fry

Chapter 6
Intra-abdominal infections 75
John E. Mazuski

Chapter 7
Perirectal abscesses and pilonidal disease 89
Susan Galandiuk

Chapter 8
Hospital-acquired and ventilator-associated pneumonia 97
Philip S. Barie

Chapter 9
Postoperative urinary tract infections 109
Jeffrey A. Claridge, Joseph F. Golob

Chapter 10
Catheter-related bloodstream infections 115
William P. Schecter

Chapter 11
Clostridium difficile infection 123
Donald E. Fry

vii
 Chapter 12
Burn wound infections 133
David N. Herndon, Noe A. Rodriguez, Katrina Blackburn Mitchell,
James J. Gallagher

Chapter 13
Fungal infections of surgical significance 143
Joseph S. Solomkin, Jianen Ren, Donald E. Fry

Chapter 14
Viral infections of surgical significance 155
Donald E. Fry

Chapter 15
Cardiothoracic surgical infections 169
Jorge A. Wernly, Charles A. Dietl, Jess D. Schwartz

Chapter 16
Head-neck infections 189
Francisco O. M Vieira, Mitchell Challis, Shawn M. Allen

Chapter 17
Vascular surgical site infection 203
Kelley D. Hodgkiss-Harlow, Dennis F. Bandyk

Chapter 18
Urological infections 209
Matthew C. Raynor, Ian Udell, Raj Kurpad, Culley C. Carson

Chapter 19
Bone and joint infections 215
Charalampos G. Zalavras, Michael J. Patzakis

Chapter 20
Obstetric and gynecological infections 225
Sebastian Faro, Jonathan Faro, Constance Faro

Chapter 21
Necrotizing enterocolitis 235
Shannon L. Castle, Henri R. Ford

Chapter 22
Postoperative infections of the central nervous system 243
H. Richard Winn, Saadi Ghatan

Chapter 23
Bioterrorism 251
Donald E. Fry

Chapter 24
Microbial translocation, gut origin sepsis,
probiotics, prebiotics, selective gut decontamination 261
Edwin A. Deitch, Jordan E. Fishman, Gal Levy

Chapter 25
Sepsis: systemic inflammation and organ dysfunction 275
John C. Marshall

Index 291

viii
Contributors

Shawn M. Allen, MD Mitchell Challis, MD

Resident in Otolaryngology University of Tennessee Health Science Center
Department of Otolaryngology – Department of Otolaryngology
Head and Neck Surgery Memphis, Tennessee
University of Tennessee USA
Memphis, Tennessee
USA William G. Cheadle, MD
Professor of Surgery; Associate Chief of Staff for Research
Dennis F. Bandyk, MD and Development
Professor of Vascular Surgery Veterans Affairs Medical Center – Louisville
Sulpizio Cardiovascular Center Department of Surgery, University of Louisville
University of California San Diego School of Medicine Louisville, Kentucky
La Jolla, California USA
USA
Jeffrey A. Claridge, MD
Philip S. Barie, MD, MBA Director, Trauma and Critical Care,
Professor of Surgery and Public Health Metro Health Medical Center
Department of Surgery Associate Professor of Surgery
Weill Cornell Medical College Department of Surgery
New York, New York Case Western Reserve University
USA Cleveland, Ohio
USA
Rebecca E. Barnett, MBBS, MRCS
Research Fellow Edwin A. Deitch, MD, FACS, FRCS Ed (Hons)
Hiram C. Polk Jr. Department of Surgery Professor of Surgery
University of Louisville Department of Surgery
Louisville, Kentucky New Jersey Medical School
USA University of Medicine and Dentistry of New Jersey
Newark, New Jersey
Adrian T. Billeter, MD, PhD USA
Ferguson Fellow
Hiram C. Polk Jr. MD Department of Surgery Charles A. Dietl, MD
University of Louisville School of Medicine Associate Professor of Surgery
Louisville, Kentucky Department of Surgery
USA Division of Cardiothoracic Surgery
University of New Mexico Health Sciences Center
Culley C. Carson, MD Albuquerque, New Mexico
Rhodes Distinguished Professor USA
Division of Urology
The University of North Carolina Constance Faro, MD
School of Medicine Department of Obstetrics and Gynecology
Chapel Hill, North Carolina The Woman’s Hospital of Texas
USA Houston, Texas
USA
Shannon L. Castle, MD
Pediatric Surgery Research Fellow Jonathan Faro, MD, PhD
Children’s Hospital Los Angeles Assistant Professor of Obstetrics and Gynecology
Los Angeles, California Department of Obstetrics, Gynecology and
USA Reproductive Sciences
University of Texas Health Science Center at Houston
Houston, Texas
USA
ix
 Sebastian Faro, MD, PhD Joseph F. Golob, MD
John T. Armstrong Professor and Vice Chairman Assistant Professor of Surgery
Chief, Obstetrics and Gynecology, Lyndon B. Johnson Department of Surgery
General Hospital Case Western Reserve University
Department of Obstetrics, Gynecology and Reproductive Cleveland, Ohio
Sciences USA
University of Texas Health Science Center at Houston
Houston, Texas David N. Herndon, MD
USA Professor of Surgery
Jesse H. Jones Distinguished Chair in Burn Surgery
Jordan E. Fishman, MD, MPH University of Texas Medical Branch – Galveston
General Surgery House Officer Chief of Staff and Director of Research
Department of Surgery Shriners Hospital for Children – Galveston
New Jersey Medical School Galveston, Texas
University of Medicine and Dentistry of New Jersey USA
Newark, New Jersey
USA Kelley D. Hodgkiss-Harlow, MD
Clinical Assistant Professor of Vascular Surgery
Henri R. Ford, MD, MHA Section of Vascular Surgery
Vice President and Surgeon in Chief Kaiser Permanente
Children’s Hospital Los Angeles San Diego, California
Professor and Vice Chair of Surgery USA
Vice Dean of Medical Education
Keck School of Medicine Ziad Kanaan, MD, PhD
University of Southern California Resident in Medicine
Los Angeles, California Department of Internal Medicine
USA Wayne State University
Detroit, Michigan
Donald E. Fry, MD USA
Adjunct Professor of Surgery
Northwestern University Feinberg School of Medicine Raj Kurpad, MD
Chicago, Illinois Resident, UNC Division of Urology
Emeritus Professor of Surgery The University of North Carolina
University of New Mexico School of Medicine School of Medicine
Albuquerque, New Mexico Chapel Hill, North Carolina
USA USA

Susan Galandiuk, MD Gal Levy, MD

Professor, Department of Surgery Surgical House Officer
Program Director, Section of Colon and Rectal Surgery Department of Surgery
Director, Price Institute of Surgical Research, University of New Jersey Medical School
Louisville University of Medicine and Dentistry of New Jersey
Department of Surgery Newark, New Jersey
University of Louisville School of Medicine USA
Louisville, Kentucky
USA John C. Marshall, MD, FRCSC
Professor of Surgery
James J. Gallagher, MD Department of Surgery
Assistant Attending Surgeon St Michael’s Hospital
Assistant Professor of Surgery University of Toronto
William Randolph Hearst Burn Center Toronto, Ontario
Weill Cornell Medical College – New York Presbyterian Hospital Canada
New York, New York
USA John E. Mazuski, MD, PhD
Professor of Surgery
Saadi Ghatan, MD Section of Acute and Critical Care Surgery
Vice Chairman, Department of Neurological Surgery Department of Surgery
Continuum Healthcare Washington University School of Medicine
New York, New York Saint Louis, Missouri
USA USA
x
Katrina Blackburn Mitchell, MD Jess D. Schwartz, MD
General Surgery Resident Assistant Professor of Surgery
Weill Cornell Medical College – New York Presbyterian Hospital University of New Mexico
New York, New York Department of Surgery
USA Division of Thoracic and Cardiovascular Surgery
Albuquerque, New Mexico
Lena M. Napolitano MD, FACS, FCCP, FCCM USA
Professor of Surgery
Division Chief, Acute Care Surgery (Trauma, Burn, Joseph S. Solomkin, MD
Critical Care, Emergency Surgery) Professor of Surgery (Emeritus)
Associate Chair of Surgery Department of Surgery
Department of Surgery University of Cincinnati College of Medicine
Director, Trauma and Surgical Critical Care Cincinnati, Ohio
University of Michigan Health System USA
Department of Surgery
University of Michigan Ian Udell, MD
Ann Arbor, Michigan Resident, UNC Division of Urology
USA The University of North Carolina
School of Medicine
Michael J. Patzakis, MD Chapel Hill, North Carolina
Professor of Orthopedic Surgery USA
Chairman, Department of Orthopaedic Surgery
Vincent and Julia Meyer Chair in Orthopaedic Surgery Francisco O. M. Vieira, MD
Department of Orthopaedic Surgery Assistant Professor of Otolaryngology –
LAC + USC Medical Center Head and Neck Surgery
Keck School of Medicine Department of Otolaryngology – Head and Neck Surgery
University of Southern California University of Tennessee
Los Angeles, California Director of Otolaryngology – Head and Neck Surgery
USA Regional Medical Center at Memphis
Memphis, Tennessee
Mathew C. Raynor, MD USA
Assistant Professor
Division of Urology Jorge A. Wernly, MD
The University of North Carolina Professor of Surgery
School of Medicine Department of Surgery
Chapel Hill, North Carolina University of New Mexico
USA Albuquerque, New Mexico
USA
Jianan Ren MD, FACS
Professor of Surgery, Vice-Director H. Richard Winn, MD
Research Institute of General Surgery Professor of Neurosurgery
Jinling Hospital, Nanjing University Director of Neurosurgery
Nanjing, Jiangsu Lenox Hill Hospital
China New York, New York
Professor of Neurosurgery
Noe A. Rodriguez, MD Hofstra University School of Medicine
General Surgery Resident Hempstead, New York
Department of Surgery USA
University of Texas Health Science Center – San Antonio
San Antonio, Texas
USA Charalampos G. Zalavras, MD, PhD, FACS
Professor of Orthopedic Surgery
William P. Schecter, MD Department of Orthopaedic Surgery
Professor of Clinical Surgery Emeritus LAC + USC Medical Center
Department of Surgery Keck School of Medicine
University of California, San Francisco University of Southern California
San Francisco General Hospital Los Angeles, California
San Francisco, California USA
USA
xi
 Dedication

To Hiram C. Polk, Jr, M.D.

In recognition of his lifetime contribution to surgical education and research in the science of surgical infection

xii
 Chapter 1 Microbiology of surgical
pathogens
Sample Donald E. Fry

The number of pathogens responsible for infections in the surgical the Gram stain, whereas the scant amount of the peptidoglycan matrix
patient increases with each passing year. Microorganisms that were is responsible for the negative Gram stain of Gram-negative bacteria.
previously thought to have little pathologic significance emerge as The cell wall serves an important role in providing protection for Gram-
having clinical relevance. Many accepted pathogens develop new positive and -negative species against adverse osmotic conditions by
virulence characteristics that create new clinical challenges. Bacterial the prevention of cell lysis. The peptidoglycan may play a role in the
pathogens, in particular, respond to environmental threats from new virulence of Gram-positive organisms (Myhre and Aasen 2006).
antibiotic therapy and evolve mechanisms of resistance that give them Gram-positive bacteria have only a single plasma membrane that
a new role in clinical infection. Fungi and viruses have become patho- lines the internal surface of the cell wall. The cell wall and the plasma
gens of concern in selected patients, in addition to the ever-expanding membrane adhere closely to each other; there is no periplasmic space
number of bacterial species. between the cell wall and around the plasma membrane of Gram-
It is the unique structure and function of each microbial species that positive bacteria. By contrast, Gram-negative bacteria have both an
results in the pathogenic expression of the organism. As the generation outer and an inner plasma membrane with the cell wall “sandwiched”
time of microbes may be measured in minutes when ideal growth con- in between. The outer membrane provides the unique virulence fac-
ditions are present, mutant species that are better adapted for survival tors (e.g., endotoxin) that are not present in Gram-positive species.
rapidly become dominant in the microenvironment. Newly acquired Furthermore, a periplasmic space exists between the internal surface of
genetic material or mutation yields new virulence characteristics and the cell wall and the inner plasma membrane. This space serves as a re-
new mechanisms for resistance to antimicrobial treatment. To under- pository for β-lactamase accumulation and Gram-negative resistance.
stand virulence and the direction of new treatments, it is essential to The special membrane configuration of the Gram-negative bacteria
understand the basics of microbiology of surgical pathogens. has significance relative to the diffusion of macromolecules, ions, and
various nutrients into the cell. The cell wall of peptidoglycan is very per-
■■BACTERIA meable to most macromolecules especially in Gram negatives where
it is so thin. The permeability of solutes into the cell of Gram-negative
Bacterial cells share many of the same structural features of mam- bacteria is dictated by the parallel plasma membranes.
malian cells. They have a cell membrane composed of a lipoprotein In Gram-negative bacteria, penetration of the outer cell wall–
bilayer which is similar to human cells. DNA is the molecular template plasma membrane complex requires the presence of pores for solute
for orchestrating the synthesis of new proteins. Translational processes transport into the cell. These pores are lined with specialized proteins,
occur with cytoplasmic ribosomes that are quite similar in all animal known as porins, which have permissive and exclusive qualities with
and plant species. respect to the passage of specific macromolecules and solutes
There are important features of the bacterial cell that set it apart
from other cell types. Bacteria have a rigid cell wall external to the
plasma membrane, which serves in protecting the cell from mechani-
cal injury but also gives unique features in the interaction with other G
bacteria and with phagocytes of the potentially infected host (Silhavy
et al. 2010). Bacteria do not have a nuclear membrane to partition their F
genetic material from the cytoplasm, although the genetic material is E
centrally located within the cell. The genome is single-stranded DNA
D
which is anchored in a single location to the plasma membrane. This
C
mesosomal attachment of the DNA demarcates the cleavage point
for cellular division of the mature mother cell into two daughter cells. B
The cell wall–plasma membrane complex is a very important fea-
ture of each bacterial species in dictating the virulence of that species,
but also in determining the sensitivities of specific bacterial cells to A
antibiotic therapy. The relationship of the cell wall and the plasma
membrane are different between Gram-positive and Gram-negative
bacteria (Figure 1.1). 1 2
Gram-positive bacteria have a cell wall that may be 20–50 times
thicker than that of Gram-negative bacteria. Although of different Figure 1.1  Schematically illustrates the difference in the cell wall–plasma
membrane relationships of Gram-positive (1) and Gram-negative (2)
thickness, the cell wall comprises a cross-linked peptidoglycan matrix
bacteria. (A) Cytoplasm; (B) plasma membrane; (C) periplasmic space; (D)
that is similar in Gram-positive and -negative bacteria. The larger thick- cell wall; (E) outer plasma membrane (only in Gram negatives); (F) location of
ness and volume of peptidoglycan give the positive blue coloration on endotoxin (only in Gram negatives); (G) bacterial capsule.
2 MICROBIOLOGY OF SURGICAL PATHOGENS

(Zeth and Thein 2010). The proteins that line the porin channel are The major components of the bacterial cell cytoplasm are ribo-
hydrophilic passages through the ordinarily hydrophobic lipid bilayer somes and metabolic enzymes. The ribosomes are temperature-
of the Gram-negative plasma membrane complex (Figure 1.2). Porins sensitive structures and are of critical significance for the synthesis
may have unique electrical charge and allosteric properties that permit of proteins by the process of translation. Bacterial cells do not have
passage of certain water-soluble compounds while excluding others. mitochondria, but rather have the machinery of oxidative phosphory-
Mutations that affect these porin molecules may confer changes to lation on the internal surface of the plasma membrane. The analogy
the way in which molecules enter the cell, so they will be excluded of the internal oxidative phosphorylation apparatus of bacteria to
(e.g., antibiotics). The growth and division of the bacterial cell can the internal location of the electron transport particles within the
be significantly altered by the macromolecules and solutes that can mitochondria of mammalian cells provides inferential evidence of
navigate the porin channel. Antibiotic access through porin channels the bacterial origin of mitochondria.
may affect resistance or sensitivity.
The outer membrane of the Gram-negative bacterial cell presents
unique antigens to the external environment. One particularly unique
■■FUNGI
antigen is the lipopolysaccharide endotoxin (Brandenburg et al. 2010). Fungal cells have morphologic characteristics that are more analogous
Endotoxin has particular significance as a virulence factor, but also as to mammalian cells than bacterial cells. Fungal cells may grow as
an important recognition antigen for the host response. individual yeast forms or divide and maintain continuous cell-to-cell
Many bacteria have a capsule that is external to the cell wall and contact as filamentous growth. The filamentous growth can be viewed
completely surrounds the microorganism (Roberts 1996). The capsule as a primitive effort at tissue formation. Despite the numerous simi-
has a different composition for different bacterial species. The capsule larities of the fungal cell to mammalian cells, the presence of the cell
may protect the microorganism from certain noxious environmental wall still makes these microorganisms plants.
threats by retarding passage of selected molecules. Most importantly, Similar to mammalian cells, fungal cells have a nuclear membrane
the capsule provides protection from antibody or opsonic adherence that segregates the chromosomal material from the cytoplasm. The
and prevents phagocytosis by neutrophils from the infected host. DNA genetic material is organized as chromosomal strands rather
In addition, the capsular material may have virulence factors that than the circular DNA of bacteria. Fungal cells have mitochondria
facilitate tissue invasion. within the cytoplasm for oxidative phosphorylation. Ribosomes and
The bacterial cell may have a large number of external appendages metabolic enzymes make up most of the cytoplasm.
with various biological functions. Flagella occur as single or multiple The rigid cell wall of fungi provides osmotic regulation and protec-
structures on the cell surface, and commonly are eccentrically located tion similar to bacteria. However, the fungal cell wall has a different
at one end of the cell, or may be found across the entire bacterial surface composition from bacteria. The fungal cell wall is a polysaccharide
(Sowa and Berry 2008). Flagella are important in locomotion, but also rather than the peptidoglycan of bacteria. For most species the poly-
have specific antigens that are recognized by the host through toll-like saccharide is N-acetylglucosamine polymers, commonly known as
receptors. Sex pili are found on Gram-negative bacteria and assume chitin. An external capsule may be found on the surface of the cell
importance in the exchange of extrachromosomal genetic material wall and may contain virulence factors.
(e.g., plasmids), which are of significance in the transfer of acquired Fungi have a dimorphic character (Figure 1.3). They commonly
antibiotic resistance and perhaps other virulence factors. Fimbriae occur as molds in nature, but are transformed into yeast forms when
and the smaller fibrillae are external filaments that primarily facilitate present in a suitable host with favorable temperature conditions (Nem-
adherence to other cells and surfaces. Fimbriae and fibrillae may be ecek et al. 2006). Candida spp. are a yeast that forms hyphae when
found on Gram-positive and -negative bacteria, and are important
virulence factors in that the protein receptors on these structures medi-
ate binding to epithelial cells of the host as the first phase of invasive
infection. Likewise, these proteins are targets for immunoglobulin IgA
antibodies which neutralize adherence to host surface cells.

P
A

Figure 1.2  Schematically illustrates the porin channels through the cell Figure 1.3  This photomicrograph demonstrates the yeast and hyphae
wall-plasma membrane complex of Gram-negative bacteria. (A) Outer phases of Candida albicans in a case of endocarditis. (From the Public
plasma membrane; (B) cell wall; (C) inner plasma membrane; (P) porin channel Health Image Library, Centers for Disease Control, Atlanta, Georgia. Courtesy of
with negatively charged molecules lining the passage into (D) the cytoplasm of Sherry Brinkman.)
the bacterial cell.
 Viruses 3

present as an invasive pathogen in tissues (Sudbery 2011). Fungi of

clinical significance to surgeons are discussed further in Chapter 13. D
Fungi have fewer recognized virulence factors than bacteria and
they are less competitive for nutrients within the microenvironment. E
However, the generalized use of antibiotics results in a reduction in
the density and composition of bacterial colonization on epithelial
surfaces, which enhances fungal colonization of the surgical host
during hospitalization. The immunosuppressive drugs used in trans- A
plant recipients and the generalized immunosuppression of sustained C
illness or severe injury then results in increased frequency of fungal B
infections in the surgical patient. Given a favorable environment and
an impaired host, surface adhesins facilitate binding to epithelial
surfaces, and secreted aspartyl proteinases and phospholipases con-
tribute to tissue invasion (Calderone and Fonzi 2001).

■■VIRUSES
Viruses are generally viewed as the most primitive form of infectious
pathogens. Viruses not only are infectious in animal cells, but also
infect plants (e.g., tobacco mosaic virus) and bacteria (e.g., bacte-
riophages). Viruses are extremely small, a feature that makes them
not filterable by methods customarily used to entrap bacteria. Viral Figure 1.4  Schematically illustrates a viral particle with the envelope
particles are in the range of 10–50 nm in diameter, whereas bacterial component. (A) The capsid shell made of capsomeres; (B) the DNA or RNA
cells are 1–3 µm and fungi 4 µm. These sizes compare with the human nuclear material; (C) the nucleocapsid unit; (D) the viral envelope; (E) spikes of
red cell which is 6–8 µm in diameter. viral protein.
The primitive viral particle is best exemplified by the fact that
viruses are obligate intracellular parasites. They have no intrinsic
mechanisms for cellular energy production. Without ribosomes, they
cannot independently synthesize protein, so metabolic activity and
replication can occur only when the virus utilizes the bioenergy and
protein synthesis resources of the infected host cell.
The complete viral particle requires basically only two structural
elements but may have as many as three. All viruses have nuclear
material that is either DNA or RNA. DNA viruses have double strands,
but RNA viruses may be either single or double stranded. One or
more nucleoproteins may be associated with the viral genome. The
viral genome is contained within a shell known as the capsid, which
is a symmetrical structure that may be helical in configuration or
icosahedral. The capsid is made up of capsomere subunits that are
viral proteins. All DNA viruses are icosahedrons whereas RNA capsids
may be icosahedron or helical. The capsid function is prevention of
degradation of the nuclear contents as the viral particle passes from
one infected cell to another. The capsid may have surface protein
receptors that mediate the binding of a specific viral particle (e.g.,
hepatitis virus) to a specific target cell (e.g., hepatocyte). Figure 1.5  Transmission electron micrograph of a hantavirus virion with
Only the nuclear genetic material and the capsid are necessary for a an outer envelope. (From the Public Health Image Library, Centers for Disease
complete viral particle (virion) capable of causing infection. However, Control, Atlanta, Georgia. Courtesy of Brian WJ Mahy, Luanne H Elliott.)
some viral particles will have a third component that is an envelope
around the perimeter of the nucleocapsid complex (Figures 1.4
and 1.5). The envelope contains both lipid and carbohydrate compo- Infection of the host cell begins with penetration through the plasma
nents, which are derived from the plasma membrane of the previously membrane into the cytoplasm. For the viral particle with an envelope,
infected host cell at the time of release of the particle. The plasma the envelope fuses with the host cell plasma membrane, which results
membrane from the host cell in the envelope may be modified by in release of the nucleocapsid into the cytoplasm. The nucleocapsid
viral glycoproteins to facilitate adherence to new host cellular targets. is then degraded and the nuclear material is released. Naked viruses
As the viral genome contains only the enzyme capacity to synthesize (those without an envelope) bind directly to the target cell surface
proteins, only the protein “spikes” that protrude through this envelope and, by the process of endocytosis, are incorporated into a vacuole
are of actual viral origin. The spikes are important for viral adherence within the infected cell. Both the membrane of the vacuole and the
to target cells. Viruses with envelopes are vulnerable to lipid solvents capsid are subsequently degraded with release of the viral genome.
and non-ionic detergents where naked viruses are not. The pattern of infection, after release of the viral genetic material
Infection of the host cell may depend on whether the virus has an into the host cytoplasm, differs between DNA and RNA viruses. For
envelope or not, and whether the virus is a DNA or an RNA particle. DNA viruses, the viral genome migrates into the host cell nucleus
4 MICROBIOLOGY OF SURGICAL PATHOGENS

where incorporation into the host cell chromosomal complement toxic. “Shedding” of the capsule of B. fragilis into the environment of
occurs. Transcription from the viral DNA template then becomes the infection may then actually provide protection of the aerobic partner
means for synthesis of viral proteins and new viruses. The RNA genome in polymicrobial infections of the peritoneal cavity or diabetic foot.
may be “sense stranded” in that it becomes a direct template for the Gram-positive bacteria have unique adhesion proteins of the cell
translational phase of protein synthesis in the host cell cytoplasm. The wall that mediate the binding to the extracellular matrix of the infected
RNA genome may be “negative sense stranded” and requires synthesis host tissues. These adhesion proteins are collectively referred to as mi-
of a RNA copy that is readable for translation of proteins. A notable crobial surface components recognizing adhesive matrix molecules,
exception to this pattern of RNA infection is the retrovirus group, as or MSCRAMMs (Patti et al. 1994). Several unique MSCRAMMs are as-
is best illustrated by human immunodeficiency virus (HIV). With sociated with increased microbial virulence, especially in Staphylococ-
retroviruses, the RNA nuclear material becomes the template for the cus aureus. These surface molecules are of interest in the development
synthesis of a complementary DNA in the cytoplasm of the host by of vaccines and specific immunotherapy for staphylococcal infections.
the enzyme reverse transcriptase, and this complementary DNA then The most notable of any structural element that has virulence
enters the nucleus of the infected cell and proceeds with viral protein potential is endotoxin, the lipopolysaccharide of Gram-negative
transcription. Viruses of interest to surgeons are discussed in Chapter bacteria. Endotoxin is almost uniformly found in all aerobic, enteric,
14. New viruses of clinical significance continue to be identified and Gram-negative bacteria. It is a component of the outer membrane
viruses of surgical significance will continue to increase. and appears to shed into the microenvironment by actively dividing
bacteria; it is certainly released in large quantities with the lysis of
■■VIRULENCE FACTORS IN Gram-negative bacterial cells.
Although each bacterial strain has a genetically different endotoxin,
MICROORGANISMS Gram-negative endotoxins customarily have the lipid A component
that is associated with many of the virulent features of these bacteria.
Virulence represents the biologic potential for a given microorganism Selected endotoxins such as the endotoxin from B. fragilis do not have
to cause infections. Although some microorganisms are viewed as the lipid A component, and accordingly the virulence of this pathogen
having different intrinsic potential to cause infection, the emergence is mediated by mechanisms other than endotoxin.
of clinical infection is not solely dependent on microbial virulence. The biologic effects of endotoxin are numerous. It is a potent activa-
It is rather determined by the microbial inoculum, the environment tor of the complement cascade through the alternative, or properidin,
of infection, and the integrity of the host. Nevertheless, virulence is pathway. The release of potent cleavage products by complement
an important issue and it is assuming greater importance as newer activation stimulates mast cells to release inflammatory proteins
treatment regimens attempt to neutralize specific virulence factors. and likewise activates neutrophils and macrophages. Endotoxin is
Virulence factors are essentially grouped into three categories. First, identified to directly activate neutrophils without the requirement
the microorganisms may have structural components that are shed of an intermediary macrophage cytokine. This activated state occurs
into the local environment or released with microbial cell lysis. Second, through the formation of an endotoxin complex to lipopolysaccharide-
the microorganisms may synthesize and secrete toxins, enzymes, or binding protein, which in turn binds to the CD-14 receptor site on the
other biological products that injure host tissues or facilitate bacterial neutrophil. Neutrophil activation leads to the synthesis and produc-
growth and proliferation. Finally, an important virulence factor is the tion of reactive oxygen intermediates, which serve an important role
development of resistance to antimicrobial chemotherapy. in intracellular killing of ingested bacteria, but may have destructive
effects on tissues and the microcirculation.
■■Structural components Endotoxin is a potent direct stimulus to macrophages and provokes
the release of biologically active cytokines. Endotoxin-stimulated
Structural components of the bacterial cell that promote virulence macrophages produce tumor necrosis factor (TMF). Endotoxin is
include specific capsular polysaccharides that are external to the cell particularly noted for causing fever either through the release of Inter-
wall (Comstock and Kasper 2006). One of the most notable of these leukin-1 (IL-1) from macrophages or even from direct hypothalamic
capsular elements is the M protein coat of Streptococcus pyogenes. stimulation without a cytokine mediator. In addition to IL-1, IL-6, IL-8,
The M protein provides significant protection to the microorganism by and many other important chemical signals, all of which are redundant
retardation of phagocytosis by host leukocytes. The M-protein coat also signals that mediate various components of the acute-phase response,
appears to facilitate binding of the streptococcal pathogen to epithelial fever, and other sequelae of inflammation, are produced by stimulated
cell surfaces. The capsules of Streptococcus pneumoniae, Neisseria macrophages. Furthermore, the role of endotoxin as an agonist signal
meningitides, and Hemophilus influenzae are also well known to resist to stimulate the neuroinflammatory response and the modulation of
phagocytosis. Although these organisms are efficiently cleared from the numerous pro- and counterinflammatory responses remain to
the blood without opsonization by the spleen, the capsule makes them be fully elucidated.
inefficiently cleared by other elements of the reticuloendothelial system Endotoxin activates both the intrinsic and the extrinsic pathways
(e.g., Kupffer cells). Accordingly, these microorganisms have assumed of the coagulation cascade. Similarly it provokes platelet aggregation
a special pathogenic role in the postsplenectomy sepsis syndrome. and the release of vasoactive compounds (e.g., thromboxane A2) from
Isolation of these capsular polysaccharides has been used for the this source. These combined effects of endotoxin on coagulation pro-
development of vaccines against these encapsulated bacterial strains. teins and platelets result in its clinical association with disseminated
The capsular polysaccharide of Bacteroides fragilis has been intravascular coagulation.
extensively studied and appears to similarly retard phagocytosis.
Purification and injection of the capsular material into the peritoneal
cavity of experimental animals cause abscesses without the presence
■■Secreted toxins
of live bacteria. Thus, it would appear that the capsule of B. fragilis Secreted products by the bacterial cell result in the expression of
may actually exert some of its pathologic potential by being leuko- virulence. Secretable expanded repertoire adhesion molecules
 Virulence factors in microorganisms 5

are identified from S. aureus that are the soluble analogues of the creted by selected bacteria that provide a competitive advantage in
MSCRAMMs in the facilitation of binding to host tissues (Chavakis capturing ferric iron (Fe3+) from the microenvironment (Krewulak
et al. 2005). Other secreted products include the exotoxins, which and Vogel 2008). Ferric iron is essential for metabolic processes and
are most notably produced by Clostridium spp. and have hemolytic, cellular division, and siderophore proteins facilitate solubility and
neurotoxic, cytotoxic, and enteropathogenic effects. capture. Siderophore-producing bacterial cells have a competitive
Hemolytic secretory products are synthesized by other groups of advantage for virulence compared with non-producing bacteria in
pathogenic bacteria besides the Clostridium spp. Potent hemolysins the microenvironment and are considered more virulent. Examples
are produced by strains of both group A streptococci and S. aureus. of siderophores include enterobactin from E. coli, bacillibactin from
The production of these hemolysins is best exemplified when the Bacillus spp., and pyoverdine from P. aeruginosa.
microorganisms are cultured on blood agar plates. The hemolytic A particularly interesting virulence factor that is of considerable
character of streptococci has long been used to classify these bacte- recent interest is the production of biofilm (Cogan et al. 2011). This
ria and has been associated with those strains that have the greatest secreted polysaccharide is produced when selected bacteria establish
pathogenic potential. contact with natural or foreign body surfaces. The biofilm facilitates
In addition to expressing toxicity to red blood cells, white blood microbial adherence to surfaces, but retards cellular and humoral
cell toxicity is another virulence factor that can be secreted by selected elements of host defense from contacting the pathogen. It will also
pathogenic bacteria. Leukocidins have been traditionally recognized interfere with antimicrobial contact with the microbe. Biofilms are
as secretory products of S. pyogenes and S. aureus. In studies designed receiving more attention because they are being recognized as being
to elucidate the pathologic adjuvant effects of hemoglobin, Pruett et more prevalent in many clinical infections. The rigid character of this
al. (1984) identified a product from the metabolism in hemoglobin by extracellular polysaccharide in selected circumstances (e.g., vascular
Escherichia coli that appears to be toxic to leukocytes. This feature of graft infections) may also pose special problems in attempts to culture
certain Gram-negative bacteria may play a significant role in the sup- the putative pathogens. Thus, sonication of suspected foreign bodies
purative character of selected Gram-negative infections, particularly and tissue implants may be necessary to disrupt the rigid configuration
those within the peritoneal cavity. Panton–Valentine leukocidin (PVL) of this polysaccharide, to permit effective cultures to be performed.
is a unique exotoxin produced by community-associated meticillin- Superantigens are secreted protein toxins that bind to the major
resistant S. aureus (CA-MRSA). PVL consists of two proteins that create histocompatibility class II and T-cell receptors to provoke a massive
plasma membrane damage in host cells and is a contributor to the proinflammatory response in the host (Alout and Müller-Alouf 2003).
virulence of CA-MRSA (Boyle-Vavra and Daum 2007). The toxic shock syndromes associated with staphylococcal and strep-
Coagulase activity is another virulence factor that provokes ac- tococcal infections are the most common clinical scenarios. A broad
tivation of the coagulation cascade. This secretory activity has been array of superantigens has been identified (Fraser and Proft 2008) and
associated with pathogenic S. aureus and has been generally identi- more than one unique toxin may be produced by a given clinical iso-
fied as a marker for bacterial virulence. The activation of fibrinogen late. Fortunately, genetic encoding for these superantigens is identified
to fibrin by this enzyme results in the precipitation of fibrin about the only in a minority of staphylococcal and streptococcal strains. Target-
staphylococcal microorganisms and provides a measure of protec- ing superantigens for newer treatment strategies is being pursued.
tion against phagocytosis. This enzyme results in thrombosis of the
microcirculation in staphylococcal infections and contributes to the
local ischemia and pyogenic character of these infections. Although
■■Antimicrobial resistance
coagulase production has been customarily identified with S. aureus, Resistance to antibiotic treatment has emerged as the major virulence
it can also be identified with E. coli, Serratia spp., and Pseudomonas factor for the surgical patient. Pathogens with only ordinary virulence
aeruginosa. characteristics can become extraordinarily difficult to manage in clini-
An important host defense mechanism for the eradication of bac- cal infections because of the development of resistance. It has been the
teria is the production of reactive oxygen intermediates by phagocytic adaptation of resistance more than the development of new virulence
cells in the process of intracellular killing of phagocytosed microorgan- characteristics that has significantly yielded suboptimal results in the
isms. A significant virulence factor is the ability of bacteria to produce prevention and management of clinical infection. Selected bacterial
enzymes that neutralize the effects of these toxic oxygen intermediates. species (e.g., S. aureus) have been uncanny in the development of
B. fragilis can produce superoxide dismutase, which converts super- resistance in very short periods of evolutionary time. This emergence
oxide ion to hydrogen peroxide and attenuates the cytotoxic effects of of resistance to specific antibiotics has meant that the search for new
this phagocytic cell product. E. coli may produce catalase, which then agents will be an endless one.
completes the neutralization process by the conversion of hydrogen As microorganisms are identified as being sensitive or resistant to a
peroxide to water. Thus, the combined effects of these two bacterial given antibiotic, it is important to understand what resistance means.
strains, which are commonly identified in polymicrobial infections Antibiotic sensitivity is described as being bacteriostatic or bacteri-
within the abdominal cavity, can totally neutralize a major phagocytic cidal for a specific microbial density (microbes/ml) and at a specific
cell mechanism for the eradication of bacteria. concentration of the drug. An antibiotic is deemed to be bactericidal
The production of enzymes that degrade the extracellular matrix of if it actually kills the microbe, and it is bacteriostatic if the organism
host tissues and facilitate bacterial proliferation is also an important remains viable but has growth inhibited by the drug. There may also
virulence factor. Collagenase production degrades the fundamental be subtherapeutic effects of the drug that neither kill nor inhibit mi-
collagen structure that constitutes the “skeleton” of many tissues. Col- crobial replication but may change the phenotype of the bacterium.
lagenase is produced by S. pyogenes, S aureus, and selected strains of P. Antibiotics generally work by binding to a target receptor. The target
aeruginosa. Hyaluronidase and heparinase similarly have the biologic receptor is usually an enzyme that is instrumental in a critical process
function of degradation of the intercellular matrix. Hyaluronidase and for synthesis or metabolism of the organism. For a given bacterial cell,
heparinase are produced by S. pyogenes, S. aureus, and by selected binding of the antibiotic molecule must occur to a critical threshold
strains of Clostridium spp. Siderophores are chelating proteins se- of receptor sites before bactericidal or bacteriostatic effects are seen.
6 MICROBIOLOGY OF SURGICAL PATHOGENS

If the drug is present in an inadequate concentration to bind the nec- change. Once a genetic change has occurred, the single mutated and
essary threshold of target sites, a resistant phenotype is observed. If phenotypically changed microorganism then becomes the predomi-
the organism is present in very high or very low concentrations, then nant strain within a given environment because sustained antibiotic
the number of target sites will be great or small, and the effect of a pressure within that environment “selects out” the resistant form.
given drug is influenced by the total number of target sites that are Mutation is a relatively rare event among bacteria. During a single
bound to achieve antimicrobial effect. Determinations of resistance generation of a bacterial cell, a mutation is estimated to have a prob-
and sensitivity are generally indexed to a microbial concentration of ability of 10-7–10-8. Many mutations that occur have no particular
105 organisms/ml for definition of cidal or static effects at achievable significance to the microorganism. Others may actually make the
drug concentrations. The “breakpoint” is the concentration of drug microorganism less resilient and result in the less suitably adapted
at which 90% inhibition is observed against the reference 10 5/ml mutant becoming extinct. An occasional mutation may lead to changes
concentration of bacteria. The inoculum effect is the identification that confer a state of less vulnerability to antibiotic activity.
of microbial resistance at high concentrations of the bacteria when Extrachromosomal acquisition of additional genetic material in
the organism is sensitive at the reference 105/ml. Although not often the form of plasmids is probably the most important mechanism for
discussed, the inoculum effect explains in part why treatment with acquired resistance. Plasmids are circular pieces of genetic material
appropriate antibiotics may yield suboptimum results if microbial that can be acquired by bacterial cells and result in acute structural or
density at the site of infection is very high (e.g., abscesses). functional changes that mediate acute changes in bacterial resistance.
Another consideration in antibiotic use is the post-antibiotic effect. Plasmids doubtlessly had their origin from liberated chromosomal ma-
The antibiotic may be irreversibly bound to the target receptor or it terial after the death and lysis of bacterial cells. Much of this liberated
may dissociate when environmental drug concentration drops below genetic material is degraded. However, those plasmids that could serve
a critical level. If the drug is irreversibly bound, the effects of the drug functional value for the recipient bacterial cell which can internalize
are sustained after drug elimination from the microenvironment. this external DNA result in phenotypic changes.
Thus, antibiotics such as the aminoglycosides bind irreversibly to The internalization of external genetic material can occur by several
the ribosomal target site and have sustained effects even though the mechanisms. Transformation is the process where external genetic
drug has been cleared. This is the basis for once-daily treatment of material is directly acquired from the surrounding environment by the
selected infections with this group of antibiotics. Other drugs such as bacterial cell. Plasmids may gain passive entrance into other bacterial
the cephalosporins in the treatment of Gram-negative infections gen- cells via the pores, which have been previously described. This external
erally require maintenance of the critical drug concentration to have genetic material remains in an extrachromosomal location within the
sustained effects, because clearance of the drug leads to dissociation cytoplasm of the recipient cell, where transcriptional processes may
of the molecules from the target site and loss of antimicrobial effect. then lead to genetic expression. Replication of the plasmid likewise
It must be emphasized that antibiotic sensitivity is determined in occurs from the cytoplasmic compartment, totally independent of the
the clinical laboratory under ideal environmental conditions. For aero- bacterial cells’ normal chromosomal complement.
bic pathogens, ideal growth conditions are chosen with appropriate Transduction is the process where the extrachromosomal genetic
oxygenation, optimum pH, and no protein present in the environment. material is transported into the bacterial cell by a bacteriophage. Bac-
Unfortunately, the microenvironment of infection is not ideal (Fry et teriophages may have free plasmids within their primitive structure
al. 1982). The microenvironment may have predominantly anaerobic from previously infected bacterial cells. Bacterial genetic material may
conditions that adversely affect those drugs (e.g., aminoglycosides) actually have been incorporated into the genome of the viral particle
that require oxygen for effectiveness (Verklin and Mandell 1977). The itself. Thus, viral DNA that is inserted into the genome of the infected
pH of pus and inflammation is acidic rather than neutral and this too bacterial cell may carry other bacterial DNA material with it, which
may affect the affinity of the drug at the target site. Furthermore, the results in the incorporation of plasmid DNA into the chromosomal
microenvironment of inflammation and suppuration is rich in fibrin complement of the bacteriophage-infected cell.
and protein, which is likely to affect highly protein-bound antibiotics. Conjugation refers to the process where bacteria may exchange
These observations about the microenvironment, when combined plasmids by direct cell-to-cell transfer (Llosa et al. 2002). Many species
with the discussion about the inoculum effect, indicate that in vitro of bacteria have sex pili that serve as direct conduits for the passage
microbial activity may not linearly translate into clinical effectiveness, of cytoplasmic components from one bacterial cell to another. The
especially in pyogenic infections. Microbial sensitivity as portrayed process of conjugation can permit the transfer of plasmids and anti-
by the microbiological laboratory must be validated by clinical trials. biotic resistance among bacterial cells within a given environment.
Plasmids can be exchanged from one species of bacteria to another.
■■Genetics of resistance Conjugation is most commonly appreciated among the Gram-negative
Enterobacteriaceae.
Bacteria may be resistant to specific antibiotics because the organism
may not have a susceptible target site for that drug (Young and Mayer
1979), e.g., conventional penicillin has never had activity against enter-
■■Mechanisms of resistance
ic Gram-negative bacteria. The development of resistance by formerly Antibiotics within the major subgroups share common mechanisms
sensitive bacteria means that a structural or functional change in the of activity and likewise share common patterns of resistance. Resis-
target site within the microorganism has mediated the susceptibility tance that develops to one drug within a group may actually confer
change. The receptor site has changed, the target metabolic enzyme resistance to the entire group. Thus, it becomes appropriate to discuss
has been bypassed by an alternative, or efflux pumps are excluding the resistance by antibiotic group.
drug from the cell. These structural or functional changes are mediated
by either acquired genetic material (e.g., plasmids) or chromosomal β-Lactams
mutation. The fact that resistance can develop during a course of an- As discussed earlier, the β-lactam group of antibiotics has the principal
tibiotic therapy clearly indicates that random chromosomal mutation action of inhibition of cell wall synthesis. Inhibition of cell wall synthe-
is not the only mechanism that is responsible for this rapid phenotypic sis results in lysis of actively dividing cells because of loss of osmotic
 Virulence factors in microorganisms 7

control (Tomasz 1979). Inhibition of cell wall synthesis may also acti- This non-hydrolytic activity of β-lactamase appears to be secondary
vate autolysins that actually mediate death of the organism (Tomasz to the enzyme binding to the antibiotic by a tight and non-reversible
et al. 1970). The activity of β-lactam antibiotics does require binding bond. The subsequent antibiotic–enzyme complex may effectively
to target sites that are on the inner aspect of the plasma membrane. neutralize drug activity by interfering with binding to the protein-bind-
The most important mechanism for resistance in β-lactam antibiot- ing site on the plasma membrane. This mechanism may actually be
ics is β-lactamase. β-Lactamases represent a broad array of enzymes activated by de-repression of genes within the normal chromosomal
that are produced by virtually every known bacterial organism. These genome. The rapidity of this de-repression and induction of enzyme
enzymes cleave the amide bond of the lactam ring by hydrolysis and production may be important in the emergence of resistance during
thus neutralize the drug effect on the cell wall target. Since the initial therapy. β-Lactamase induction by this mechanism has been associ-
isolation of an enzyme that hydrolyzed penicillin (Abraham and ated with cross-resistance to other drugs within the group.
Chain 1940), literally hundreds of these types of β-lactamases have Although β-lactamases have been the major focus of investigation
been isolated. into acquired resistance for β-lactam antibiotics, non-β-lactamase
This β-lactamase activity appears to be ubiquitous among all bacte- mechanisms may mediate resistance. Movement of the antibiotic
rial species and found even among some yeast isolates. β-Lactamases through the cell wall may be impeded by acquired or mutational
are coded as part of the normal chromosomal genetic information phenotypic changes. Changes in the penicillin-binding proteins them-
and have been identified from bacteria recovered from times before selves may alter the affinity of the drug. Either reduced binding or en-
the use of antibiotics. Naturally occurring β-lactamases may play a hanced ability of the bacterial cell to synthesize new penicillin-binding
role in the cleavage of chemical intermediates in the polymerization sites will result in attenuation of the drug effect on the organism.
of peptidoglycans as part of normal cell wall biosynthesis.
However, the development of acquired bacterial β-lactamases Aminoglycosides
from plasmids has become a more clinically important source of Aminoglycoside antibiotics are actively transported into the bacterial
β-lactamase production and resistance. The threat of acquired resis- cell where binding to cytoplasmic ribosomes results in inhibition of
tance by this mechanism can be so great and acquired so efficiently protein synthesis. The transport process is energy dependent and
that resistance may occur even during the course of treatment. requires an electrochemical gradient of protons. The active transport
The activity of each β-lactamase enzyme appears to be unique, with process results in concentrations that are much greater within the cell
each enzyme having substrate specificity. As there are nearly 1000 dif- than in the external environment. The absence of a transport mecha-
ferent β-lactamases that have been identified, efforts have been made nism excludes aminoglycosides from human cells, except proximal
to categorize these enzymes by functional or molecular criteria (Bush renal tubule and cochlear cells. An additional undefined mechanism
and Jacoby 2010). These enzymes are commonly viewed as being on a of aminoglycoside activity has been suspected, because inhibition of
continuum, with some being principally penicillinases, cephalospo- protein synthesis alone may not account for the potent bactericidal
rinases, or even carbapenemases (Table 1.1). Unique enzymes are effect of the aminoglycosides (Hancock 1981). The aminocyclitol
identified in Gram-positive, Gram-negative, and anaerobic bacteria. antibiotics (e.g., spectinomycin) have chemical and mechanism simi-
The mechanisms whereby β-lactamases mediate resistance are larities to aminoglycosides (Holloway 1982), although the ribosomal
actually twofold. First, the enzyme may simply be synthesized by the target appears to be different.
organism, released into the environmental milieu, and then it hydro- Resistance to the aminoglycosides (and presumably the aminocy-
lyzes the lactam ring of the antibiotic. However, strains of Pseudomo- clitols) may be mediated by several mechanisms (Jana and Deb 2006).
nas spp. have been isolated that appear to have developed β-lactam First, drug transport into the bacterial cell may be impaired or efflux
resistance, but the new β-lactamase does not hydrolyze the drug. pumps exclude the drug from the bacterial cell. Another mechanism of

Table 1.1  Identifies the functional group and the molecular class of the commonly identified β-lactamase enzymes.
Functional group Molecular class Genetics Comments
1. Cephalosporinases C Mostly chromosomal Most active on cephalosporins, cephamycins, aztreonam. Resistant to clavulanate.
Some plasmid Large amounts affect carbapenems
2. Serine β-lactamases
2a A Mostly chromosomal Responsible for Gram-positive resistance to benzyl penicillin; Inhibited by clavulanate
2b A Plasmids Hydrolyze cephalothin and cephaloridine; inhibited by clavulanate; 2b(e) subset
are extended-spectrum β-lactamases that hydrolyze cefotaxime, ceftazidime, and
aztreonam; subgroup 2b(r) are resistant to clavulanate; subgroup 2b(er) are extended
spectrum enzymes and are resistant to clavulanate
2c A Plasmids Rapid hydrolysis of carbenicillin and ticarcillin; easily inhibited by clavulanate; 2c(c)
subgroup hydrolyzes cefepime
2d D Plasmids Rapid hydrolysis of cloxicillin, oxacillin, and carbenicillin; inhibited by clavulanate;
subgroup 2d(e) hydrolyzes oxyimino-β-lactams; subgroup 2d(f ) hydrolyzes
carbapenems
2e A Plasmids Hydrolyze extended-spectrum cephalosporins; inhibited by clavulanate
2f A Chromosomal or plasmid Hydrolyze carbapenems
3. Metallo-β-lactamases B Chromosomal or plasmid Hydrolyze carbapenems but not aztreonam. Not inhibited by clavulanate
4. Unknown Not Classed Unknown Penicillinases not inhibited by clavulanate
8 MICROBIOLOGY OF SURGICAL PATHOGENS

resistance is alteration of the molecular target on ribosomal proteins. esterase enzyme that hydrolyzes erythromycin. Efflux pumps have re-
Drug transport is normal but the host cell ribosomes are not bound by cently been implicated in Gram-positive resistance (Varaldo et al. 2009).
the drug. Enzymatic conjugation or degradation of the aminoglycoside
can occur after the drug is internalized into the bacterial cell. Every Clindamycin
known aminoglycoside is vulnerable to enzymatic neutralization by The lincosamide antibiotics have a similar action to erythromycin
any one of several known enzymes. Plasmid exchange allows this with reversible binding to the 50-S ribosome. Resistance occurs in
resistance to then be transmitted to other organisms. No inhibitors of a similar fashion to erythromycin, and resistance to one drug may
these anti-aminoglycoside enzymes have yet been identified. carry resistance to both. CA-MRSA will be identified that is sensitive
to clindamycin but resistant to erythromycin. These organisms will de-
Tetracyclines velop inducible resistance if treated with clindamycin, and the D-test
Tetracyclines are actively transported across the plasma membrane should be used to avoid this adverse event in treatment (Woods 2009).
of bacterial cells. Adequate intracellular concentrations result in
threshold binding to the 30-S ribosome and blocks protein synthesis Vancomycin
by the bacterial cell. Tetracycline binding to ribosomes is reversible Vancomycin is a bactericidal drug that interferes with glycopeptide
and concentration dependent. As many as 46 different determinants polymerization, or transglycosylation, after monomeric units of the
have been identified that account for tetracycline resistance (Nelson peptidoglycan are synthesized in the cell cytoplasm. Cell lysis en-
and Levy 2011). Most are plasmid mediated and include: Reduced sues when actively replicating bacteria have an incomplete cell wall.
drug penetration of the bacterial cell, efflux pump systems, ribosomal Vancomycin does affect the growth of protoplasts, reflecting a level
protection proteins that dislodge the antibiotic from the ribosomes, of bacterial action that is not just the inhibition of cell wall synthesis.
and clinical inactivation of the antibiotic by specific enzyme systems. Vancomycin resistance is increasing as the minimum inhibitory
concentration for MRSA is increasing, and intermediate and frankly
Trimethoprim–sulfamethoxazole resistant staphylococci are being identified (Linden 2008). Emerging
These two separate antibiotics have a very similar mechanism of resistance likely relates to impaired penetration of the cell wall or mu-
antibacterial action in that both drugs inhibit different enzyme tation, which reduces and precludes binding of drug to the target site.
systems involved in the biosynthesis of tetrahydrofolate by the
bacterial cell. The sulfonamides competitively inhibit the enzyme Metronidazole
dihydropteroate synthetase, which is essential for the chemical reac- Resistance to metronidazole among anaerobic bacteria remains un-
tion of aminohydroxy-tetrahydropteridine and p-aminobenzoic acid. common (Löfmark et al. 2010). The drug activity is characterized by
Sulfamethoxazole is the most commonly used sulfonamide at the penetration of the bacterial cell, followed by reduction of the drug,
present time. Trimethoprim has its focus of activity at a subsequent binding to DNA and other macromolecular structures being the re-
step in tetrahydrofolate synthesis by the inhibition of dihydrofolate sult. Cell penetration of the drug into resistant strains is slower, and
reductase. The sequential inhibition of sulfonamide and trimethoprim reduction of the compound after penetration is dramatically slower.
has resulted in the two agents being used together to impede folate These changes are probably chromosomal mutation.
synthesis among susceptible organisms.
Naturally occurring resistance to sulfonamides and trimethoprim Quinolones
occurs by the inability of either drug to penetrate the cytomatrix of The quinolones have anti-bacterial action by inhibition of DNA synthe-
the bacterial cell. Acquired resistance occurs from plasmid-mediated sis and inhibition of DNA gyrase enzymes, which are important in the
alternative enzyme pathways that permit folate metabolism to pro- supercoiling of bacterial DNA. Resistance is mediated by mutation in
ceed by bypassing both dihydropteroate synthetase and dihydrofolate the gene for DNA gyrase, which appears to reduce affinity of the drug
reductase. This results in resistance to both sulfonamide and trime- target, or chromosomal changes in porin proteins, which excludes
thoprim. Other resistance mechanisms include increased endogenous access of the quinolones from the intracellular compartment (Drlica
synthesis of p-aminobenzoic acid to overcome competitive inhibition, et al. 2009). Although plasmid replication is potentially inhibited by
enzymatic degradation of the sulfonamide, mutational changes to the DNA gyrase, this acquired mechanism for resistance has assumed
both sulfonamide and trimethoprim target sites, and efflux pumps greater significance with the identification of several plasmids that
(Masters et al. 2003). mediated quinolone resistance.

Erythromycin Other antibiotics

Erythromycin is transported into the cell where it has reversible Many other antibiotics are being employed in patient care and are
binding to the 50-S ribosome, blocks transpeptidation or transloca- summarized relative to mechanisms of action and mechanisms of
tion, and subsequently inhibits protein synthesis. Plasmid-mediated resistance in Table 1.2. The pressure of evolving resistance among S.
resistance results in changes in the binding sites on the ribosomes. aureus and Gram-negative bacteria has resulted in new drug develop-
This mechanism has its greatest significance among Gram-positive ment but also in the revival of older drugs (e.g., rifampicin). It should
organisms. Chromosomal mutation may result in decreased cell wall be apparent that new drug development must continue or that treat-
penetration in Gram-negative bacteria, loss of ribosomal binding ment of clinical infections will need to pursue alternative treatment
sites similar to that seen with plasmid acquisition, and synthesis of an models for the future.
 References 9

Table 1.2 Details less frequently used antibiotics, their mechanisms of action, and the mechanisms of resistance that have been identified.
Antibiotic Mechanisms of action Resistance mechanisms
Linezolid (Nannini et al 2010) Binds reversibly to ribosomal receptors and inhibits Mutational changes in ribosomal target sites; cfr
protein synthesis gene encoding a ribosomal RNA methyltransferase
Daptomycin (Nannini et al 2010) Inserts into and damages bacterial plasma Cell wall and membrane changes adversely
membrane affecting drug binding to target sites
Lipoglycopeptides (dalbavancin, telavancin, Impair cell wall synthesis, bacterial plasma Changes in peptidoglycan synthesis target sites
oritavancin) (Zhanel et al 2010) membrane effects
Teicoplanin (Jung et al 2009) Inhibits final stage of peptidoglycan synthesis Alternative pathways for peptidoglycan synthesis;
reducing binding affinity for target sites
Polymixins (polymixin B, colistin) (Falagas et al 2010) Binding to lipopolysaccharides and disruption of Modification of outer membrane structure
outer plasma membrane
Tigecycline (Peterson 2008) Strongly and reversibly bound to ribosomal targets Anecdotally reported; mechanism undefined
to inhibit protein synthesis
Rifampicin (Tupin et al 2010) Inhibition of RNA polymerase Target site mutation
Fosfomycin (Karageorgopoulos et al 2012) Inhibits peptidoglycan synthesis Decreased drug uptake; target site modification;
drug inactivation

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 Chapter 2 Antimicrobial agents
Lena M. Napolitano

The initial management of all surgical infections should include the be broad spectrum to cover all possible pathogens, but should always
initiation of early empiric antimicrobial therapy to cover all potential be followed by directed narrow-spectrum therapy once the organism’s
possible pathogens, because early and appropriate empiric antibiotic identify and sensitivity to antibiotics have been established – this is
therapy improves patient outcomes (Box 2.1) (Kollef et al. 1999, Kumar the process of “de-escalation” of antibiotics. Antimicrobials should be
et al. 2006, Napolitano 2010). The choice of early empiric antimicro- selected based on the likely bacterial pathogens that are responsible for
bial therapy is guided by the specific site of infection, the common the infectious disease, categorized as Gram-positive, Gram-negative,
pathogens associated with that infection, and local and regional an- or anaerobes (Table 2.1).
tibiograms. The goal of antimicrobial therapy is to achieve antibiotic
concentrations at the site of the infection that exceed the minimum
inhibitory concentration (MIC) of the microbial pathogens present.
■■Antibiotic effect
In surgical infections, antimicrobial agents are used together with Antibiotics may have a bactericidal (killing) effect or a bacteriostatic
adequate source control of the initial infection. This chapter reviews (inhibitory) effect on a range of microbes. Bactericidal drugs may be
antimicrobial agents that are currently available and in development. desirable in infections characterized by poor regional host defenses,
such as endocarditis and meningitis. But in most surgical infections,
particularly complicated intra-abdominal infections or complicated
Box 2.1  Appropriate antimicrobial therapy of surgical infections
skin and skin structure infections, there are few data to suggest that
• Early diagnosis of surgical infection bactericidal antibiotics are associated with better outcomes than
• Early initiation of appropriate empiric broad-spectrum bacteriostatic antibiotics. Clinical efficacy of antimicrobials in large
antimicrobial therapy clinical trials should be considered rather than whether the specific
• Adequate source control
antimicrobial is bactericidal or bacteriostatic.
• Pathogen identification and appropriate de-escalation of
antimicrobial therapy
■■Mechanisms of action of antibiotics
Antibacterial drugs prevent bacterial growth by disrupting the func-
■■ANTIMICROBIALS – SPECTRUM tion of a wide variety of molecular targets located within bacteria and
at the cell surface (Figure 2.1). The penicillins, cephalosporins, and
OF ACTION carbapenems all target cell wall synthesis by inhibiting transpeptidases
required for peptidoglycan formation and the crosslinking of struc-
The range of bacteria or other microorganisms that are affected by a tures in the cell wall. Metronidazole interacts with DNA and inhibits
certain antibiotic is expressed as its spectrum of action. Antibiotics ef- nucleotide synthesis, leading to cell death. The fluoroquinolones block
fective against a wide range of Gram-positive and Gram-negative bac- DNA synthesis by inhibiting DNA gyrase, which is responsible for fold-
teria are said to be broad spectrum or expanded spectrum. If antibiotics ing and supercoiling of the replicating DNA. The sulfonamides and
are effective mainly against Gram-positive or -negative bacteria, they trimethoprim–sulfamethoxazole (TMP-SMX) inhibit the metabolism
are narrow spectrum. If effective only against a single organism, they of bacteria by inhibiting enzymes of folic acid synthesis. The peptide
are referred to as limited spectrum. Empiric antibiotic therapy should antibiotics (e.g., vancomycin) form complexes with the peptidoglycans

Table 2.1 Spectrum of activity of specific antimicrobials for specific pathogens.

Resistant Resistant
Antibiotic Gram negative Gram positive Anaerobe Pseudomonas spp.
Gram negative Gram positive
b-Lactam/b-lactamase inhibitor + + # 0 + #
First-generation cephalosporins 0 + 0 0 0 0
Second-generation cephalosporins # # 0 0 0 0
Third-generation cephalosporins + + # 0 0 #
Fourth-generation cephalosporins + + # 0 0 #
Fifth-generation cephalosporins 0 + 0 + 0 0
Tigecycline + + + + + 0
Glycopeptides 0 + 0 + 0 0
Carbapenems + + # 0 + #
Quinolones + + 0 0 # #
0 = no activity; + = activity; # = activity, but varies by product within class.
12 ANTIMICROBIAL AGENTS

Figure 2.1  Antimicrobial mechanisms of action

Cell wall integrity DNA synthesis DNA gyrase
of various antibiotics.
-lactamases Metronidazole Quinolones

Cell wall
Cell wall synthesis
D-cycloserine Replication
DNA
Vancomycin
Bacitracin Transcription
Penicillins RNA polymerase
Ribosomes
Cephalosporins Rifampin
Cepharmycins 50S 50S 50S
30S 30S 30S

Translation Cytoplasmic Phospholipid

membrane membranes
Polymyxins
Protein synthesis Protein synthesis
(50S inhibitors) (30S inhibitors)
Erythromycin Tetracylines
Choramphenicol Streptomycin
Clindamycin Spectinomycin
Lincomycin Kanamycin

that prevent binding to the transpeptidases responsible for crosslink- Antibiotic modification
ing cell membrane structures into a rigid matrix. The bacteria avoid the antibiotic’s deleterious effects by inactivation
A large number of antibiotics, including the aminoglycosides, of the antibiotic, such as enzymatic degradation of the antibiotic itself,
macrolides, oxazolidinones, streptogramins, lincosamides, and tet- as seen in b-lactamase-producing bacteria that destroy the b-lactam
racyclines/glycylcyclines, interact with bacterial ribosomes to inhibit ring of penicillins and cephalosporins.
protein synthesis (Tables 2.2 and 2.3).
Alterations of the targets of
■■Antimicrobial resistance mechanisms antibiotic agents
Bacteria employ one or more of five basic mechanisms for developing Bacteria can also evade antibiotic action through the alteration of
resistance to antibiotics (Figure 2.2), as follows. the compound’s target, e.g., Streptococcus pneumoniae may express

Table 2.2 Mechanisms of action of selected antibiotics.

Antibiotic Mechanism
Inhibitors of cell wall synthesis
Inhibits transpeptidase enzymes. Activates lytic enzymes of cell wall. The affected bacterium will eventually lyse because the unsupported
Penicillin
cell wall cannot withstand its growth
Carbenicillin Inhibits transpeptidation enzymes. Activates lytic enzymes of cell wall
Inhibits transpeptidation in crosslinking peptidoglycans. Interferes with bacterial cells at many levels, disrupting cell wall synthesis,
Vancomycin
interfering with RNA, and damaging the plasma membrane
Inhibitors of nucleic acid synthesis
Ciprofloxacin Inhibits DNA gyrase; interferes with DNA replication
Rifampin Blocks RNA synthesis by binding to and inhibiting RNA polymerase
Inhibitors of protein synthesis
Tetracyclines Binds to the 30-S subunit and blocks the addition of amino acids, producing incomplete and probably nonfunctional proteins
Linezolid Binds rRNA to prevent translation initiation and thus protein synthesis
Erythromycin Binds the 50-S subunit and blocks translocation of the new protein on the ribosome, thus effectively halting synthesis
Chloramphenicol Blocks formation of new peptide bonds during protein synthesis by binding to the 50-S subunit of the ribosome
Binds the 30-S ribosomal subunit of the tuberculosis bacterium and prevents the ribosome from forming the complex necessary to initiate
Streptomycin
protein translation
Fusidic acid Blocks translocation
Metabolic inhibitors
Competitively inhibits dihydropteroate synthase, an enzyme that converts p-aminobenzoic acid into folic acid. These drugs can also be
Sulfonamides incorporated into a compound that resembles dihydrofolate and which in turn can inhibit another enzyme in the pathway, dihydrofolate
reductase
Trimethoprim Inhibits dihydrofolate reductase, blocking tetrahydrofolate synthesis
 Antimicrobials – spectrum of action 13

Table 2.3 Classes of antibiotics and their properties.

Chemical class Examples Biological source Spectrum (effective against) Mode of action
b-Lactams (penicillins Benzylpenicillin, Penicillium notatum and Gram-positive bacteria Inhibits steps in cell wall
and cephalosporins) cephalothin Cephalosporium spp. (peptidoglycan) synthesis and murein
assembly
Semisynthetic Ampicillin, amoxicillin Gram-positive and -negative bacteria Inhibits steps in cell wall
b-lactams (peptidoglycan) synthesis and murein
assembly
Clavulanic acid Augmentin is Streptomyces clavuligerus Gram-positive and -negative bacteria Inhibitor of bacterial b-lactamases
clavulanic acid plus
amoxicillin
Monobactams Aztreonam Chromobacterium Gram-positive and -negative bacteria Inhibits steps in cell wall
violaceum (peptidoglycan) synthesis and murein
assembly
Carbapenems Imipenem, Streptomyces cattleya Gram-positive and -negative bacteria Inhibits steps in cell wall
meropenem, (peptidoglycan) synthesis and murein
doripenem, ertapenem assembly
Aminoglycosides Streptomycin Streptomyces griseus Gram-positive and -negative bacteria Inhibits translation (protein synthesis)
Gentamicin Micromonospora spp. Gram-positive and -negative bacteria, Inhibits translation (protein synthesis)
especially Pseudomonas spp.
Glycopeptides Vancomycin Amycolatopsis orientalis, Gram-positive bacteria, especially Inhibits steps in murein
Nocardia orientalis Staphylococcus aureus (peptidoglycan) biosynthesis and
(former designation) assembly
Lincomycins Clindamycin Streptomyces lincolnensis Gram-positive and -negative bacteria, Inhibits translation (protein synthesis)
especially anaerobic Bacteroides spp.
Macrolides Erythromycin, Streptomyces erythreus Gram-positive bacteria, Gram-negative Inhibit translation (protein synthesis)
azithromycin bacteria not enterics, Neisseria,
Legionella, Mycoplasma spp.
Polypeptides Polymyxin Bacillus polymyxa Gram-negative bacteria Damages cytoplasmic membranes
Bacitracin Bacillus subtilis Gram-positive bacteria Inhibits steps in murein (peptidoglycan)
biosynthesis and assembly
Rifamycins Rifampicin Streptomyces Gram-positive and -negative bacteria, Inhibits transcription (bacterial RNA
mediterranei Mycobacterium tuberculosis polymerase)
Tetracyclines Tetracycline Streptomyces spp. Gram-positive and -negative bacteria, Inhibit translation (protein synthesis)
rickettsiae
Semisynthetic Doxycycline Gram-positive and -negative bacteria, Inhibit translation (protein synthesis)
tetracycline rickettsiae, Ehrlichia, Borrelia spp.

Glycylcycline Tigecycline Gram-positive and -negative bacteria. Inhibit translation (protein synthesis)
No activity against Pseudomonas spp.
or Proteus spp.
Chloramphenicol Chloramphenicol Streptomyces venezuelae Gram-positive and -negative bacteria Inhibits translation (protein synthesis)

Fluoroquinolones Ciprofloxacin, Synthetic Gram-negative and some Gram- Inhibits DNA replication
levofloxacin positive bacteria (Bacillus anthracis)

modified penicillin-binding proteins (PBPs) which renders them of genetically mobile tetracycline resistance genes, which encode
resistant to penicillins. efflux pump proteins that expel tetracyclines from the cell or code for
proteins that protect the ribosomes.
Active efflux of antibiotic
Bacteria can actively pump out and expel the antibiotic from the cell Prevention of antibiotic entry
with the production of efflux pumps. Efflux pumps can be drug spe- into the cell
cific, as is the case in tetracycline-resistant Gram-negative bacteria, or
may expel a wide variety of antibiotics from multiple classes, such as Bacteria may induce changes in cell wall permeability that reduce
those seen in some strains of Escherichia coli, Staphylococcus aureus, antibiotic entry into the bacteria. These alterations can arise from
Streptococcus pneumoniae, and Pseudomonas aeruginosa. An example point mutations in bacterial DNA or through the exchange of DNA
would be the energy-dependent efflux of tetracyclines widely seen in fragments via the processes of transformation (i.e., “naked” DNA
Enterobacteriaceae. Tetracycline resistance results from acquisition transfer), bacteriophage-mediated transduction, or plasmid-mediated
14 ANTIMICROBIAL AGENTS

Figure 2.2  Antimicrobial resistance mechanisms.

Antibiotic A
A
A
Antibiotic A 2

A
degrading
enzyme Chromosome
Bacterial cell
Plasmid
Cell wall
3 Antibiotic
altering enzyme
A A 1
A
A
Efflux pump
A A
A
No peptidoglycan = penicillin resistant
A
Gram-positive = peptidoglycan = penicillin suscepitble

conjugation. Production of enzymes that degrade or otherwise alter

antibiotics and synthesis of antibiotic-insensitive targets are the
■■SPECIFIC ANTIMICROBIALS
primary mechanisms for resistance to trimethoprim and the sulfon-
amides, aminoglycosides, and quinolones. Reduced permeability is
■■b-Lactam antibiotics
implicated in resistance to b-lactam antibiotics, aminoglycosides, and b-Lactam antibiotics are among the most commonly prescribed drugs,
quinolones. In Gram-negative bacteria, porins are transmembrane and are grouped together based on a shared structural feature, the
proteins that allow for the diffusion of antibiotics through their highly b-lactam ring. b-Lactam antibiotics include the following:
impermeable outer membrane. Modification of the porins can bring ⦁⦁ Penicillins
about antibiotic resistance, as is the case of Pseudomonas aeruginosa ⦁⦁ Cephalosporins
resistance to imipenem. ⦁⦁ Cephamycins
⦁⦁ Monobactams
Bypassing drug’s action ⦁⦁ Carbapenems
The bacteria can bypass the deleterious effect of the drug without ⦁⦁ b-Lactam/b-lactamase inhibitor combinations.
changing the original sensitive target. Examples are the alterna- b-Lactam antibiotics are generally bactericidal. The mechanism
tive PBPs produced by meticillin-resistant Staphylococcus aureus of bacterial cell killing is an indirect consequence of the inhibition of
(MRSA) in addition to the normal PBPs, and some sulfonamide- bacterial cell wall synthesis.
resistant bacteria that use environmental folic acid such as mam-
malian cells, and in this way bypass the sulfonamide inhibition of
folic acid synthesis.
■■Penicillins
Penicillin, derived from the penicillium mold, is one of the earliest dis-
■■Pharmacokinetics and covered antibiotics (Zaffiri et al. 2012). Originally noticed by a French
medical student, Ernest Duchesne, in 1896, penicillin was rediscovered
pharmacodynamics of by bacteriologist Sir Alexander Fleming working at St Mary’s Hospital in
antimicrobial agents London in 1928. But it was not until the 1940s that the use of penicillin
began when Howard Florey and Ernst Chain developed a useful form
The goal of antimicrobial therapy is to select an appropriate antibiotic of the antibiotic. Fleming, Florey, and Chain were awarded the 1945
to eradicate microorganisms at the site of the infection, and correct Nobel Prize in Physiology or Medicine for the discovery of penicillin.
dosing must be used to achieve the maximal effect and avoid toxicity. Penicillins are b-lactam antibiotics that bind to PBPs and trans-
Pharmacokinetics refers to the disposition of drugs in the body and peptidases on the bacterial cell surface, and inhibit cell wall synthesis
includes absorption, bioavailability, distribution, protein binding, and crosslinking of the peptidoglycan chains. Penicillins are excreted
metabolism, and elimination. Pharmacodynamics relates to the unchanged in urine via both glomerular filtration and tubular secretion.
interaction between the drug concentration at the site of action over Ampicillin and nafcillin are also excreted in bile.
time and the desired antimicrobial effect. Both of these concepts Natural penicillins include benzylpenicillin or penicillin G (ad-
are important to optimize antimicrobial use in surgical patients, ministered parenterally) and phenoxymethylpenicillin or penicillin V
particularly in critically ill patients. Impairment of renal or hepatic (administered orally) and are active against streptococci, peptostrep-
function may require alteration of the drug dosage or the dosing tococci, oral anaerobes, Bacilllus anthracis, actinomycoses, Coryne-
interval, and knowledge about which antimicrobials require dosing bacterium, Listeria, Neisseria, and Treponema spp. Natural penicillins
adjustment is mandatory. are commonly used for oral infections. Anti-staphylococcal penicillins
 Specific antimicrobials 15

include meticillin, nafcillin, oxacillin, cloxacillin, and dicloxacillin, and A recent study documented that avoidable metronidazole use occurred
resist penicillinase degradation. Nafcillin is the preferred parenteral in 23.4% of all days of therapy, and that piperacillin/tazobactam was
drug for the treatment of meticillin-sensitive S. aureus (MSSA) infec- the most commonly administered drug with avoidable metronidazole
tions, including bacteremia. use (Huttner et al. 2012). Clearly, additional education is necessary for
Aminopenicillins (ampicillin, ampicillin/sulbactam, amoxicillin, clinicians about the adequacy of anaerobic coverage with piperacillin/
amoxicillin/clavulanate) have extended the antimicrobial spectrum tazobactam and that metronidazole is not necessary. Penicillins are
for Gram-negative organisms, and sulbactam and clavulanate increase associated with a hypersensitivity reaction in 5% of patients; anaphy-
activity against b-lactamase-producing organisms. These agents are laxis occurs only in 1 in 10 000 patients but has a 10% mortality rate.
used as first-line therapy for acute otitis media and sinusitis; however,
they should not be used in the empiric treatment of intra-abdominal
infections. The recent guidelines by the Surgical Infection Society
■■Cephalosporins
and the Infectious Diseases Society of America (SIS/IDSA) state: Cephalosporins are b-lactam antibiotics that act on the bacterial cell
“Ampicillin–sulbactam is not recommended for use in the treatment wall, similar to penicillins. Cephalosporins demonstrate concentration-
of complicated intra-abdominal infections because of high rates of independent bactericidal activity, with maximal killing at four to five
resistance to this agent among community-acquired E. coli” (Solomkin times the MIC of the organism. A clinically significant post-antibiotic
et al. 2010a, 2010b). effect is not observed with cephalosporins. Given these pharmaco-
Anti-pseudomonal penicillins (piperacillin, ticarcillin, piperacil- dynamic properties, it is imperative that optimal dosing regimens
lin/tazobactam, ticarcillin/clavulanate) have increased activity for continuously maintain drug concentrations above the MIC of the
Pseudomonas spp. and other Gram-negative isolates, and decreased pathogens. Bacterial resistance to cephalosporins is via b-lactamases.
activity against Gram-positive organisms. In particular, piperacillin/ Cephalosporins are divided into five generations based on antimicro-
tazobactam is commonly used for the treatment of surgical infections. bial spectrum (Table 2.4).

Table 2.4 Cephalosporin antibiotics.

Spectrum of activity Infectious diseases
First-generation cephalosporins
Cephalothin Gram positive
Cefazolin Activity against penicillinase-producing, meticillin-susceptible staphylococci and streptococci (although they are
Cephapirin not the drugs of choice for such infections). No activity against meticillin-resistant staphylococci or enterococci.
Cephadrine Gram negative
Cephalexin Activity against Proteus mirabilis, some Escherichia coli strains, and Klebsiella pneumoniae, but no activity against
Cefadroxil Pseudomonas, Acinetobacter, Enterobacter, indole-positive Proteus, or Serratia spp.
Second-generation cephalosporins
Cefuroxime Gram positive
Cefamandole Less than first-generation
Cefoxitin Gram negative
Cefotetan Greater than first generation: Hemophilus influenzae, Enterobacter aerogenes, and some Neisseria and Proteus
Cefaclor spp., E. coli, and K. pneumoniae described above
Third-generation cephalosporins
Cefotaxime Gram positive
Ceftriaxone Some (especially those with anti-pseudomonal activity) have decreased activity against Gram-positive organisms
Ceftazidime Gram negative
Cefoperazone Further increased activity against Gram-negative organisms. Increasing ESBLs are reducing the clinical utility of
Cefixime this class of antibiotics. They are also able to penetrate the CNS, making them useful against meningitis caused
by pneumococci, meningococci, H. influenzae, and susceptible E. coli, Klebsiella spp., and penicillin-resistant
Neisseria gonorrhoeae. Since 2007, third-generation cephalosporins (ceftriaxone or cefixime) have been the
only recommended treatment for gonorrhea in the USA
Fourth-generation cephalosporin
Cefipime Gram positive Pneumonia, febrile
They are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation neutropenia, urinary tract
cephalosporins infection, skin infection,
Gram negative complicated intra-abdominal
Fourth-generation cephalosporins are zwitterions that can penetrate the outer membrane of Gram-negative infection
bacteria. They have greater resistance to b-lactamases than third-generation cephalosporins; used for
Pseudomonas aeruginosa infections. Can cross the blood–brain barrier and are effective in meningitis
Cephalosporin with expanded Gram-positive activity including MRSA
Ceftaroline Gram positive FDA approved for treatment
Broad expanded Gram-positive activity, including MRSA and vancomycin-resistant S. aureus of complicated skin and
Gram negative skin structure infections;
Activity against common respiratory pathogens and Enterobacteriaceae isolates community-acquired
pneumonia
CNS, central nervous system; ESBLs, extended-spectrum b-lactamases; FDA, Food and Drug Administration.
16 ANTIMICROBIAL AGENTS

Cephalosporins are one of the most widely prescribed class of cephalosporin, has recently undergone significant scrutiny since
antimicrobials due to their broad spectrum of activity and safety meta-analyses identified that cefipime had a statistically significant
profile. The earlier generation cephalosporins are commonly used (risk ratio 1.26, 95% CI 1.08–1.49) increase in mortality rates when
for community-acquired infections, whereas the later generation compared with other antibiotics in randomized controlled clinical
agents (with their better spectrum of activity against Gram-negative trials (Paul et al. 2006, Yahav et al. 2007). However, a review by the
bacteria) make them more useful for nosocomial, hospital-acquired, Food and Drug Administration (FDA) of 88 clinical trials concluded
or complicated community-acquired infections. that: “data do not indicate a higher rate of death in cefepime-treated
Hypersensitivity reactions to cephalosporins are manifested by patients” (Leibovici et al. 2010). However, a Bayesian reappraisal of the
rashes, eosinophilia, fever (1–3%), and interstitial nephritis. Given the FDA and Yahav meta-analysis data indicates that there is a 90.9% (by
structural similarity of cephalosporins and penicillins, an estimated FDA trial meta-analysis), 80.8% (by FDA patient-level meta-analysis),
10% of patients with penicillin allergies will also be hypersensitive to and 99.2% (by Yahav meta-analysis) probability that cefepime raises
cephalosporins. Cephalosporins should be avoided in patients with mortality in neutropenic febrile patients. A similar harmful probability
immediate allergic reactions to penicillins (e.g., anaphylaxis, bron- was observed with SSIs, but not with pneumonia, intra-abdominal
chospasm, hypotension). Cephalosporins may be tried with caution infection, and urinary tract infections (Kalil 2011). Some have con-
in patients with delayed or mild reactions to penicillin. Among indi- cluded that cefepime should be avoided in patients with neutropenic
viduals with true immediate-type allergy to penicillin, desensitization fever or SSIs. The FDA concludes that cefepime is an appropriate
to cephalosporins is usually an option in cases where no alternate treatment option for patients with approved indications (Food and
antimicrobials are available (Lagacé-Wiens and Rubinstein 2012). Drug Administration 2012a).
First-generation cephalosporins are most commonly used for The fifth-generation cephalosporins include ceftaroline and cefto-
surgical site infection prophylaxis where skin pathogens are the com- biprole. Ceftaroline is the newest addition to the cephalosporin class
mon causative pathogens. Second-generation cephalosporins fall into of antibiotics (Steed and Rybak 2010, Poon et al. 2012). It is unique
two groups, including the “true” second-generation cephalosporins with activity against multidrug-resistant (MDR) Staphylococcus aureus
(cefuroxime, cefamandole) and the cephamycins (cefoxitin, cefo- which includes MRSA, vancomycin-intermediate S. aureus (VISA),
tetan). The cephamycins are active against most anaerobes found in heteroresistant VISA, and vancomycin-resistant S. aureus, Streptococ-
the mouth and colon (e.g., Bacteroides spp., including B. fragilis). The cus pneumoniae (including drug-resistant strains), and respiratory
“true” second-generation agents are useful for community-acquired Gram-negative pathogens. Ceftaroline exhibited a favorable safety
infections of the respiratory tract (Hemophilus influenzae, Moraxella and tolerability profile, consistent with other cephalosporins.
catarrhalis, Streptococcus pneumoniae) and uncomplicated urinary Two phase 3, multinational, randomized, double-blind, active-
tract infections (Escherichia coli). The cephamycin group is useful for controlled clinical trials of identical design (CANVAS 1 and CANVAS
mixed aerobic/anaerobic infections of the skin and soft tissues, intra- 2) compared the effectiveness of ceftaroline with the combination of
abdominal, and gynecological infections, and surgical site infection vancomycin and aztreonam in patients with complicated skin and skin
prophylaxis in abdominal surgery. In a recent, randomized, double- structure infections (cSSSIs) (Corey et al. 2010a, Wilcox et al. 2010).
blind trial of antimicrobial prophylaxis in elective colorectal surgery, The investigators concluded that the efficacy of ceftaroline (cure rate
ertapenem was found to be more effective than cefotetan (17.1% skin 85.9%) was noninferior to that of vancomycin and aztreonam (cure
structure infection [SSI] rate in ertapenem group vs. 26.2% in cefotetan rate 85.5%) in the treatment of patients with cSSSIs (Corey et al. 2010b).
group (absolute difference -9.1; 95% confidence interval [CI] -14.4 to Two phase 3, multinational, randomized, double-blind, active-
-3.7) (Itani et al. 2006). controlled clinical trials (FOCUS 1 and FOCUS 2) of similar nonin-
Third-generation cephalosporins have increased activity against feriority design compared the efficacy and tolerability of ceftaroline
the Enterobacteriaceae associated with hospital-acquired infections. and ceftriaxone in the treatment of community-acquired pneumonia
Some agents are also active against Pseudomonas aeruginosa. How- (CAP) (File et al. 2011, Low et al. 2011). The efficacy of ceftaroline was
ever, nosocomial Gram-negative isolates have a tendency to acquire comparable to ceftriaxone in the treatment of CAP with equivalent cure
antimicrobial resistance during cephalosporin therapy, and caution rates in the clinically evaluable cohort (84.3% ceftaroline versus 77.7%
is required in prescribing these agents, particularly in critically ill pa- ceftriaxone) in the combined analysis (File et al. 2010). Ceftaroline is an
tients. Ceftriaxone is a notable agent in this group because of its long expanded-spectrum cephalosporin that is clinically effective for cSSSIs
half-life requiring less frequent dosing, adequate drug concentrations and community-acquired bacterial pneumonia, and it has distinctive
in the cerebral spinal fluid to constitute reliable empiric therapy for activity against many MDR Gram-positive organisms.
bacterial meningitis, and as the recommended drug of choice for The cephalosporin ceftobiprole was the first β-lactam antibiotic to
gonococcal disease. Ceftazidime has increased activity against P. ae- have bactericidal activity against MRSA, as well as penicillin-resistant
ruginosa, but its current use is significantly limited due to the rapidly streptococci and a wide array of Gram-negative pathogens. It is highly
evolving group of extended-spectrum b-lactamases (ESBLs). ESBLs active against both community-acquired and hospital-acquired forms
will hydrolyze third-generation cephalosporins and aztreonam, and of MRSA. In time-to-kill analysis, ceftobiprole was bactericidal at all
are inhibited by clavulanic acid and increasing in frequency among concentrations tested (Leonard et al. 2008).
Enterobacteriaceae (Paterson and Bonomo 2005). In a randomized, multicenter, global, double-blind trial compar-
The fourth-generation cephalosporins are extended-spectrum ing ceftobiprole with vancomycin plus ceftazidime in 729 clinically
agents that have activity against most staphylococci (except MRSA), evaluable patients with cSSSIs (including diabetic foot infections),
streptococci, and many Gram-negative organisms including isolates of the clinical cure rate was 90.5% for ceftobiprole-treated and 90.2%
Serratia, Pseudomonas, and Enterobacter spp. They also have a greater for comparator-treated patients (95% CI -4.2, 4.9) (Noel et al. 2008a).
resistance to b-lactamases than third-generation cephalosporins. In patients with MRSA infection, the clinical cure rate was 89.7% for
They do not have anaerobic activity, but can be used in the treat- ceftobiprole-treated and 86.1% for comparator-treated patients (95%
ment of pneumonia and other Gram-negative infections. Cefipime, CI -8.0, 19.7). Ceftobiprole was well tolerated, and the incidence of
a broad-spectrum, anti-pseudomonal, fourth-generation, oxyimino- serious adverse events was similar in the two treatment groups.
 Specific antimicrobials 17

A second global, randomized, double-blind trial compared the 2. Group 2 includes broad-spectrum carbapenems, with activity
efficacy of ceftobiprole (500 mg every 12 h) against vancomycin (1 g against non-fermentative Gram-negative bacilli, which are par-
every 12 h) in patients with cSSTIs caused by Gram-positive bacteria ticularly suitable for the treatment of nosocomial infections (e.g.,
(Noel et al. 2008b). Of 559 clinically evaluable cases, 93.3% treated imipenem, meropenem, doripenem).
with ceftobiprole and 93.5% treated with vancomycin were cured (95% A recent longitudinal study documented that the use of the group
CI -4.4, 3.9). The cure rates for patients with MRSA infections were 2 carbapenems (imipenem and meropenem) was associated with sig-
91.8% (56/61) with ceftobiprole and 90.0% (54/60) with vancomycin nificantly increased emergence of P. aeruginosa resistance, which was
(95% CI -8.4, 12.1). At least one adverse event was reported in 52% of not identified with group 1 (ertapenem) carbapenem use. This study
the ceftobiprole-treated patients and 51% of the vancomycin-treated supports the preferential prescription of ertapenem when clinically ap-
patients. The most common adverse events in ceftobiprole-treated pa- propriate (Carmeli et al. 2011). Similarly, results from 10 clinical trials
tients were nausea (14%) and taste disturbance (8%). Discontinuation evaluating the effect of ertapenem use on the susceptibility of Pseu-
of the study drug because of adverse events occurred in 4% (n = 17) of domonas spp. to carbapenems confirmed that ertapenem use does
the ceftobiprole-treated patients and 6% (n = 22) of the vancomycin- not result in increased pseudomonas resistance (Nicolau et al. 2012).
treated patients. Irregularities in the FDA review of clinical trial sites Doripenem is the newest carbapenem to be FDA approved in 2007
resulted in no approval of this drug for clinical use at present. The for complicated intra-abdominal infections (doripenem vs imipenem)
European Committee for Medicinal Products for Human Use (CHMP) and complicated urinary tract infections (doripenem vs levofloxacin)
has similarly concluded that ceftobiprole should not be authorized for and commercially released (Paterson and Depestel 2009). In addition,
use. Both Canada and Switzerland have discontinued the sale and use recent studies evaluated doripenem for the treatment of hospital-ac-
of ceftobiprole. Its clinical future is uncertain at this point. quired pneumonia (HAP). The first randomized, open-labeled, phase
3 trial compared doripenem (500 mg i.v. every 6 h) with piperacillin/
■■Monobactams tazobactam (4.5 g i.v. every 6  h) for nosocomial or early onset (<5
days) ventilator-associated pneumonia (VAP) (Réa-Neto et al. 2008).
Monobactams are monocyclic b-lactam compounds with a spec- Step-down therapy to oral levofloxacin was allowed after ≥72 h of study
trum of antimicrobial activity against Gram-negative bacteria. Its drug, for a complete treatment course of 7–14 days. The clinical cure
mechanism of action is suppression of bacterial cell wall formation. rates in the clinically evaluable (CE) population were 81.3% (109/134)
It has no activity against Gram-positive or anaerobic bacteria. The and 79.8% (95/119), and in the clinical modified intention-to-treat
only commercially available monobactam antibiotic is aztreonam. (cMITT) population were 69.5% (148/213) and 64.1% (134/209) in
Aztreonam has no cross-hypersensitivity reactions with penicillin, the doripenem and piperacillin/tazobactam arm, respectively (p is
and therefore it is commonly used for the treatment of infections in not significant). Overall microbiological cure rates were 84.5% for
penicillin-allergic patients. Aztreonam is indicated for the treatment doripenem and 80.7% for piperacillin/tazobactam.
of intra-abdominal infections, lower respiratory tract infections, pelvic A second, randomized, open-label, phase 3 trial in patients solely
organ, and urogenital infections, and skin and soft-tissue infections. with VAP compared doripenem (500 mg i.v. every 8 h) with imipenem
An additional antibiotic is required with aztreonam to cover Gram (500 mg every 6 h or 1000 mg every 8 h) (Chastre et al. 2008). The clini-
positives and anaerobes. cal cure rates were 68.3% for doripenem versus 64.2% for imipenem
and 59.0% for doripenem versus 57.8% for imipenem in the CE and
■■Carbapenems cMITT populations, respectively. Doripenem met noninferiority
criteria to imipenem for the treatment of VAP. In a subgroup analysis
Carbapenems are very broad-spectrum antibiotics that are structurally of patients with P. aeruginosa, there was a nonstatistically significant
related to b-lactam antibiotics (Zhanel et al. 2007). The carbapenem trend toward higher clinical cure rates with doripenem 80.0% versus
class of antibiotics includes imipenem, meropenem, ertapenem, imipenem 42.9%.
and doripenem. Carbapenems are used for serious Gram-negative The US FDA (2012b) issued a statement regarding the early cessa-
infection (complicated abdominal infection, pneumonia) treatment tion of the clinical trial of doripenem in the treatment of VAP due to
because they provide enhanced Gram-negative and anaerobic cover- significant safety concerns. The study demonstrated excess mortal-
age compared with other b-lactam antibiotics. The carbapenems are ity and a numerically poorer clinical cure rate among participants
classified based on bacterial spectrum of activity: treated with doripenem compared with those treated with imipe-
1. Group 1 includes broad-spectrum carbapenems, with limited nem–cilastatin (Table 2.5). The FDA is reviewing the trial results. Of
activity against non-fermentative Gram-negative bacilli, which note, doripenem is not approved in the USA for the treatment of any
are particularly suitable for community-acquired infections (e.g., type of pneumonia; it is, however, licensed for this indication in the
ertapenem) European Union.

Table 2.5 Summary of clinical cure rates and all-cause 28-day mortality rate in doripenem clinical trial for ventilator-associated pneumonia.
Analysis population Doripenem group (%) Imipenem group (%) Difference (%) Two-sided 95% CI (%)
Clinical cure rates  
MITT 45.6 56.8 -11.2 -26.3 to 3.8
ME 49.1 66.1 -17 -34.7 to 0.8
All-cause 28-day mortality
21.5 14.8 6.7 -5.0 to 18.5
rate (MITT)
From: www.fda.gov/Drugs/DrugSafety/ucm285883.htm
CI, confidence interval; ME, microbiologically evaluable; MITT, modified intent to treat.
18 ANTIMICROBIAL AGENTS

A significant advantage of the carbapenems in the treatment of pharmacodynamic analyses, the vast majority of KPC-producing
infections due to MDR Gram-negative bacteria is their stability to Enterobacteriaceae (>99%) would be reported as resistant to imipenem,
hydrolysis by many ESBLs. Carbapenems are therefore the antibiotic meropenem, and ertapenem, and would diminish the need for clini-
of choice for the treatment of ESBL-producing bacteria. But other cal laboratories to perform the modified Hodge test to guide therapy.
mechanisms of resistance have been reported for carbapenems, and
in vitro susceptibility testing must be performed on clinical isolates
to determine whether these agents are appropriate in the clinical
■■Colistin
management of severe infections. The emergence of nosocomial infections due to MDR Gram-negative
The recent report of a new type of carbapenem resistance gene bacteria have led to the revival of forgotten antibiotics, such as the
(New Delhi metallo-b-lactamase 1 – NDM-1) poses a worldwide polymyxins. Colistin, mainly colistimethate sodium (polymyxin
public health problem, and coordinated international surveillance is E), has been predominantly used as monotherapy or combination
required (Yong et al. 2009). NDM-1 was initially discovered in a strain therapy in these MDR infections (Michalopoulos and Karatza 2010).
of Klebsiella pneumoniae from a Swedish patient of Indian origin who Recent retrospective cohort studies document that the use of com-
traveled to New Delhi and acquired a urinary tract infection there. bination therapy (colistin–polymyxin B or tigecycline–carbapenem)
The original organism was found to be resistant to all antimicrobial for definitive therapy of KPC-producing K. pneumoniae bacteremia
agents tested except colistin (Kumarasamy et al. 2010). Molecular was associated with significantly improved survival (odds ratio 0.07,
examination of the isolate revealed that it contained a novel metallo- 95% CI 0.009–0.71, p = 0.02). The 28-day mortality was 13.3% in the
b-lactamase that readily hydrolyzed penicillins, cephalosporins, and combination therapy group compared with 57.8% in the monotherapy
carbapenems (with the exception of aztreonam). The gene encoding group (Hirsch and Tam 2010, Qureshi et al. 2012).
this novel b-lactamase (which had not been known previously) was MDR Gram-negative bacteria (Pseudomonas, Enterobacter,
found on a large 180-kb resistance-conferring genetic element that Acinetobacter spp.) are increasingly common causes of VAP with
was easily transferred to other Enterobacteriaceae and that contained limited antibiotic options for treatment. A systematic review and meta-
a variety of other resistance determinants, including a gene encoding regression documented that colistin may be as safe and efficacious as
another broad-spectrum b-lactamase (CMY-4) and genes inactivat- standard antibiotics for the treatment of VAP (Florescu et al. 2012).
ing erythromycin, ciprofloxacin, rifampicin, and chloramphenicol. Aerosolized colistin is sometimes used as an adjunctive treatment
In addition, the genetic element encoded an efflux pump capable of of VAP due to MDR Gram-negative bacteria and is safe, although its
causing additional antimicrobial resistance and growth promoters efficacy (particularly its incremental benefit to systemic colistin treat-
that insured the transcription of the genes contained in the genetic ment) is unclear (Michalopoulos et al. 2008). In patients with HAP
element (Moellering 2010). or VAP, inhaled colistin should be used in a combined regimen with
The Clinical and Laboratory Standards Institute (2011) recently systemic antibiotics (Antoniu and Cojocarii 2012).
established revised criteria for the interpretation of sensitivity break-
points for carbapenems (Table 2.6). This is an important change,
because a number of clinical laboratories were having difficulties
■■Aminoglycosides
correctly identifying Klebsiella pneumoniae carbapenemase (KPC)- Aminoglycosides are experiencing resurgence in use because of the
producing Enterobacteriaceae. Furthermore, utilizing the pre-2010 spread of MDR Gram-negative pathogens. Aminoglycosides are now
breakpoints, a significant percentage of KPC-producing organisms commonly used in empiric antimicrobial regimens in critically ill
were identified as being susceptible to the carbapenem being tested, patients and in life-threatening infections, as part of combination
especially imipenem and meropenem. Based on MIC distributions antimicrobial therapy to cover all possible Gram-negative causative
presented to the committee, it became apparent that, by decreasing the pathogens. Aminoglycosides (gentamicin, tobramycin, amikacin,
carbapenem breakpoints to levels consistent with pharmacokinetic/ streptomycin) are bactericidal drugs that inhibit bacterial protein

Table 2.6 New carbapenem breakpoints for Enterobacteriaceae.

Drug Minimum inhibitory concentration (µg/ml) Standard dose used for breakpoint determination (mg)
Susceptible Intermediate Resistant
New carbapenem breakpoints
Doripenem ≤1 2 ≥4 500 every 8 h
Ertapenem ≤0.25 0.5 ≥1 1 g every 24 h
Imipenem ≤1 2 ≥4 500 every 6 h or 1 g every 8 h
Meropenem ≤1 2 ≥4 500 every 6 h or 1 g every 8 h
Old carbapenem breakpoints
Ertapenem ≤2 4 ≥8
Imipenem ≤4 8 ≥16
Meropenem ≤4 8 ≥16
Data from: Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. Twentieth Informational Supplement (June 2010 Update) M100-
S20-U. CLSI, Wayne, PA, USA (2010).
 Specific antimicrobials 19

synthesis by inhibiting the function of the 30-S subunit of the bacterial (cSSTIs): Vancomycin, linezolid, daptomycin, tigecycline, telavancin,
ribosome. Nephrotoxicity and ototoxicity are of significant concern and most recently ceftaroline. The two investigational glycopeptides,
with the use of aminoglycosides, but an additional risk is also under- dalbavancin and oritavancin, are under investigation for treatment of
dosing of aminoglycosides, which will impair efficacy. Optimization cSSSIs, as is iclaprim, a diaminopyrimidine.
of aminoglycoside therapy therefore requires pharmacokinetic and
pharmacodynamic dosing to minimize risk and maximize microbial Vancomycin
killing and optimal patient outcomes (Drusano et al. 2007, Drusano Vancomycin, a bactericidal glycopeptide, emerged as an important
and Louie 2011). Although once-daily aminoglycoside regimens may antibiotic in the 1980s and 1990s with the rise of MRSA infections. Van-
be appropriate for some patients, this strategy may not be adequate in comycin has been the reference standard for treating MRSA infections
critically ill patients and careful drug monitoring is required to both because of its relatively safety, its durability against the development
manage efficacy and limit toxicity (Conil et al. 2011). of resistance (fewer than 20 cases of S. aureus with overt vancomycin
resistance worldwide), and – until recently – the lack of other approved
■■Quinolones alternatives for the treatment of MRSA (Liu et al. 2011).
However, vancomycin is being linked increasingly to clinical fail-
The quinolones are synthetic analogs of nalidixic acid with a broad ures, possibly caused by underdosing, poor tissue penetration, loss
spectrum of activity. The action of all quinolones involves inhibition of accessory gene-regulator function in the organism, slower bacteri-
of bacterial DNA synthesis by blocking the enzyme DNA gyrase. The cidal effect, escalation of vancomycin MICs, and reduced vancomycin
earlier quinolones (nalidixic acid, oxolinic acid, cinoxacin) did not susceptibility related to heteroresistant isolates (Haque et al. 2010,
achieve systemic antibacterial levels after oral intake and thus were Howden et al. 2010, van Hal and Paterson 2011). In a single-center
useful only as urinary antiseptics. The fluoroquinolone derivatives review of 288 patients who required surgical intervention for cSSTIs
(ciprofloxacin, levofloxacin, gemifloxacin, and moxifloxacin) have from 2000 to 2006, 100% of the MRSA isolates from SSTIs in 2003 had
more potent antibacterial activity, achieve clinically useful levels in vancomycin MICs ≤0.5 mg/ml, whereas in 2006, 62% had vancomycin
blood and tissues, and have low toxicity. MICs ≤0.5 mg/ml, with 7% having an MIC of 1 mg/ml and 31% of 2 mg/
The spectrum of activity for quinolones is similar among the avail- ml (Awad et al. 2007).
able agents. In general, these drugs have moderate-to-excellent activity Vancomycin has a relatively low rate of tissue penetration, typically
against Enterobacteriaceae but are also active against other Gram- between 10% and 20%, sometimes resulting in drug concentrations
negative bacteria such as Hemophilus, Neisseria, Moraxella, Brucella, too low to be therapeutic (Daschner et al. 1987, Graziani et al. 1988,
Legionella, Salmonella, Shigella, Campylobacter, Yersinia, Vibrio, and Cruciani et al. 1996). It also has delayed penetration into skin and soft
Aeromonas spp. Resistance to E. coli has significantly increased over tissues. Vancomycin concentrations in breast tissues were evaluated
the past decade, with some centers reporting up to 20–40% resistance. in 24 women undergoing reconstructive surgery after mastectomy for
Ciprofloxacin and levofloxacin are the only quinolones with activity breast cancer. Patients were given a single prophylactic dose of vanco-
against P. aeruginosa, but the increasing resistance of P. aeruginosa mycin (1 g i.v.) 1–8 h before surgery, and tissue concentrations were
to fluoroquinolones has limited their utility. measured by high-performance liquid chromatography. Vancomycin
In general, the fluoroquinolones are less potent against Gram- was not detectable in most patients at 1–3 h postdose (Luzzati et al.
positive than against Gram-negative organisms. Levofloxacin, 2000). Vancomycin concentrations in serum, tissue, and sternal bone
gemifloxacin, and moxifloxacin have the best Gram-positive activity, in patients receiving antimicrobial prophylaxis for coronary artery
including against pneumococci and strains of S. aureus and S. epi- bypass surgery were also examined. The lowest drug concentrations
dermidis, including some cases of MRSA. However, the emergence (4.0–4.8 mg/g) were found in fat when the mean serum concentration
of resistant strains of staphylococci has limited the use of these drugs was 55.1 ± 22.8 mg/ml. At 210 min after vancomycin dosing, the serum
in infections caused by these organisms. Moxifloxacin demonstrates concentration decreased to 16.2 ± 4.6 mg/ml, with fat concentrations
modest activity against many of the significant anaerobic pathogens, in the range 5.4–7.7 mg/g and skin concentrations 15.8–23.5 mg/g, thus
including B. fragilis and mouth anaerobes, and is approved for the documenting delayed tissue penetration (Kitzes-Cohen et al. 2000).
treatment of intra-abdominal infection. However, increased rates of To overcome poor tissue penetration, a vancomycin loading dose
anaerobic resistance over time have been reported. of 25–30 mg/kg (actual body weight) is recommended in seriously ill
Quinolones may be used in the treatment of complicated intra- patients. Continued dosing at 15–20 mg/kg per dose every 8–12 h, not
abdominal infections in combination with metronidazole for anaero- to exceed 2 g per dose, in patients with normal renal function is recom-
bic coverage; however, the recent SIS/IDSA guidelines state: “because mended, or targeted vancomycin dosing aimed at pharmacodynamic
of increasing resistance of Escherichia coli to fluoroquinolones, local targets with area under the curve (AUC)/MIC ratio >400. Vancomycin
population susceptibility profiles and, if available, isolate susceptibility can trigger synergistic nephrotoxicity when administered in high
should be reviewed” (Solomkin et al. 2010a). Quinolones are also used doses or together with other nephrotoxic agents (Wong-Beringer et al.
in the treatment of complicated urinary tract infections and pyelone- 2011), and can cause ototoxicity. In addition, it must be administered
phritis, bacterial prostatitis, in combination with b-lactam antibiotics parenterally (except in colitis caused by Clostridium difficile), which
for febrile neutropenia and in some lower respiratory tract infections requires skilled nursing time for intravenous catheter care, monitor-
(although increasing rates of Gram-negative bacterial resistance have ing, and dosage adjustments.
significantly limited their use).
Linezolid
■■Vancomycin and newer agents After vancomycin, linezolid is the most studied treatment of MRSA
infections. Linezolid, first in the class of oxazolidinones, offers
for MRSA infection broad-spectrum Gram-positive activity with 100% oral bioavailabil-
There are currently six antibiotics approved by the US FDA for the ity. Linezolid is approved for the treatment of vancomycin-resistant
treatment of MRSA complicated skin and soft-tissue infections Enterococcus faecium infections, cSSSIs, and nosocomial pneumonia
20 ANTIMICROBIAL AGENTS

caused by MSSA and MRSA, and uncomplicated SSSIs and CAPs In the largest cSSSI trial to date, 1200 adult patients with suspected
caused by MSSA. or proved MRSA were randomized to treatment with linezolid (intra-
The 2008 LEADER surveillance program (initiated in 2004 to moni- venous or oral) or vancomycin (1 g every 12 h i.v.). Results showed
tor emerging linezolid resistance in US medical centers) assessed more significantly better clinical cure rates in patients treated with linezolid
than 6113 clinical isolates from 57 medical centers throughout the (94.4%) than in those treated with vancomycin (90.4%; p = 0.023)
USA, and reported that 99.64% of S. aureus isolates remain susceptible (Weigelt et al. 2005). For those with MRSA isolated at baseline in the
to linezolid (Farrell et al. 2009). Only 0.36% of sampled strains were modified intent-to-treat (mITT) and microbiologically evaluable (ME)
nonsusceptible to linezolid, a slight decrease from 0.45% and 0.44% populations, the clinical success (cure) rate was better for linezolid-
in 2006 and 2007, respectively. The nonsusceptible strains (n = 22) treated patients than for the vancomycin-treated ones (MITT 92.0%
were S. aureus (n = 33), coagulase-negative staphylococci (n = 14), vs 81.8%, p = 0.0114; ME 94.0% vs 83.6%, p = 0.0108) (Weigelt et al.
and Enterococcus faecium (n = 5), each with defined target mutations. 2006). The number of participants with MRSA at baseline was similar
These data document that linezolid activity sampled by the fifth year in the treatment groups. In this study, microbiologic eradication rates
of the LEADER program showed sustained potency and spectrum were better for linezolid (88.6%) versus vancomycin (66.9%, p <0.0001)
(99.64% susceptibility levels). The nonsusceptible strain isolation rates in patients with confirmed MRSA. An earlier study in patients with
remained stable and the plasmid-mediated ribosomal-based resis- MRSA-complicated surgical site infections also found that significantly
tance mechanism that emerged in S. aureus and S. epidermidis strains more patients treated with linezolid experienced microbiologic suc-
in 2007 showed no evidence of dissemination or increased prevalence. cess (87%) than did patients treated with vancomycin (48%; p = 0.0022)
In an outbreak in the USA, 12 cases of linezolid-resistant S. aureus (Weigelt et al. 2004).
(LRSA, MIC >4 mg/l) were detected (Sanchez Garcia et al. 2010). All Most recently, a phase 4 clinical trial was designed to specifically
patients had been in an intensive care unit (ICU) for a prolonged examine the efficacy of linezolid versus appropriately weight-based
period with prior broad-spectrum antibiotic use. The duration of dosing of vancomycin in the treatment of cSSSIs caused by culture-
linezolid before detection of LRSA was short (7.5 days). The overall proven MRSA (Itani et al. 2010). MRSA was confirmed in 322 patients
mortality rate was 50%. Restriction of linezolid was required, as one randomized to linezolid and 318 patients randomized to vancomycin.
of the measures, to effectively eradicate the outbreak. The rate of clinical success was similar in linezolid- and vancomycin-
The European linezolid surveillance network (ZAAPS program) treated patients (p = 0.249). The rate of success was significantly higher
reported its 8-year (2002–2009) linezolid susceptibility rates as >99.9, in linezolid-treated patients in the mITT population (p = 0.048). The
99.7, and 99.6% for S. aureus, coagulase-negative staphylococci, and microbiologic success rate was higher for linezolid at the end of treat-
enterococci, respectively, and all streptococcal strains were suscep- ment (p = 0.001) and was similar at the end of the study (p = 0.127). Pa-
tible. The ZAAPS program surveillance confirmed high, sustained tients receiving linezolid had a significantly shorter length of stay and
levels of linezolid activity from 2002 to 2009, without evidence of MIC duration of intravenous therapy than patients receiving vancomycin.
creep or escalating resistance in Gram-positive pathogens across Both agents were well tolerated. Linezolid has a 100% bioavailable oral
monitored European nations (Ross et al. 2011). formulation, which shortens the length of hospital stay and duration
Prior post-hoc analyses of clinical trials of nosocomial pneumonia of intravenous treatment compared with vancomycin.
and VAP have suggested that linezolid may yield significantly better A systematic review and meta-analysis of linezolid versus van-
clinical outcomes than vancomycin in patients with serious infections comycin for MRSA SSTIs included four trials and concluded that
resulting from MRSA, but controversy still remains (Wunderink et al. no difference was detected between the two treatments, but a trend
2003, Kollef et al. 2004). Two separate meta-analyses, one with eight toward higher effectiveness of linezolid was observed (Dodds and
trials (1641 patients) (Walkey et al. 2011) and one with nine trials Hawke 2009). An additional meta-analysis included 5 trials with a
(2329 patients) (Kalil et al. 2010) confirmed no evidence of superi- total of 2652 patients and concluded that linezolid was more likely to
ority of linezolid over glycopeptide antibiotics for the treatment of consistently achieve microbiologic eradication in MRSA ME patients.
nosocomial pneumonia. But study limitations included an inability to assess for the effects of
A recent, prospective, double-blind multicenter trial compared heteroresistance and appropriate vancomycin dosing on outcomes
linezolid (600 mg every 12 h) with vancomycin (15 mg/kg every 12 (Bounthavong and Hsu 2010). A third meta-analysis compared line-
h) in hospitalized adult patients with MRSA pneumonia (n = 1184). zolid with vancomycin for the treatment of Gram-positive bacterial
Clinical success was higher in the linezolid cohort (57.6% vs 46.6%, infections and concluded that linezolid was more effective than van-
95% CI 0.5–21.6, p = 0.042). All-cause 60-day mortality rate was simi- comycin in patients with cSSSIs (odds ratio 1.40, 95% CI 1.01–1.95);
lar (linezolid 15.7%, vancomycin 17.0%). Nephrotoxicity was more however, there was no difference in treatment success for patients
frequent with vancomycin (18.2% vs 8.4% linezolid) (Wunderink et with bacteremia or pneumonia (Beibei et al. 2010).
al. 2012). Limitations of this study include no serum vancomycin Thrombocytopenia is a potential complication of linezolid, and
levels for 21% of patients, and day 3 trough levels <12.3 mg/ml for 52% monitoring of complete blood counts is recommended, particularly
of the remaining patients (Wolff and Mourvillier 2012). Additional in those requiring longer courses of therapy.
limitations included unequal distribution of medical comorbidities
between participants, more vancomycin-treated than linezolid- Daptomycin
treated patients received mechanical ventilation at baseline (73.9% Daptomycin, a cyclic lipopeptide available in intravenous form only,
vs 66.9%) and had MRSA bacteremia (10.8% vs 5.2%) (Lahey 2012). is a potent bactericidal agent (Owens et al. 2007). Daptomycin is
The current pneumonia guidelines by the IDSA and American FDA approved for the treatment of cSSSIs caused by Gram-positive
Thoracic Society (ATS) recommend either vancomycin or linezolid, pathogens and for bacteremia, but not for treatment of pneumonia.
with linezolid preferred in case of baseline renal failure or in non- Daptomycin is also often used off-label to treat patients infected with
responding patients and in patients with higher vancomycin MIC vancomycin-resistant enterococci (VREs). Recently, however, the
≥2 mg/l (33 of 174 cases in this current study) (American Thoracic emergence of resistance to daptomycin during therapy threatens its
Society 2005, Torres 2012). usefulness. Whole genome sequencing and characterization of the
 Specific antimicrobials 21

cell envelope of a clinical pair of vancomycin-resistant Enterococcus Gram-positive isolates, tigecycline inhibited all strains, including those
faecalis isolates from the blood of a patient with fatal bacteremia resistant to other tetracyclines. Its coverage includes VREs, penicillin-
documented that mutations in genes were responsible for the devel- resistant S. pneumoniae, and MRSA.
opment of resistance to daptomycin during the treatment of VREs Tigecycline was first approved by the FDA in 2005 for use in
(Arias et al. 2011). cSSSIs and complicated intra-abdominal infections. Currently it is
An analysis of 902 evaluable patients from two randomized, multi- also approved for use in community-acquired bacterial pneumonia
national trials demonstrated clinical equivalency between daptomycin (CABP). Treatment begins with an initial dose of 100 mg i.v. followed
and conventional antibiotics (vancomycin- or penicillinase-resistant by 50 mg i.v. every 12 h.
penicillins) in the treatment of cSSSIs (Arbeit et al. 2004). Success rates In two phase 3, double-blind studies of hospitalized patients with
in the clinically evaluable population were 83.4% for daptomycin- cSSSIs, tigecycline demonstrated clinical cure rates equivalent to those
treated patients and 84.2% for comparator-treated patients (95% CI of vancomycin plus aztreonam among the 833 clinically evaluable
-4.0, 5.6). Only 64 patients with MRSA were evaluated microbiologi- patients (86.5% vs 88.6%, respectively; 95% CI -6.8, 2.7) (Ellis-Grosse
cally in the study cohort. Among the 64 patients with MRSA, the clinical et al. 2005). Among the 65 ME patients with MRSA infection, the eradi-
success rates were 75.0% for daptomycin and 69.4% for the comparator cation rates were 78.1% for tigecycline-treated patients and 75.8% for
drug (95% CI -28.5, 17.4). The frequency, distribution, and severity of vancomycin-treated patients. More adverse events (AEs) related to the
adverse events were similar in the two treatment groups. digestive tract were reported in the tigecycline group, and more rash,
The efficacy of daptomycin in cSSTIs also has been examined in cardiovascular events, and liver enzyme increases were reported in
the Cubicin Outcomes Registry and Experience 2004 (CORE) Registry, the vancomycin/aztreonam group. In clinical trials, the most frequent
a multicenter observational registry involving 45 institutions. A total side effects associated with tigecycline were nausea and vomiting.
of 165 patients were identified, including 145 with MRSA and 20 with A recent meta-analysis of eight randomized controlled trials (n =
MSSA cSSTIs, but without bacteremia, endocarditis, osteomyelitis, or 4651) provides evidence that tigecycline monotherapy may be used
other major infectious processes. Clinical success was achieved with as effectively as the comparison therapy for cSSSIs, complicated intra-
daptomycin in 89.1% of patients overall, including 89.7% in patients abdominal infections, CAPs, and infections caused by MRSA and VRE.
with MRSA. Prior antibiotic therapy had been administered to 74.2% However, because of the high risk of mortality, AEs, and emergence of
of patients and concomitant antibiotic therapy to 39.4% (Martone resistant isolates, prudence with the clinical use of tigecycline mono-
and Lamp 2006). therapy in infections is required (Cai et al. 2011). The FDA Drug Safety
Another study examined daptomycin efficacy in 53 adult patients Communication (FDA 2010d) reported an increased adjusted overall
with cSSTIs at risk for MRSA infection compared with a matched mortality rate of 0.6%, predominantly as a result of tigecycline use in
retrospective cohort of 212 patients treated with vancomycin. The the treatment of VAP and HAP, suggesting that alternative antibiotics
proportions of patients with clinical improvement or resolution of their should be considered in these serious infections.
infections on days 3 and 4 were 90% versus 70% and 98% versus 81% in
the daptomycin and vancomycin groups, respectively (Davis et al. 2007). Telavancin
The serum creatine phosphokinase (CPK) concentration should be Telavancin is a semisynthetic lipoglycopeptide with a dual mechanism
monitored weekly during use of daptomycin, especially if high doses of action: Inhibition of cell wall synthesis and disruption of membrane
are given. Caution is necessary in patients previously treated with van- barrier function. It has a 7- to 9-h half-life, which allows once-daily
comycin, which may influence daptomycin susceptibility (Sakoulas dosing. Telavancin is approved for the treatment of cSSSIs caused by
et al. 2006). Clinical data from the retrospective daptomycin CORE susceptible Gram-positive bacteria, including MRSA and MSSA. In
registry confirmed that patients failing vancomycin were more likely two phase 2 trials for treatment of cSSTIs, similar clinical success rates
to fail daptomycin salvage therapy compared with patients switched were achieved in patients receiving telavancin or standard therapy for
for other reasons (p = 0.0009). In an attempt to prevent resistance infections caused by S. aureus and MRSA (Stryjewski et al. 2005, 2006).
selection, higher doses of daptomycin (8 mg/kg) were associated with Two parallel, randomized, double-blind, active-control, phase 3
better therapeutic outcomes compared with lower doses (4–6 mg/kg) studies were conducted in patients aged ≥18 years who had cSSSIs
(Bassetti et al. 2010). caused by suspected or confirmed Gram-positive organisms (Stryjew-
The FDA released a Drug and Safety Communication about ski et al. 2008). Patients (n = 1867) were randomized to receive either
daptomycin-induced acute eosinophilic pneumonia (AEP), charac- telavancin (10 mg/kg i.v. every 24 h) or vancomycin (1 g i.v. every 12 h).
terized by new lung infiltrates and hypoxemia (FDA 2010c, Lal and In the clinically evaluable population; at 7–14 days after receipt of the
Assimacopoulos 2010). Peripheral eosinophilia and rash may not be last antibiotic dose, success was achieved in 88% and 87% of patients
present, although eosinophilia was invariably detected in bronchoal- who received telavancin and vancomycin, respectively (95% CI -2.1,
veolar samples (Miller et al. 2010). The role of steroids is unclear but 4.6). MRSA was isolated at baseline in 579 clinically evaluable patients
daptomycin should be withheld pending appropriate investigations – the largest series to date. Among these patients, the cure rate was
in patients developing new infiltrates. Daptomycin rechallenge is not 91% among patients who received telavancin and 86% among patients
recommended. The incidence of daptomycin-induced AEP is small who received vancomycin (95% CI -1.1, 9.3). Microbiologic eradication
(determined from the FDA’s Adverse Event Reporting System data- of MRSA was achieved in 90% of the telavancin group and 85% of the
base) at approximately 0.43 per 10 000 patients treated. vancomycin group (95% CI -0.9, 9.8). This study confirmed that tela-
vancin given once daily was at least as effective as vancomycin for the
Tigecycline treatment of patients with cSSSIs, including those infected with MRSA.
Tigecycline is the first agent of the glycylcycline class. Chemically A recent post-hoc analysis of the two phase 3 trials examined ef-
similar to minocycline, tigecycline is better tolerated and more active ficacy in different types of skin infections, and concluded that cure
against tetracycline-resistant strains (Boucher et al. 2000). Tigecycline rates were similar for telavancin and vancomcyin including infections
is effective over a broader spectrum than many other agents, but does caused by MRSA and Panton–Valentine leukocidin (PVL)-positive
not cover P. aeruginosa or Proteus spp. In a study of more than 500 strains of MRSA (Stryjewski et al. 2012).
22 ANTIMICROBIAL AGENTS

Telavancin is also undergoing investigation for treatment of pneu- The multicenter, double-blind, randomized, active-control, parallel-
monia. The global results of two phase 3 randomized, double-blind, assignment, phase 3 trial (ASSIST-1), compared IV iclaprim (0.8 mg/kg,
clinical trials in patients (n = 1503) with nosocomial pneumonia (AT- n = 250) with IV linezolid (600 mg, n = 247), both administered for 10–14
TAIN-1 and ATTAIN-2) have recently been published (Rubinstein et al. days, in patients with cSSSI who had extensive cellulitis, abscesses,
2011). The clinical evaluation of 654 patients (312 telavancin 10 mg/kg ulcers, burns, or wounds (Arpida 2012a). The primary objective was
i.v. once daily, 342 vancomycin 1 g i.v. every 12 h, both groups treated clinical cure rates of iclaprim versus linezolid. Secondary outcomes
with aztreonam) showed no outcome differences between groups. The included clinical efficacy at the end of the trial and clinical outcomes
subgroup analysis of patients with MRSA pneumonia with a vancomycin of the ME and ITT populations. Approximately 70% of the pathogens
MIC of at least 1 mg/ml showed better results for telavancin (clinical re- isolated were S. aureus, 25% of which were MRSA. For the ME patients,
sponse 87.1% vs 74.3%; p = 0.03). In a subgroup analysis of patients with the cure rates were 94.7% and 98.8% for iclaprim and linezolid, respec-
VAP, there was a trend toward higher clinical cure rates with telavancin tively. The overall clinical cure rate for the ITT population was 85.5% and
(80.3% vs 67.8%). However, treatment with telavancin was accompanied 91.9% for iclaprim and linezolid, respectively. The clinically evaluable
by a non-significant higher rate of renal dysfunction compared with patients had cure rates of 93.8% and 99.1%, respectively.
vancomycin (16% vs 10%). The telavancin-associated renal dysfunc- A subsequent multicenter, double-blind, randomized, active-
tion was restricted to patients with abnormal baseline renal function. control, parallel-assignment, phase 3 clinical trial (ASSIST-2), was
The European Commission approved telavancin for the treatment initiated in cSSSI patients with extensive cellulitis, abscesses, ulcers,
of adults with HAP, including VAP, known, or suspected, to be caused burns, or wounds to compare intravenous iclaprim (n = 251) with
by MRSA. The FDA has not approved telavancin for pneumonia use intravenous linezolid (n = 243) (Arpida 2012b). The primary and
in the USA. secondary endpoints were the same as those in the ASSIST-1 trial.
Preliminary analysis indicated overall clinical cure rates for the ITT
■■Investigational semisynthetic population of 84.9% and 87.2% for iclaprim and linezolid, respectively.
The most common baseline pathogen was S. aureus (approximately
glycopeptides 60%), 50% of which were MRSA. The microbiological eradication
Two additional anti-MRSA intravenous glycopeptides are being evalu- rates for MSSA were 83.5% and 84.7% for iclaprim and linezolid, re-
ated: Dalbavancin and oritavancin. spectively, and 77.0% and 80.0% for MRSA, respectively. For patients
with Gram-positive pathogen infections at baseline, the clinical cure
Dalbavancin rates were 83.3% and 85.9% for iclaprim and linezolid, respectively.
The unique feature of dalbavancin is its extraordinarily long half-life In a preliminary analysis of the clinically evaluable population, the
(6–10 days), which allows once-weekly dosing. In a phase 3 trial, in- cure rates were 89.6% and 96.4% for iclaprim and linezolid, respec-
travenous dalbavancin, administered on days 1 and 8, was compared tively. It has not been approved for use and clinical evaluation of this
with intravenous/oral linezolid, given twice daily for 14 days, in 660 antibiotic continues.
clinically evaluable patients with cSSSIs; 88.9% of the dalbavancin-
treated patients and 91.2% of the linezolid-treated patients had clinical Tedizolid (TR-701)
success. The rates of MRSA eradication in 278 patients with confirmed Tedizolid is the active moiety of the prodrug torezolid phosphate, a
MRSA cSSTIs were 91% in the dalbavancin group and 89% in the line- second-generation oxazolidinone with 4- to 16-fold greater potency
zolid group. The safety profiles for the two agents were similar (Jauregui than linezolid against Gram-positive species including MRSA. A dou-
et al. 2005). Dalbavancin was similar to vancomycin in a phase 2 trial ble-blind phase 2 study evaluated three doses (200, 300, or 400 mg) of
of the treatment of catheter-related bloodstream infection (Raad et al. oral once-daily torezolid over 5–7 days for cSSSIs (Prokocimer et al.
2005). Two new phase 3 studies are underway (Discover 1 and 2) for 2011). Cure rates in clinically evaluable patients were 98.2% at 200 mg,
the treatment of acute bacterial skin and skin structure infections. It 94.4% at 300 mg, and 94.4% at 400 mg. Results of this study show a
currently remains unapproved for use in the USA. high degree of efficacy at all three dose levels with no safety issues. The
phase 3 clinical trials in acute bacterial skin and skin structure infec-
Oritavancin tions confirmed non-inferiority comparing Tedizolid 200 mg daily for
Oritavancin is another broad-spectrum semisynthetic glycopeptide 6 days to Linezolid 600 mg twice daily for 10 days (http://www.triusrx.
under development for the treatment of cSSTIs, catheter-related com/trius-therapeutics-tedizolid-results.php)
bloodstream infections, and nosocomial pneumonia. It has demon-
strated activity against vancomycin-resistant strains of staphylococci
and enterococci, and has a long half-life (100 h), which is expected
■■CONCLUSION
to allow once-daily or every-other-day dosing. Two phase 3 trials for Inadequate treatment of severe infections in surgical patients contrib-
treatment of cSSSIs have been completed, with the primary endpoints utes to in-hospital death and prolonged duration of hospitalization.
reportedly being met in each. The drug has not been approved for use Prompt, appropriate antimicrobial treatment of infections in surgical
because of a lack of MRSA-specific data. Subsequently, two studies patients increases the chances of a successful outcome. The choice of
(SOLO I and SOLO II) are being conducted with completion expected antimicrobial agent for empiric treatment of surgical infections should
in January 2013. be guided by a number of considerations, including the site and type
of infection, presence of immunocompromised state or neutropenia,
Iclaprim adequacy of source control, and risk factors for MDR bacteria. Patients
Iclaprim is a synthetic diaminopyrimidine. It is a selective inhibitor of with severe infection or comorbidities should be treated aggressively
the enzyme dihydrofolate reductase (similar to trimethoprim), with with empiric broad-spectrum antimicrobial therapy in appropri-
bactericidal activity against MRSA and clinically important Gram- ate dosing strategies, and then de-escalated to narrower-spectrum
positive pathogens (Peppard and Schuenke 2008). Two phase 3 trials agents depending on the culture findings and clinical response. It is
for the treatment of cSSSIs, comparing iclaprim with the comparator, of paramount importance to obtain specimens for culture and anti-
linezolid, were conducted in 2007. microbial susceptibilities given the high prevalence of MDR bacteria
 References 23

as causative pathogens in surgical infections. Surgeons must have a in the number of antimicrobials that are FDA approved for the treat-
working knowledge of appropriate antimicrobial agents for surgical ment of Gram-positive infections, but very few new Gram-negative
infections, particularly for use in acute bacterial skin infections and antimicrobials are currently undergoing clinical trials. Antimicrobial
SSIs, complicated intra-abdominal infections, pneumonia, bactere- stewardship is therefore necessary to retain the activity of our current
mia, and urinary tract infections. There has been a significant increase antimicrobials for use in Gram-negative infections.

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with specific types of complicated skin and skin structure infections. J Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant
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aureus hospital- and ventilator-acquired pneumonia: a step forward but the Yahav D, Paul M, Fraser A, Sarid N, Leibovici L. Efficacy and safety of
battle continues. [Editorial]. Clin Infect Dis 2012;54:630–2. cefepime: a systematic review and meta-analysis. Lancet Infect Dis
van Hal SJ, Paterson DL. Systematic review and meta-analysis of the significance 2007;7:338–48.
of heterogeneous vancomycin-intermediate Staphylococcus aureus isolates. Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-β-
Antimicrob Agents Chemother 2011;55:405–10. lactamase gene, blaNDM-1, and a novel erythromycin esterase gene carried
Walkey AJ, O’Donnell MR, Wiener RS. Linezolid vs glycopeptide antibiotics on a unique genetic structure in Klebsiella pneumoniae sequence type 14
for the treatment of suspected methicillin-resistant Staphylococcus aureus from India. Antimicrob Agents Chemother 2009;53:5046–54.
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Weigelt J, Kaafarani HM, Itani KM, Swanson RN. Linezolid eradicates Zhanel GG, Wiebe R, Dilay L, et al. Comparative review of the carbapenems.
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2004;188:760–6.
 Chapter 3 Surgical immunology
William G. Cheadle, Ziad Kanaan, Adrian T. Billeter, Rebecca E. Barnett

■■INTRODUCTION local infection, and can be directed against most foreign microbes
regardless of whether the host has previously encountered such
The human immune system consists of a highly complex and redundant organisms. Mediators of such inflammation include histamine,
arrangement of immune cells and secreted proteins that have evolved kinins, and arachidonic acid metabolites. Tissue injury results in
extensively over time. These cells and proteins are located throughout the release of histamine from mast cells, as well as bradykinin and
the body and include the bone marrow, thymus, liver, spleen, intestine, kallikrein production, which act directly on vascular endothelium
lymphatics, and various mucous membranes. Its role in defense of to transport cellular and protein elements of the immune system
the host has been summarized as encounter, recognition, activation, to the site of injury (Ley et al. 2007). Arachidonic acid is produced
deployment, discrimination, and regulation (Table 3.1). Intuitively, by breakdown of cellular membranes and the action of phospholi-
this system developed to recognize pathogens and defend the host pase A (Funk 2001). It is then degraded by either lipooxygenase to
against microbial invasion; however, products of tissue injury are now form leukotrienes or cyclooxygenase to form prostaglandins and
known to stimulate the immune system as well (Lotze et al. 2007). There thromboxanes. Most of these inflammatory mediators are formed
are numerous pattern recognition receptors, both cell associated and quickly and locally, where their effect is maximal and short-lived.
secreted, that allow host recognition of various microbial pathogens and These mediators act in a paracrine fashion, and therefore serum
products of host tissue injury (Netea et al. 2004). Thus, pathogen- and measurements may not reflect local activity.
danger-associated molecular patterns (PAMPs and DAMPs), which are Phagocytosis is essential to eradication of most live invading mi-
products of pathogens and damaged host cells, respectively, can both crobial organisms and is carried out primarily by polymorphonuclear
stimulate an immune response that is mediated via these specific recep- leukocytes (neutrophils) and cells of the mononuclear phagocyte
tors. An excessive or unabated immune response may be associated system, which include tissue macrophages. This multistep process
with inappropriately vigorous systemic inflammation, which can lead includes immune cellular adherence to the capillary endothelium,
to organ failure without infection. Discrimination of foreign pathogens diapedesis to the site of inflammation via chemotaxis, possible prior
from self-tissues is critical to avoid the immune system turning on the opsonization of foreign antigens (mostly by complement or immu-
host and the potential ‘horror autotoxicus’ described by Paul Ehrlich noglobulins), engulfment of the microbes into the cell, and finally
over a century ago. microbial killing and degradation (Figure 3.1). The process is de-
It has been known since antiquity that survival from an infectious pendent on intrinsic cellular function for bacterial killing, but highly
disease often conferred lifetime immunity to it; however, Jenner was dependent on the surrounding milieu for most of the process. Immune
first to systematically vaccinate against microbes (smallpox virus) in cell necrosis amplifies the local immune response, whereas apoptosis,
the eighteenth century, which eventually led to eradication of this dis- or programmed cell death, actually helps to resolve the inflammatory
ease. Immunization against a variety of viral and bacterial diseases, and response (Wesche et al. 2005).
the development of antimicrobial therapy, have both reduced mortality Cytokines are proteins by which cells communicate between them-
from many common infectious diseases during the twentieth century. selves, usually in a paracrine fashion (Table 3.2). These proteins are
An increasingly immune-suppressed population has led to emergence involved in immune cell development and also help to regulate the
of multi-resistant pathogens. A persistent inflammatory response in overall immune and inflammatory response by activating other im-
the setting of sepsis has also been associated with development of mune cells (Medzhitov 2007). Chemokines and growth factors are also
organ failure and mortality. cytokines with specific functions such as chemotaxis and augmenta-
The immune system classification is now generally divided into tion of immune cell differentiation. Almost all cytokines interact with
innate and adaptive immunity. Components of the innate system immune cells via specific receptors, although they shed receptors
include mechanical barriers such as the skin, and respiratory, and may also bind cytokines in the intravascular space. There are 17
genitourinary, and gastrointestinal tracts, as well as complement interleukins (IL-1 to IL-23) that have been well studied and regulate
proteins, certain cytokines and inflammatory mediators, and the the immune response. Cytokines can also be produced by mono-
phagocytic process itself. These are activated with tissue injury or nuclear cells in response to specific antigenic stimulation, e.g., tumor
necrosis factor-α (TNFα) is produced by macrophages in response
to antigenic stimuli, most notably endotoxin. Its production occurs
Table 3.1  Immune system classification.
rapidly and binding to soluble receptors has probably accounted for
Innate Adaptive the inconsistency in its detection from the blood of patients in Gram-
Mechanical barriers Macrophage/dendritic cell antigen negative septic shock (Rittirsch et al. 2008). The interferons are a family
presentation of proteins that were initially described in the supernatant of virally
Complement and coagulation T lymphocyte infected cell cultures, which “interfered” with such viral superinfection.
cascades Interferon-γ is produced primarily by mononuclear cells and has been
shown to increase class II histocompatibility antigens (HLA-DR, Ia)
Mediators, cytokines, chemokines B lymphocyte and plasma cell
(antibody production) on the surface of monocyte/macrophages, which may amplify antigen
recognition (Polk et al. 1992). T-helper cells have been divided into
Inflammation
Th-1 and Th-2 subpopulations, both of which have distinct patterns of
Phagocytosis cytokine secretion that augment or inhibit various components of the
28 SURGICAL IMMUNOLOGY

Figure 3.1  Neutrophil

migration from the
intravascular space into the
interstitium at the site of
infection. This migration is
PMN Migration regulated by adhesion molecule
expression and a chemokine
gradient. The ultimate fate is
either necrosis or apoptosis.

PECAM-1

Selectins Integrin ICAM-1 Chemokine receptors

Chemokine gradient

Apoptosis
MIP-2 C-3a Necrosis
TNF- C-5a
PAF
L-8

Infection

immune system. Th-1 cells secrete IL-2, IFN-γ, and TNFα which aug- This results in B-cell expansion by specific Th-2 cytokine produc-
ment cell-mediated immunity by activating monocyte/macrophages, tion and maturation into plasma cells with subsequent antibody
T cells, and natural killer (NK) cells. Th-2 cell secrete IL-4, -10, and production. Antibodies produced are specific to the original foreign
-13 which activate B cells and aid in their maturation to plasma cells antigen, and memory B cells are then capable of an intense second-
and antibody production. These cytokines are also anti-inflammatory ary response to a previously recognized antigen. The innate response
and inhibit the actions of the Th-1 cytokines. may be augmented by antibody production, because phagocytosis
The complement cascade is a series of enzymatic cleavage reac- proceeds more rapidly when microbes are opsonized and the process
tions (Figure 3.2) that are triggered by either antigen–antibody com- is receptor mediated.
plexes (classic pathway) or bacterial cell wall components (alternate
pathway) (Ricklin et al. 2010). The complement system is highly
conserved, indicating its early evolutionary development as a means
■■BASIC CELLULAR IMMUNOLOGY
of host defense. The latter pathway does not require prior exposure There is an overview in Table 3.3.
to a particular microbe, and represents a mechanism for immediate
defense against microbial invasion. The membrane attack complex
of complement is capable of direct bacterial lysis. Complement
■■Monocyte, macrophages,
components recruit neutrophils to the site of infection by acting as and dendritic cells
chemoatttractants (C3a, C5a), and facilitate both phagocytosis and Monocytes, macrophages, and dendritic cells are mononuclear granu-
bacterial killing by opsonization of bacteria (C3b) and stimulation of locytic myeloid cells, which play a crucial role in the immune response.
neutrophil degranulation. All three cell types can recognize PAMPs with their innate immune
The specific immune system includes B (bursa-equivalent de- receptors, the so-called pathogen recognition receptors (PRRs), and
rived) and T (thymus derived) lymphocytes, and antigen-presenting an overview of the different classes of PRRs is provided in Table 3.4.
cells such as macrophages and dendritic cells. Lymphocytes are Besides PAMPs, they can also recognize endogenous proteins such
formed from stem cells in the bone marrow, yolk sac, and liver, and as heat shock proteins or high-mobility group protein B1 (HMGB1),
then undergo differentiation into T cells by exposure to the thymus which is released from host cells after tissue damage. These proteins
or continue to mature into B cells in the bone marrow. Foreign an- are called alarmins and both PAMPs and alarmins are summarized as
tigen recognition, uptake, degradation, and expression on the cell Danger Associated Molecular Patterns (DAMPs). Monocytes, macro-
surface of macrophages or dendritic cells are the initial steps in the phages, and dendritic cells have a high density of PRRs, and thus play
adaptive immune response. IL-1α is produced, and T-helper cells a major role in the activation of the immune system after infection
bind to the processed foreign antigen in contiguity with the class II or tissue damage. These cells are considered the first line of defense
histocompatibility antigen HLA-DR on the macrophage cell surface and attract other cells of the innate immune systems such as granulo-
(Murphy 2011). The activated T-helper cell (CD4) then produces IL-2 cytes and new monocytes, and importantly dendritic cells, which are
which stimulates cytotoxic T-cell clonal expansion. Th-2 cells also responsible for the activation and initiation of the adaptive immune
bind to specific B cells that have been exposed to the same antigen. system (Medzhitov 2007). Dysfunction of these cells occurs during
 Basic cellular immunology 29

Table 3.2  Cytokines.

Name Function/Actions Source
Fibroblasts
G-CSF Stimulates neutrophil development and differentiation
Monocytes
CSF

Macrophages
GM-CSF Stimulates myelomonocytic cell growth and differentiation, especially dendritic cells
T cells
Antiviral Leukocytes
IFN- α
Increased MHC class I expression Dendritic cells
Interferons

Antiviral
IFN-β Fibroblasts
Increased MHC class I expression
Monocyte/Macrophage activation
T cells
IFN-γ Increased MHC II expression
NK cells
Promotes Ig class switch
Fever
Monocytes/Macrophages
IL-1β Monocyte/Macrophage activation
Epithelial cells
T-cell activation

IL-2 T-cell proliferation T cells

B-cell activation
T cells
IL-4 Induces IgE switch
Mast cells
Induces Th2 differentiation
T cells
IL-5 Eosinophil growth and differentiation
Mast cells
Interleukins

Fever
T cells
Acute phase response
IL-6 Monocytes/Macrophages
T-cell growth and differentiation
Endothelial cells
B-cell growth and differentiation
IL-10 Suppresses monocyte, macrophage and dendritic cell functions Monocytes
Activates NK cells Macrophages
IL-12
Induces differentiation of CD4 T cells into Th1 Dendritic cells
B cells growth and differentiation
Inhibits monocyte/macrophage inflammatory cytokine production
IL-13 T cells
Inhibits Th1 cells
Induces allergy/asthma
IL-17 Induces strongly production of proinflammatory cytokines Th17 T cells
Monocytes/Macrophages
Promotes inflammation
TNF-α NK cells
Endothelial cell activation
Others

T cells
Inhibits cells growth Chondrocytes
TGFβ1 Anti-inflammatory properties Monocytes/Macrophages
Induces switch to IgA T cells
G-CSF, Granulocyte colony-stimulating factor; GM-CSF, Granulocyte-macrophage colony-stimulating factor; IFN, Interferons; Ig, Immunoglobulin; IL, Interleukin; Nk, Natural killer; TGF,
Transforming growth factor; Th, T-helper cell; TNF, Tumor necrosis factor.

sepsis and after trauma (Polk et al. 1986, Docke et al. 1997). Monocytes, All three of these cell types are derived from the multipotential
macrophages, and dendritic cells have an array of common features: hemopoietic stem cells, which differentiate into the common myeloid
All of them express receptors of the innate immune systems such as progenitor cell. This cell then develops into a myeloblast, which is the
toll-like receptors (TLRs), and they produce multiple cytokines and progenitor of the granulocyte and monocyte cell lines. There is not
chemokines. All are capable of phagocytosis, antigen presentation in such a high plasticity, as previously believed, and all three cell types,
the development of the adaptive response, and secretion of various despite having a related function, originate from different precursors,
proteins. The types of cytokines and chemokines may vary among and cannot completely differentiate into each other. Monocytes,
different subsets, and they are capable of presenting antigens to cells however, are capable of replenishing macrophages in tissues and can
of the adaptive immune system such as B and T cells via the major differentiate into some types of dendritic cells (Geissmann et al. 2010,
histocompatibility complex II (MHC-II) (Gordon and Taylor 2005, Shi Shi and Pamer 2011). It seems that the local environment influences
and Pamer 2011). The expression level of MHC II on the surface, such the further development of monocytes, macrophages, and dendritic
as HLA-DR, is widely accepted as a reliable marker for the functional cells strongly (Murray et al. 2011). This differentiation depends on the
state of the immune system, and several clinical trials aiming to restore expression of certain growth factor receptors and transcription factors
HLA-DR expression in critically ill patients have been performed (Polk such as PU.1 and MafB, which then activate the transcription of the
et al. 1992, Docke et al. 1997, Meisel et al. 2009). cell-specific genes (Bakri et al. 2005).
30 SURGICAL IMMUNOLOGY

Figure 3.2  The complement

Classical/lectin pathway Alternative pathway cascade is activated by either
antigen–antibody complexes
Microbial polysaccharaides
Initiation: Antigen bound immunoglobulin or microbial products. C3b
C-reactive protein, lipid A functions as an opsonin and
mannose-binding lectin C3a and C5a as chemokines. The
membrane attack complex is
Activation Stabilization directly lytic to microbes.
(C4b2a) C3 convertase (C3bBbP)

C3 C3b, C3a, C3b

C5 C5b, C5a

C6 + C7 C8 + C9

C5b-9 (membrance attack complex)

sepsis, but also other systemic inflammatory disease. In addition,

Monocytes they have been associated with formation of thrombotic plaques
After production in the bone marrow, monocytes circulate in the (Fingerle et al. 1993, Mizuno et al. 2005, Kim et al. 2010).
blood, spleen, and bone marrow for several days. The spleen stores ⦁⦁ Intermediate monocyte: This has a high expression of CD14, but
a considerable number of these cells (Shi and Pamer 2011). Under also expresses CD16 at a lower level. The cytokine production is
normal conditions they cannot proliferate outside the bone marrow. not defined.
During infection, monocytes are released from both the bone marrow The current concept of monocyte development is that the classic
and the spleen, and become effector cells which produce cytokines monocyte differentiates first into the intermediate and then into the
as well as phagocytosing cell debris and toxic molecules (Gordon and inflammatory monocyte (Ziegler-Heitbrock 2007, Shi and Pamer
Taylor 2005). The chemokine receptor CCR2 plays an important role in 2011). Furthermore, inflammatory monocytes are believed to be the
the release of monocytes from the bone marrow (Shi and Pamer 2011). precursor of inflammatory dendritic cells (Geissmann et al. 2010, Shi
These cells leave the bloodstream at the site of infection, during which and Pamer 2011). Circulating monocytes have two main roles. Under
time the endothelium expresses adhesion molecules; these allow the normal conditions they replenish macrophages and dendritic cells
attachment of monocytes as well as their transmigration. Monocytes can in various different tissues. Under inflammatory conditions, blood
then develop into inflammatory dendritic cells and tissue macrophages, monocytes are attracted to the site of inflammation and differentiate
depending on exposure to the local cytokine and growth factor milieu into macrophages. The main functions of monocytes are the produc-
(Ziegler-Heitbrock 2007, Shi and Pamer 2011). Monocytes constitute tion of cytokines, antigen presentation and phagocytosis.
3–8% of the leukocytes in the blood, and about half are stored in the
spleen to replenish monocytes that have left the bloodstream for sites Macrophages
of inflammation. Macrophages are found in almost all tissues and have different names
Monocytes are divided into three subgroups. The criteria are the depending on the tissue, i.e., Kupffer cells in the liver, histiocytes in
expression of the surface markers CD14, CD16, HLA-DR, and CCR2 the skin, alveolar macrophages in the lung and osteoclasts in the bone
(a chemokine receptor), as well as the production of the cytokines (Gordon and Taylor 2005). Macrophages develop from monocytes,
TNFα and IL-10 (Ziegler-Heitbrock 2007, 2010, Shi and Pamer 2011). which differentiate further after leaving the bloodstream, depending
⦁⦁ Classic monocyte: The hallmark is high expression of CD14, on the tissue that they enter. The role of tissue macrophages is twofold:
medium expression of HLA-DR and no expression of CD16 and Activation of the early, initial immune response in the case of infection
CCR2. These monocytes produce both TNFα and IL-10, and seem or tissue damage, and phagocytosis of pathogens and cell debris. They
to be the main cells that enter infectious sites and replenish tissue actively patrol in healthy tissue with amoeboid movements as part of
macrophages. These monocytes cannot re-enter the bloodstream the immune surveillance and phagocytose debris of cells and potential
once they are in the tissue (Belge et al. 2002). pathogens (Medzhitov 2007). When macrophages recognize PAMPs,
⦁⦁ Non-classic monocyte (inflammatory monocyte, Tip-DC): The they produce proinflammatory cytokines such as TNFα, IL-1β, and
hallmark is high expression of CD16, HLA-DR, and CCR2, but IL-6, which serve as messengers between the immune cells and other
low expression of CD14. It secretes more TNFα than the classic tissues. The development and origin of certain macrophages such as
monocyte, but no IL-10. This monocyte subtype is believed to be microglia, dermal macrophages, and marginal zone macrophages
the precursor of the inflammatory dendritic cell. These monocytes in the spleen remain unclear (Geissmann et al. 2010). Current data
are capable of transmigrating through the endothelium in both suggest that these cells enter these tissues very early during embryo-
directions, from blood to tissue and back into blood and lymph genesis, are able to replicate themselves, and are thus not dependent
vessels. CD16+ cells expand during inflammatory states such as on monocytes from the blood.
 Basic cellular immunology 31

Table 3.3  Cells of the immune system.

Name Function Contents/Secreted Cytokines Surface Markers
Classic monocyte Response to tissue injury Proinflammatory cytokines: CD14 (high)
Phagocytosis of pathogens   TNF-α, IL-1β, IL-6 HLA-DR
Antigen presentation T-cell stimulation: CD33
Induction of Th1 response  IL-12
Replacement of tissue macrophages Anti-inflammatory cytokines:
  IL-10, TGFβ
Inflammatory monocyte (Tip-DC) Response to tissue injury Proinflammatory cytokines: CD14 (low)
Antigen presentation   TNF-α, IL-1β, IL-6 CD16
Production of proinflammatory No production of IL-10 HLA-DR (high)
cytokines CCR2
CD33
Macrophage Surveillance of tissues Proinflammatory cytokines: CD14
Phagocytosis of pathogens   TNF-α, IL-1, β IL-6 CD16
Induction of innate immune response T-cell stimulation: HLA-DR
Antigen presentation  IL-12 CD11b
Anti-inflammatory cytokines:
  IL-10, TGFβ
Dendritic cell Surveillance of tissues Proinflammatory cytokines: HLA-DR
–  Myeloid dendritic cell (mDC) Antigen presentation in lymph node   TNF-α, IL-1β IL-6 CD85
– Plasmacytoid dendritic cell Induction of Th1 response T-cell stimulation:
(pDC) Induction of adaptive immunity  IL-12
Antiviral response (pDC) Anti-inflammatory cytokines:
  IL-10, TGFβ
Antiviral response (pDC)
 IFN-α/β
Neutrophil Response to tissue injury Granule contents: CD11
Phagocytosis of pathogens   Toxic oxygen derived products CD15
Antimucrobial Killing via release of granules  O2– , H2O2 O, OH, OCI– CD16
and NETs   Toxic nitrogen oxides NO CD17
Induction of adaptive immunity   Defensins cationic proteins CD33
  Lysozyme acid hydrolases
  Lactoferrin and vitamin B12 binding protein
 Cytokines:
  Il-1, IL-6, IL-8 (CXCL-8), TNF-α GM-CSF
Mast cell Response to tissue injury: Granule contents: CD117
  IgE-dependent degranulation  Serine-proteases CD23 (high)
  Complement-triggered release  Histamine
Production of:  Heparin
  Lipid mediators (eicosanoids)  Serotonin
Lipid mediators:
  Thromboxane, prostaglandins, leukotriene
Cytokines;
 TNF-α
B lymphocyte Humoral immune response: Secreted by regulatory B cells: CD45
–  Plasma cells – Secretion of antibodies   IL-10 or TGFβ-1 CD19
–  Memory cells Development into memory B cells for fast Secreted by effector B-cells: CD45
response in second infection   IL-2, IL-4, TNF-α, IL-6 (Be-2 cells) or CD20
  IFN-γ, IL-12 and TNF-α (Be-1 cells)
T lymphocyte T cells: CD3 (T-cell receptor)
Helper T cells: Cytokines and growth factor production IL-4 Helper T cells:
IL-5 CD4
IL-10 CD45
IL-12
Cytotoxic T cells: Lysis of virally infected cells, tumor cells and Cytotoxic T cells:
allografts CD8
Natural killer (NK) cells Cytotoxic lymphocyte and part of the innate IL-3 CD8 – 80% of human NK cells
immune response: IL-13 CD16 (Fcγ RIII)
–  Killing to tumor cells, non-self cells, and IL-21 CD56
virus-infected cells
–  Secretion of perforin and granzyme to
destroy target cells by apoptosis
–  Cytokine production
GM-CSF, Granulocyte – macrophage colony-stimulating factor; IFN,.Interferons; Ig, Immunoglobulin; IL, Interleukin; NET, Neutrophil extracellular traps; NO, Nitric oxide; TGF, Transforming
growth factor; TNF, Tumor necrosis factors.
32 SURGICAL IMMUNOLOGY

Table 3.4  Pathogen recognition receptors.

Location Receptor Ligand Source of ligand Adaptor protein Cell type
Toll-like Receptors (TLR) TLR 1 Triacyl lipopeptides Bacteria MyD88 Monocytes/Macrophages
MAL Dendritic cells
B-cells
TLR 2 Glyco- and lipopeptides Bacteria MyD88 Monocytes/Macrophages
Lipoteichoic acid Gram-positive bacteria MAL Dendritic cells
Zymosan Fungi Mast cells
Heat Shock Protein 70 Host cells
TLR 4 Lipopolysaccharide Gram-negative bacteria MyD88 Monocytes/Macrophages
Heat shock proteins Host cells MAL Dendritic cells
Fibrinogen Host cells TRIF Mast cells
Cell Surface Receptors

Heparan sulfate Host cells TRAM B lymphocytes

HMGB1 Host cells
Morphine and its derivates
TLR 5 Flagellin Bacteria MyD88 Monocytes/Macrophages
Dendritic Cells
TLR 6 Diacyl lipopeptides Mycoplasma MyD88 Monocytes/Macrophages
Dendritic Cells
TLR 10 Pili Bacteria MyD88 Monocytes/Macrophages
B lymphocytes
Receptor for Advanced Glycolysated protein Host cells ? Endothelial cells
Glycation Endproducts HMGB1 Host cells Pneumocytes
(RAGE) S100 Host cells Immune cells
Scavenger Receptor Lipopolysaccharide Bacteria Monocytes/Macrophages
Lipoteichoic acid
Oxidized lipoproteins
Toll-like Receptors TLR 3 Double-stranded RNA Viruses TRIF Dendritic cells
Poly I:C Immunostimulants B lymphocytes
TLR 7 Single-stranded RNA Viruses MyD88 Monocytes/Macrophages
Dendritic cells
B lymphocytes
TLR 8 Single-stranded RNA Viruses MyD88 Monocytes/Macrophages
Dendritic cells
Mast cells
Cytosolic Receptors

TLR 9 Unmethylated CpG Bacteria MyD88 Monocytes/Macrophages

DNA Dendritic cells
B lymphocytes
TLR 11 Profilin Toxoplasma gondii MyD88 Monocytes/Macrophages
NOD-like Receptors NLRC 1 Peptido-glycan Gram-negative bacteria RIPK2 Mammalian cells
(NOD 1)

NLRC 2 Muramyl dipeptide Bacteria RIPK2 Mammalian cells

(NOD 2)

NLRP 3 Muramyl dipeptide Bacteria ? Mammalian cells

Unmethylated CpG Bacteria
Double-stranded RNA Viruses
Adenosine triphosphate Host cells
Uric acid Host cells
Mannose-Binding Lectin Certain sugar residues Gram-negative bacteria Secreted by liver cells
(Mannose, Glucose) Fungi
Secreted Receptors

Viruses
Complement Proteins C3b Mannose Bacteria Secreted by
Liver cells
Monoctyes/Macrophages
Epithelial cells
Pentraxin Proteins Serum Bacterial cell wall Bacteria Secreted by liver cells
Amyloid A
 Basic cellular immunology 33

Dendritic cells TLR-4 recognizes a broad range of pathogens and host-associated

In the current concept of the immune response, dendritic cells are molecules such as lipopolysaccharide (LPS) or heat shock proteins. For
considered the main antigen-presenting cells to B-and T cells (Geiss- the recognition of LPS additional proteins are required: LPS-binding
man et al. 2010). Dendritic cells are also highly phagocytic cells and protein (LBP), CD14, and lymphocyte antigen 96 (MD-2) (Guha and
patrol tissues. On recognition of DAMPs, they leave the tissue, enter Mackman 2001). LBP is bound by CD14, which is a surface molecule
the lymphoid system, and present phagocytosed and processed with high density of monocytes. CD14 is anchored to the cell mem-
antigens to B and T cells in the lymph nodes. The ability to enter brane by a glycosylphosphatidylinositol (GIP) anchor, has no intra-
and leave tissues, as well as the homing to lymphoid tissues, is one cellular domain, and is unable to signal directly. CD14 can be shed
the key features of dendritic cells (Auffray et al. 2009). To activate B from the cell membrane or directly secreted by both monocytes and
and T cells, dendritic cells express coactivating molecules, which are hepatocytes, and as such is a soluble receptor (Levine 2008). MD-2
necessary for successful initiation of the adaptive immune response. is another surface molecule that seems necessary for recognition
Dendritic cells originate from the common dendritic cell precursor and response to LPS. The interplay of all these molecules, LBP, CD14,
(CDP) and differentiate into two main types of dendritic cells: Classic and MD-2, allows TLR-4 to recognize LPS and initiate the signaling
and plasmacytoid dendritic cells. Classic dendritic cells patrol as im- cascade (Netea et al. 2004). TLR-4 is a transmembrane molecule but
mature cells through tissues and blood with a high phagocytic activity without a signaling domain. The main signaling molecule of TLR-4,
(Geissmann et al. 2010). After uptake of antigens, they develop into and all other TLRs except TLR-3, is MyD88 (myeloid differentiation
mature dendritic cells with high cytokine production and the ability primary response gene 88). In addition, TLR-4 can interact with three
to stimulate T cells. In addition, they are highly migratory and move other signaling proteins (MAL, TRIF, TRAM). MyD88 starts a cascade
into lymphoid organs to stimulate T and B cells. These cells are usually of signaling events (Li and Jiang 2010b, O’Neill et al. 2011). It interacts
short-lived. Plasmacytoid dendritic cells are long-lived and mainly with IRAK-1/2, which in turn activates TRAF6. TRAF6 activates two
involved in the antiviral response by the production of large amounts different signaling pathways, the mitogen-activated protein kinases
of Interferon-α and -β (type I interferons, IFNs). However, they can (MAPKs) and the nuclear factor-kB (NF-kB) pathway. Both are major
also stimulate T cells and present antigens. signaling pathways and involved in response to stress such as radia-
tion, ultraviolet light, temperature, or infection (Guha and Mackman
■■Function and regulation of 2001, Zhang and Dong 2005). The organization of these pathways is
outlined in Figure 3.3.
monocytes, macrophages, Activation of both pathways results in production of cytokines as
and dendritic cells signaling molecules to coordinate the response of the whole organism,
and also the production of defensive molecules such as complement;
The main function of all these three cells, monocytes, macrophages, however, they also lead to expression of intracellular proteins, which
and dendritic cells, is recognition of invading pathogens and tissue may reduce intracellular damage (e.g., heat shock proteins) (Bianchi
injury, and to respond to this danger by initiation of the immune 2007). Interestingly, both pathways are not independent of each other.
response to clear the pathogens and restore homeostasis (Janeway There is a broad cross-activation of both pathways, which is completed
and Medzhitov 2002). The key elements for this response are cytokine within minutes. This is possible because the molecules are preformed
and chemokine production, antigen presentation, and phagocytosis. in the cytoplasm and are consecutively phosphorylated, which results
Monocytes, macrophages, and dendritic cells interact with other cells in activation. The organization of both pathways is comparable in that
of the innate as well as the adaptive immune system. they are both arrayed in several levels that lead to amplification, inte-
Regulation of the function of monocytes, macrophages, and gration, and modulation of the incoming signal from several upstream
dendritic cells has been a focus of research in recent years. The first receptors. It is important to consider that the response produced by
step of an immune response is the recognition of pathogens or tissue cytokines results in feedforward and feedback mechanisms, which
damage. For that purpose, monocytes are equipped with an array of modulate the immune response. The receptors for TNFα and IL-1β,
several so-called PRRs (Table 3.3) (Medzhitov 2007). These receptors for example, signal through the same pathways as the TLRs (Hu et
can be further divided into signaling molecules and phagocytosis al. 2008). Other cytokines such as IL-6 and IL-10 use the JAK-STAT
receptors. Importantly, these receptors are constant and encoded in signaling system (Murray 2007). These signaling systems have a high
the genome, and are not rearranged as the receptors of the adaptive level of interaction leading to either suppression or priming of one of
system (Janeway and Medzhitov 2002). For the early initiation of an the receptor systems. Interferon-γ, for example, can suppress IL-10
innate immune response, the signaling PRRs are the most important. signaling. The exact mechanisms by which these signaling cascades
The best studied PPRs are the TLRs, which are extracellular receptors lead to their response and how these responses are regulated remain
and able to recognize a wide variety of pathogen-associated molecules largely unknown (Murray 2007, Murray and Wynn 2011).
but also endogenous host proteins, which are typically released during Once activated, the different arms of the MAPK pathway are deacti-
tissue injury (Netea et al. 2004). Thirteen TLRs have been described, vated by dephosphorylation by specific phosphates, the group of dual
and the most studied is TLR-4. Other receptors include the receptor specificity phosphatases (DUSPs) also known as MAPK-phosphatases
for advanced glycation endproducts (RAGE), which mainly recognizes (MKPs). (Patterson et al. 2009). These proteins have been recently
endogenous proteins such as HMGB1, advanced glycation endprod- discovered and so far 30 proteins containing the phosphatase do-
ucts (AGE) or S-100, and the large group of NOD-like (nucleotide main have been described in whole genome studies. However, only
oligomerization domain) receptors. These are intracellular receptors 11 of those contain a MAPK-binding domain. These phosphatases
and can recognize products of Gram-positive and Gram-negative are upregulated upon activation of the MAPK pathway within 30 min
bacterial cell walls, double-stranded RNA, or adenosine triphosphate to 1 h by the same stimulus, which activates the MAPK pathway. A
(ATP). Importantly, the same molecule, e.g., glycopeptides or double- certain DUSP is specific for the molecule, which it can inactivate.
stranded RNA, can be recognized by several, different receptors and DUSP 1, for example, inactivates p38 and JNK, but can inactivate Erk
this overlap shows the tremendous redundancy of the immune system. only marginally. Of note, the specificity of inactivation investigated
34 SURGICAL IMMUNOLOGY

LPS TNF

TLR-4 TNF-R
Extracellular space

Cytoplasm
PI3K

Rac1 CDC42 Ras PC-PLC PKC

MAP3K PAK1 RAF1 ASK1 TAK1 NIK IKK

lk
MAP2K MKK MEK MKK
1/4 1/2 3/4/6 NFk-p65
NFk-p50
P
lk

MAPK JNK ERK p38

NFk-p65
1-3 1/2 MAPK Proteasomal
NFk-p50
Degradation

Nucleus
NFk-p65
c-Jun ATF1 NFk-p50
Elk-1
c-Fos CREB

Figure 3.3  Overview of inflammatory signaling pathways. Toll-like receptor 4 (TLR-4) activates the NF-kB pathway. The key activator of NF-kB is inhibitory
k kinase (IKK), which phosphorylates the Inhibitory k protein β, leading to its degradation. The NF-kB complex (p50 and p65 subunits) can then translocate into the
nucleus and start transcription of inflammatory genes. TLR-4 can also activate the mitogen-activated protein kinase (MAPK) pathway, which consists of the JNK, Erk,
and p38 arms. The MPAK pathway activates several different transcription factors such as c-Jun/c-Fos or Elk-1. MAPK leads to the transcription of proinflammatory
cytokine and IL-10 mRNA.

in in vitro models differs remarkably from the specificity observed The activation of these pathways by alarmins leads to production of
in animal models. proinflammatory cytokines such as TNFα, IL-1β, and IL-6. In addition,
Inactivation of NF-kB is slightly different. After degradation of the chemokines such as macrophage migration inhibitory factor (MIF)
inhibitory kappa protein (Ikα) or Ikβ and subsequent migration of and IL-8 are produced and secreted. Of note, surface receptors such
the p50/p65complex into the nucleus, where it acts as transcription as HLA-DR and proteolytic enzymes are also upregulated. Following
factor, Ikα/Ikβ are constitutively re-expressed and inactivate the p50/ this early proinflammatory response is a delayed, counter-regulatory
p65 complex (Karin and Ben-Neriah 2000). As a result of the activa- response, which aims to inhibit the production of proinflammatory
tion of the MAPK pathway, common transcription factors such as products. One of the key cytokines in this anti-inflammatory response
PU1, CREB (cAMP response element-binding protein), and c-Myc is IL-10. The same pathways (NF-kB and MAPK) that are responsible
are activated. The p65 and p50 subunits of NF-kB are transcription for the production of pro-inflammatory cytokines are responsible
factors themselves. These factors then initiate transcription of mRNA for the induction of IL-10 (Saraiva and O’Garra 2010). In the MAPK
for various cytokines, chemokines, and other proteins and enzymes pathway, it seems that the Erk arm is crucial for the induction of IL-10.
involved in the immune response. However, as an immediate re- It is important to note that this response pattern of sequential
sponse, preformed proteins are activated such as heat shock proteins, phases is highly reproducible and uniform in the innate immune
or preformed cytokines are secreted without the delay of transcription response. In addition, cytokines in the circulation or local tissue
and translation. The secretion of preformed cytokines followed by the modulate these response patterns. Some cytokine receptors signal
secretion of newly produced cytokines allows a very fast response to through NF-kB and MAPK, and this leads to a highly complex in-
any kind of infection or tissue damage. tracellular response with synergistic, but also sometimes contrary,
 Basic cellular immunology 35

signals. The phosphorylation or dephosphorylation of these pathways in Figures 3.4 and 3.5, virtually every level of the signaling pathways,
is the principal means by which the immediate response functions; but also the production of cytokines, is believed to be modulated by
however, different amounts of these signaling proteins can alter the micro-RNAs. MiRNA-155 is easily upregulated in endotoxin shock
overall response profoundly. The organization of these pathways at after TLR-4 activation, and seems essential for an adequate immune
several levels and the diverse nature of these interactions allow fine- response. Once upregulated, miR-155 targets negative regulators of
tuning and adaptation in response to changes in the environment. the inflammatory response such as SOCS1 (suppressor of cytokine
The discovery of the role of micro-RNAs in the immune response can signaling 1) and SH2 domain-containing inositol 5’-phosphatase 1
explain the mechanisms of this fine-tuning. (SHIP), which act on the signaling transducers of the TLR family and
inhibit proinflammatory signals. Interestingly, miR-155 acts also as
■■Role of micro-RNAs in regulation a negative regulator by reducing MyD88 or TAB2, an activator of the
MAPK-pathway. in a later phase of the response.
of monocyte function The anti-inflammatory cytokine IL-10 downregulates miR-155,
Monocytes/macrophages serve here as an example of cells in which the supporting its primary proinflammatory role. Both miR-146a and
role of micro-RNAs has been described most extensively thus far. Mature miR-125b have been shown to inhibit TNFα and production of
micro-RNAs are short, single-stranded, 20- to 22-nucleotide-long RNA other proinflammatory cytokines (Tili et al. 2007, Bhaumik et al.
molecules, folded in a characteristic hairpin structure, which protects 2009); miR-125b directly binds TNFα and suppresses TNFα protein
the mRNA from cleavage and degradation. Therefore, micro-RNAs are production. Other cytokines are also subject to profound regulation
very stable molecules and can be found even in stored, paraffin-fixed by micro-RNAs such as IL-6 (Sun et al. 2011). Murphy et al. (2010)
tissue samples. Micro-RNAs are part of the non-coding RNA family, to recently demonstrated that miR-125b is involved in the regulation of
which ribosomal RNA (rRNA), translational RNA (tRNA), and silencing NF-kB activity by decreasing NF-kB activation. MiR-146a is upregu-
RNA also belong. Micro-RNAs can inhibit protein translation in three lated on exposure of cells to LPS but also to IL-10 and seems to act
different ways by binding to the 3’-untranslated region (UTR) of the as a major anti-inflammatory micro-RNA; it also targets upstream
mRNA: First, they suppress protein translation via the RISC or, rarely, signaling molecules of the TLRs such as IRAK1/2 and TRAF6, and
the RNA-induced silencing complex (RISC) can activate other proteins, inhibits proinflammatory signals from the TLRs (Hou et al. 2009).
which splice the mRNA directly. The third way was discovered recently Due to its anti-inflammatory features, miR-146a plays a crucial role
and is called the mRNA decay. Here, the poly(A) tail is degraded (dead- in endotoxin tolerance, whereas miR-146a is upregulated after the
enylation) and the ‘cap’ of mRNA is subsequently removed, resulting first LPS exposure and consecutively protects the host from the
in rapid mRNA degradation. All three mechanisms result in decreased second LPS hit and reduces the TNFα levels (Nahid et al. 2009,
protein production. Of note, the mRNA level is not necessarily reduced 2010). In addition, miR-146a is predicted to bind proteins of the
despite reduced protein expression. MAPK-signaling cascade.
Several micro-RNAs have been reported to modulate the TLR signal- Micro-RNAs are also involved in regulation of the inflammatory
ing pathway. The best-described are miRNA-155 and -146a. As outlined signaling cascades, e.g., miR-15a and -16, which are expressed as

Figure 3.4  In the

proinflammatory phase, two
Extracellular space LPS TNF- protein
micro-RNAs (miRNA-155 and
-101) play an important role
TLR4 by inhibiting the production
of negative regulators of the
Cytoplasm toll-like receptor-signaling
MyD88

Ship1/soscs1 miR-155 pathway such as SHIP1/SOCS1

and DUSP1 (aka MKP1). In this
situation, the effect of the micro-
IRAK1 IRAK2 RNAs is immediate, because
these proteins SHIP1/SOCS1
TRAF6 and DUSP1 are newly produced
TAK1 IKK after monocyte activation.
This inhibition of negative
Ik regulators leads to an enhanced
TNF- mRNA inflammatory response. Only the
MKK NFk-p65 p38-arm of the MAPK pathway is
3/4/6 NFk-p50 P shown here.
Ik
DUSP1
p38 NFk-p65
MAPK NFk-p50 Proteasomal
miR-101 Degradation

Nucleus
Gene expression
36 SURGICAL IMMUNOLOGY

LPS TNF- protein

Extracellular space

TLR4

Cytoplasm

Myd88
SHIP1/SOSCS1

miR-155

IRAK1 IRAK2 miR-146a

TRAF6
TAK1 IKK miR-223 miR-125b

Ik
miR-15a /16 miR-124a
MKK NFK-p65 TNF- mRNA
3/4/6 NFkb-p50
P
lk
DUSP1 miR-9
NFK-p65
p38 NFkb-p50
MAPK Proteasomal
Degradation

Nucleus

Gene expression

Figure 3.5  In the counterinflammatory phase of the monocyte/macrophage response, several micro-RNAs act on virtually every level of the signaling
pathways and inhibit the production of signaling proteins. As these signaling proteins exist at the time of activation of the cells, the effect of micro-RNAs
is delayed because they can inhibit only the new production of these signaling proteins. MiRNA-146a plays an important role because it inhibits the central
activating complex for the NF-kB and MAPK pathway consisting of IRAK-1 and -2 and TRAF6. MiRNA-155 plays a dual role in the inflammatory response: It first has a
proinflammatory effect by inhibiting the production of SHIP1/SOCS1, but has in the secondary phase an inhibiting effect by downregulation of the central signaling
pathway of almost all toll-like receptors, MyD88.

a cluster, are critical regulators of both the NF-kB and the MAPK Besides the regulation of the signaling cascade, micro-RNAs
pathways, and Li et al. showed that they target IKKα, one of the ac- have also been shown to directly downregulate specific protein re-
tivators of NF-kB (Li et al. 2010a). Another study revealed that both ceptors, which recognize the DAMPs. Let-7i, for example, directly
micro-RNAs (15a and 16) act on the MAPK pathway, especially on downregulates TLR-4 (Chen et al. 2007). Furthermore, miRNA-21
the MAP3 kinases, which are responsible for the cross-activation of has been shown to induce IL-10 expression by a complex feedback
the NF-kB pathway, such as TAK1 (Roccaro et al. 2009). MiR-124a mechanism, which is already induced on LPS stimulation of TLR-4
and -223 also influence IKKβ, exemplifying the redundant role of (Sheedy et al. 2010). These data draw an intensively regulated network
several micro-RNAs in regulating the same gene (Lindenblatt et al. of proteins and their activation but also gene expressions with post-
2009). It has also been shown that miR-9 regulates NF-kB activa- transcriptional modification (mRNAs and micro-RNAs), which affect
tion, but not by inhibiting the inhibitory protein. It directly acts on each other, resulting in the final response to inflammation – measured
the p50 subunit of NF-kB (Bazzoni et al. 2009). In addition to the as systemic cytokines. It seems that micro-RNAs are especially impor-
direct regulation of the signaling proteins, the negative regulator of tant for the switch from pro- to the counter-regulatory phase of the
the MAPK signaling, the DUSPs, are also regulated by micro-RNAs. immune response. Based on their profound impact on cell function,
MiR-101 has been shown to control DUSP-1 directly (Zhu et al. micro-RNAs offer opportunities as diagnostic and probably thera-
2010). MiR-101 is upregulated early upon activation of the TLRs, peutic targets. Some micro-RNAs have been described as marker for
but it is downregulated by the PI3K-Akt pathway, an important anti- sepsis, potentially with prognostic capabilities in humans (Vasilescu
inflammatory signaling pathway. et al. 2009, Wang et al. 2010).
 Basic cellular immunology 37

■■Polymorphonuclear is exposed on the tips of leukocyte microvilli, and reversibly bind,

leading to rolling along the vessel wall. Integrins LFA-1 and CRB bind
leukocytes (neutrophils) the intercellular adhesion molecules ICAM-1 (induced by TNFa) and
Neutrophils, similar to all other cellular components of the blood, are ICAM-2. This usually results in a weak binding, but a conformational
derived from pluripotent hemopoietic stem cells in the bone marrow, change induced by CXCL 8 increases adhesion, and the firmly attached
which then give rise to myeloid and subsequent granulocyte progenitors. neutrophil stops rolling along the endothelial wall.
These granulocytes or polymorphonuclear leukocytes (PMNs) include There are two routes for transendothelial migration: Transcellular
neutrophils, basophils, and eosinophils. Neutrophils, similar to other (20%) whereby neutrophils penetrate the individual endothelial cell,
granulocytes, are distinctive for their multilobed nucleus and granules; or paracellular (80%), whereby the neutrophils diapedese between
they are the most abundant granulocyte and are found mostly dormant in endothelial cells (Borregaard 2010).
the blood, although they are not present in normal healthy living tissue. Further interactions between integrins and Ig-related molecules
They have a key role in the innate immune response due to their ability to PECAM or CD31, which is expressed on neutrophils and the intracel-
recognize, ingest (phagocytose), and destroy pathogens without the aid lular junction of endothelial cells, allow the neutrophil to squeeze
of the adaptive immune response. Congenital or acquired deficiencies between endothelial cells, and then penetrate the basement mem-
of neutrophil function lead to life-threatening infections. brane with the help of matrix metalloproteinases that break down
Neutrophils are short lived (8–20 h), although their lifespan can the extracellular matrix of the basement membrane. Tissue migration
be extended by cytokines (IL-6, IFN-β, and granulocyte–macrophage then occurs under the influence of chemokine concentration gradients
colony-stimulating factor [GM-CSF]), hypoxia and microbial products produced at the site of infection and bound to proteoglycans in the
to enhance function at sites of infection (El Kebir and Filep 2010). extracellular matrix. Neutrophils that have migrated into tissues are
Neutrophils contain three different subsets of granules, or stores more active than the dormant blood-circulating population, and are
of proteins that kill microbes and digest tissues, based on the char- able to recruit additional inflammatory cells via necrosis and CXCL 8
acteristic granule proteins (Borregaard 2010). Primary or azurophil production (Borregaard 2010).
granules contain myeloperoxidase (MPO), secondary or specific
granules contain lactoferrin, and tertiary ones contain gelatinase.
Azurophilic granules are considered the most potent, containing
■■Pathogen recognition
many antimicrobial peptides including lytic enzymes and defensins, PMNs recognize pathogens via cell-surface receptors, and can also
presumed to work by making pores in bacterial membranes. Specific discriminate the host from pathogens. PRRs recognize PAMPs pres-
or secretory granules are important early in inflammation, easily ent on extra- and intracellular microbes and include TLRs, NOD-like
mobilized, and contain multiple membrane-associated receptors, receptors, and Dectin-1. Neutrophils are activated by the detection
including those mediating endothelial attachment and complement of pathogen and tissue damage via PRRs. Some pathogens, notably
receptors involved in host–pathogen interactions (Nordenfelt and Staphylococcus epidermidis, are able to shield themselves from the
Tapper 2011). Gelatinase granules contain enzymes to degrade the phagocyte receptor by coating themselves with a thick polysaccha-
extracellular matrix and receptors for direct migration when the ride capsule (biofilm). Activated neutrophils release soluble pattern
neutrophil has migrated into the tissues. recognition molecules that enhance phagocytosis, activate comple-
ment, and regulate inflammation. Complement facilitates the uptake
■■Neutrophil migration and destruction of pathogens by phagocytic cells, because specific
complement receptors (CRs) recognize bound complement compo-
Neutrophils are the first blood cell attracted to the site of infection in nents and complement-coated particles are more efficiently taken
large numbers as the early part of the innate immune response, be- up by phagocytes. CR3 receptor engagement on neutrophils induces
ginning in minutes. They are attracted by chemoattractants, including phagocytosis. C5a acts directly on neutrophils and macrophages to
complement fragments C3a and C5a, and CXCL8 (previously known increase vessel wall adherence, migration toward sites of antigen de-
as IL-8). CXCL8 is produced by macrophages and dendritic cells in position, increasing the ability to ingest pathogens and upregulating
response to infection, and binds to CXCR receptors 1 and 2, causing the expression of CR1 and -3 on the cell surface.
mobilization, activation, and degranulation of neutrophils.
Bacterial formylated peptides (fMLP) also act as chemoattractants
for neutrophils. PMNs possess the fMLP receptor, which is a G-protein-
■■Phagocytosis and microbial killing
coupled receptor similar to complement and chemokine receptors. Neutrophils eliminate many pathogens by phagocytosis, where the
Leukocytes usually flow in the center of small vessels where flow cell wall is extended around the target to internalize it in a membrane-
is fastest (see Figure 3.1). However, vessel dilation in areas of inflam- bound vacuole or phagosome. Phagocytosis is initiated by a phagocytic
mation, with resulting decreased flow rates, allow the leukocytes to receptor which interacts with IgG, among other proteins to initiate
interact with the endothelium. A change in the adhesion molecules particle uptake (Nordenfelt and Tapper 2011). Neutrophils exhibit
on both neutrophils and endothelial cells, in response to infection, more rapid rates of phagocytosis and higher intensity of oxidative
leads to the recruitment of large numbers of circulating neutrophils. respiratory response than macrophages. This is likely due to the secre-
Neutrophil movement across the endothelial wall of blood vessels tion of preformed granules, enhancing the speed of efficient pathogen
(extravasation) occurs mostly in postcapillary venules, where there killing. One of the key features of neutrophils is the generation of
is a sufficiently thin wall and flow can continue around the adherent reactive oxygen species (ROS) by activation of the NADPH oxidase
neutrophils (Silva 2011). The first stage of neutrophil extravasation is complex within the phagosome. This occurs after the fusion of granule
the expression of P-selectin on endothelial cells in response to leu- contents with phagosomes and/or the plasma membrane, and to a
kotriene B4 (LTB4), TNFα, IL-1β, IL-17, C5a, or histamine, which also greater extent in neutrophils than in macrophages. NADPH oxidase
leads to the later expression of E-selectin (after exposure to TNFα or activation induces molecular oxygen reduction to the superoxide
LPS) (Ley et al. 2007). Selectins recognize sulfated sialyl Lewis that anion, which is transformed into ROS, including hydrogen peroxide,
38 SURGICAL IMMUNOLOGY

hydroxyl radicals, and hypochlorous acid (see Table 3.2) by myelo- Formation of neutrophil extracellular traps (NETs) is an alterna-
peroxidase. The generation of ROS also affects the local pH, as does tive to death by necrosis or apoptosis. During necrosis, the nuclei
bicarbonate, ion transport, and exchange systems. Phagosomal pH is swell and the chromatin is dissolved, and large strands of decon-
often determined by vacuolar-type ATPase (V-ATPase) activity, with densed DNA are extruded from the cell, carrying with them proteins
increasing acidification with recruitment of increasing number of V- from the cytosol, granules, and chromatin (histones) (Borregaard
ATPases, although this is more important in macrophages, because 2010). NET proteins are primarily the cationic bactericidal proteins:
neutrophils tend to have a more neutral pH, which does not seem Histones, defensins, elastase, proteinase 3, lactoferrin, and MPO. The
to impair antimicrobial activity and changes in pH are more likely mechanism of formation is not yet completely known but depends
to come from the oxidative burst. Necrotic neutrophils contribute a on hydrogen peroxide generated by NADPH oxidase and further
major component of pus (especially in extracellular pyogenic bacteria) metabolized by MPO. NETs also contain some neutrophil-derived
and amplify local inflammation as opposed to apoptotic neutrophils, pattern recognition molecules (PRMs) with antibody-like proper-
which do not incite an inflammatory response. ties. NETs act to trap microorganisms such as Eschericha coli and
Staphylococcus aureus, and allow interactions with their associated
■■Other cell signaling granular proteins to facilitate elimination. NETs are cleared by DNA-
ases, a strategy of some bacteria such as Streptococcus pyogenes and
Neutrophils in tissues produce agents that attract additional neu- Streptococcus pneumoniae which are known to cause necrotizing
trophils and macrophages, and regulate their activity. Macrophages fasciitis, but these DNAases can damage the surrounding tissues,
and neutrophils cooperate to potentiate antimicrobial effector likely having a proinflammatory role.
functions and accelerate the resolution of infection-associated
inflammation via apoptosis (Silva 2011). Neutrophils also produce
cytokines involved in the survival, maturation, and differentiation of
■■Clinical implications from
both B and T cells, and can increase the cytokine production of NK PMN-mediated lung injury
cells via ROS generation and granule content release (Mantovani et The balance of neutrophil recruitment and activation during inflam-
al. 2011). Through contact dependent interactions, neutrophils may mation is important because the mechanisms by which these cells
also induce the maturation of monocyte-derived dendritic cells in can destroy pathogens via ROS and proteases can also inflict damage
vitro, via CD18. These dendritic cells acquire the ability to induce on the host tissues. Acute respiratory distress syndrome (ARDS) can
T-cell proliferation, with a Th-1 propensity. Activated neutrophils occur as a complication of pneumonia or as a consequence of trauma
are also able to migrate to lymph nodes after antigen capture, to or sepsis, where there is failure of oxygen transfer between the alveolar
influence the available lymphocyte population and the adaptive sac and the pulmonary circulation. Neutrophil activation and seques-
immune response. tration in the alveolar capillaries, correlate with the severity of gas
exchange and protein leak (Segel et al. 2011). The release of neutrophil
■■Neutrophil extracellular traps elastase, defensins, and ROS causes local damage to the epithelium
increasing paracellular permeability and fluid leakage, which occurs
The short lifespan of resting neutrophils can be prolonged when in the acute lung injury associated with ARDS. Neutrophil-derived
recruited to sites of infection, but apoptosis spontaneously occurs proteinases also inhibit surfactant activity, worsening the decreased
after 24–28 hours and may be accelerated by pathogens (Silva 2011). gas exchange. There is also a decrease in neutrophil apoptosis pro-
Macrophage and neutrophil cooperation continues in the resolution portional to the severity of the sepsis.
phase when apoptotic and non-apoptotic neutrophils are removed
by macrophages. Neutrophils may express ‘eat-me’ signals as a
pro-clearance mechanism before they release cytotoxic and immu-
■■Mast cells, basophils,
nogenic components through “open autolysis.” Macrophages may and eosinophils
even induce apoptosis of neutrophils through secreted molecules These granulocytes all have a multitude of granules which contain
or direct cell interactions. The apoptosis of neutrophils and inges- compounds that amplify the local innate immune response, including
tion by macrophages are important to the resolution of the local histamine, chemokines, leukotrienes, prostaglandins, and interleukins.
inflammatory response (Serhan et al. 2008). Neutrophils are very These cells have Fc receptors for IgE, and mediate inflammation by
cytotoxic, especially when they lyse, hence the need for regulation causing intense vasodilation, capillary leak, and neutrophil accumu-
due to the risk of collateral tissue damage. Macrophage phagocy- lation after degranulation and mediator release (Kawakami and Galli
tosis not only protects host tissues, but also allows the granules of 2002). Mast cells also metabolize arachidonic acid to produce addi-
the neutrophil to be added to its arsenal of antimicrobial activity, tional prostaglandins and leukotrienes, in addition to those existing in
enhancing its own effector function. In addition this reduces neu- preformed granules. Eosinophils also have compounds (oxides) that
trophil necrosis and downregulates the production of G-CSF to limit are directly lytic to extracellular pathogens, notably parasites. Mast cells
local neutrophil activation and bone marrow release. Neutrophils are mostly located in tissues underlying skin and mucous membranes,
are also able to phagocytose apoptotic neutrophils, usually after whereas basophils circulate in the vascular compartments. Comple-
exposure to activating substances such as LPS or IFN-γ (Nordenfelt ment components C3a and C5a also trigger mast cell degranulation.
and Tapper 2011). This enhances the resolution of inflammation,
because the neutrophils are present in greater numbers than mac-
rophages. Neutrophils contribute to the synthesis of resolvins, lipid
■■LYMPHOCYTES
mediators of the resolution phase of inflammation, which are able
to inhibit neutrophil activation. In the resolution stage of inflamma-
■■T cells
tion, neutrophils also aid by blocking and scavenging cytokines and When hemopoietic progenitor cells migrate to the fetal thymus, they
chemokines (Mantovani et al. 2011). acquire the phenotypic characteristics of T cells under the influence of
 Lymphocytes 39

thymic hormones. CD2 and CD3 (TCR) are the major markers retained T cells as well, so Treg function is determined primarily by their cytokine
on all peripheral T cells, which consist of a and b chains (ab T cells). secretion profile.
Other T lymphocytes include natural killer T cells, which express the
NK1.1 molecule, similar to NK cells and gd T cells, the TCR of which
is composed of these different chains. These two subpopulations can
■■Killer cells
bind antigens directly or via other MHC molecules, and are often Cytotoxic T cells are mostly CD8+ cells and are part of the cell-me-
located in submucosal tissues. Two major types of T cells exist and diated immune response directed primarily against virus-infected
they are classified based on the expression of the cell surface proteins cells or tumor cells by apoptosis. Cytotoxic T cells act by recognizing
CD4 or CD8. CD4 defines a T-helper (Th) subset, which differentiates foreign antigen peptide in contiguity with MHC class I molecules and
in the molecules they secrete (cytokines). CD8 defines a cytotoxic- specific surface TCRs. Activation of the cells can also occur through
suppressor cell (Tc or Ts) subset. Th-17 cells produce IL-17 which CD40–CD ligand interactions and IL-2 is necessary for T-cell function.
augments inflammation via PMN recruitment and stimulation of Target cell destruction occurs by initial adhesion of the cytotoxic T cell,
pro-inflammatory cytokine production. subsequent release of toxic cytoplasmic granules, and finally target cell
apoptosis. A portion of cytotoxic T cells becomes a memory population
Th cells (CD4+ T lymphocytes) capable of rapid recognition and deployment.
These cells enhance both humoral and cell-mediated immunity, and NK cells represent around 10–15% of lymphocytes in the peripheral
consist of two distinct subtypes of Th cells with different functions circulation. They kill certain tumor cells (without damaging normal
(Th-1 and Th-2), which are mutually inhibitory through their patterns tissues) and defend the host against viral infection (Sun and Lanier
of cytokine secretion: 2011). Unlike T cells, NK cells recognize foreign antigen that does not
⦁⦁ Th-1 lymphocytes: These are primarily made in response to mi- have to be presented on MHC molecules. NK cells also mediate ADCC
crobes that infect or activate macrophages and NK cells, and in toxicity and secrete several proinflammatory cytokines. This allows NK
response to viruses. The Th-1 cell’s function is to promote cytotoxic cells to kill antibody-coated target cells. NK cells are usually activated
T-cell (CD8+ cell) responses and the delayed-type hypersensitivity by IFN-y and IL-2 and also induce target cell apoptosis.
response. Th-1 lymphocytes produce cytokines such as IFN-γ, lym-
photoxin, and tumor necrosis factor-β (TNFβ). Cytokines produced
by Th-1 lymphocytes activate macrophages, enabling them to kill
■■B lymphocytes
microbes in phagolysosomes, release inflammatory cytokines to Differentiation and types of B cells
promote inflammation, recruit phagocytes, and increase expres- B lymphocytes terminally differentiate into plasma B cells. These cells
sion of MHC molecules and cofactors for T-lymphocyte activation. secrete large amounts of immunoglobulin (antibodies) in response to
In addition, these Th-1-produced cytokines stimulate B lympho- antigenic stimulation. There are two major subtypes of B lymphocytes:
cytes to produce complement-binding and -opsonizing antibody CD5+ cells which produce IgM antibody to soluble polysaccharides
molecules for enhanced attachment of microbes to phagocytes and self-antigens. They are stimulated by non-specific cytokines
during phagocytosis. from Th cells, and CD5- cells, which produce IgG, IgA, or IgE an-
⦁⦁ Th-2 lymphocytes: These lymphocytes are primarily made in tibody specific to individual protein antigens, and bacterial LPSs.
response to helminths, allergens, and extracellular microbes and These cells require direct physical interaction with specific Th cells.
toxins. Th-2 lymphocytes produce cytokines such as IL-4, IL-5, Memory B cells are produced after primary exposure to an antigen.
and IL-13. The cytokines produced by Th-2 lymphocytes stimulate: They produce antibody with increased affinity for its antigen because
–– B lymphocytes to produce immunoglobulin E (IgE). IgE serves of somatic mutation of Ig genes. Mature B cells have both surface IgM
as an opsonizing antibody to bind eosinophils to helminths and IgD which serve as the B-cell receptor and bind antigen. B cells
and triggers mast cells to release mediators of inflammation. can also present antigen to Th cells via class II MHC. Generally, B cells
–– B lymphocytes to produce a subclass of the antibody IgG that respond to two types of antigens: (1) T-cell-independent antigens
is able to neutralize microbes and toxins. activate B cells in the absence of CD4+ Th cells. These antigens are
Cytokines produced by Th-2 cells mainly include IL-4, IL-5, IL-6, IL- usually composed of polysaccharides or carbohydrates with repeating
10, and IL-13. Th-2 cells stimulate B lymphocytes to proliferate and structures. (2) T-cell-dependent antigens (almost all protein antigens)
differentiate into antibody-producing cells. In general, the activation that require B- and T-cell interaction. The T cell then drives B cells
and proliferation of Th cells depends on the co-recognition of specific to switch antibody classes (class switching) via direct contact and
antigenic peptides and MHC class II molecules on antigen-presenting cytokine secretion.
cells (APCs) such as macrophages, dendritic cells, or B cells. In turn, B cells play an important role in immune responses through an-
the activated Th cells produce cytokines, differentiation factors, and tibody production, APC function, and cytokine secretion (Johnson
inflammatory cytokines. 1999). Immunoglobulins are secreted by B cells and these are Y-shaped
proteins consisting of two identical light (L) and two identical heavy
■■Regulatory T cells (Treg) (H) chains, which are held together by disulfide bridges. Both the
low-molecular-weight L and the high-molecular-weight H chains
This subpopulation actually inhibits many immune functions and have constant and variable regions. These regions are subdivided
includes cells within ab, NK, and gd T-cell populations. These have into segments called domains. The L chain has one variable and one
a particularly important function in the developing thymus to sup- constant domain whereas H chains have one variable and three or four
press cells that recognize self, thus preventing the development of constant domains. The variable domains are responsible for antigen
autoimmunity and allergy. These cells also produce several cytokines binding and the constant chains are responsible for other functions.
including IL-4, -10, -21, and -22, and transforming growth factor (TGF) Differences in the amino acids in the constant region divide the L chain
b. Collectively Treg cells stimulate T and NK cells, promote mast cell into a κ or λ type. Two important peptides of the immunoglobulins
growth, but inhibit Th-1 cells and macrophages. TGFb actually inhibits are the Fab fragment containing the antigen-binding sites, and the Fc
40 SURGICAL IMMUNOLOGY

fragment, which is involved in specifically assigned functions such lymph node B-cell follicles, in a manner analogous to that postulated
as complement fixation, attachment to cells, and placental transfer. for mouse splenic MZ B cells. In addition to their important role in
T-independent responses, MZ B cells may also participate in T-cell-
Development and function of B cells dependent immune responses to protein and lipid antigens.
B-cell development is a highly regulated process whereby functional
peripheral subsets are produced from hemopoietic stem cells, in the
fetal liver before birth and in the bone marrow afterward. If stem cells
■■IMMUNOGLOBULINS
remain in the bone marrow, they acquire the phenotypic CD markers There are mainly five classes of immunoglobulins: IgG, IgM, IgA, IgE,
characteristic of the stages of B-cell differentiation (Johnson 1999). and IgD. These are identified by differences in the heavy chains and
A membrane-bound, epitope-specific, antigenic receptor that is a the γ H chain is expressed on IgG, the α on IgA, the μ on IgM, the ε on
monomeric immunoglobulin M (IgM) antibody distinguishes the B- IgE, and the δ on IgD.
cell antigenic receptor from that of the T cell. There are specific B-cell ⦁⦁ IgG is composed of two L chains and two H chains. IgG has the high-
homing areas that primarily exist in the splenic follicles and red pulp, est serum levels of all the other four classes of immunoglobulins
the lymph nodes, and mucosal-associated tissues. Partial maturation and a half-life of 18–25 days. IgG is the only maternal immuno-
in the thymus and bone marrow in utero is followed by migration to globulin that crosses the placental barrier and confers immunity.
and seeding of the peripheral lymphoid tissues. After birth, the T and It is specifically produced during the secondary immune response.
B cells differentiate further and gain immune competency under IgG adheres to cells that possess a receptor for the Fc fragment from
antigenic stimuli. IgG (Fcγ), is bound by staphylococcal protein A, fixes and activates
Naïve B cells in the bone marrow are generally divided into three complement (resulting an enzymatic reaction that leads to cell
subsets, B-1 B cells, follicular B cells, and marginal zone (MZ) B cells lysis), and mediates placental passage of maternal antibody to the
(Allman and Pillai 2008). Cells of the follicular and MZ subsets vary fetus. There are four subtypes with varying capabilities to activate
in terms of their location, ability to migrate, and the likelihood that complement or affinity to the Fc receptor on phagocytic cells.
they will be activated in a T-dependent or a T-independent fashion. ⦁⦁ IgM mainly exists in two structural forms: A monomer (one four-
In addition to the well-recognized role of peripheral B cells in medi- chain Y structure) synthesized by and retained on the membrane
ating humoral immune responses, B cells can also secrete cytokines of B cells as an antigen receptor and a pentamer secreted after
and have the potential to present antigen to naïve T cells. Some of antigen and cytokine activation of plasma cells. The pentameric
the functions of B cells that are less well understood include the po- IgM molecule has five Y-shaped molecules joined by a J chain and
tential role of some B-cell populations as regulatory cells inhibiting is the major immunoglobulin produced by the primary antibody
tissue-specific inflammation, the potential role of activated cytokine- response. IgM has ten binding sites, giving it the highest avidity for
producing B cells in the activation of T cells that drive inflammation, antigen, and its five chains with Fc complement-binding sites also
and the possible role of B cells in the induction of tertiary lymphoid make it the most efficient complement-binding activating immu-
organs at sites of disease-related inflammation. noglobulin. IgM is the first to be produced in infancy and possibly
Naïve, mature, follicular B cells occupy two niches during their in the fetus in utero as a defense against infection.
re-circulatory paths. Once they mature and are able to re-circulate ⦁⦁ IgA exists in three main forms: A monomer, a dimer, and a dimer
in the spleen or bone marrow, they migrate repeatedly through the plus secretory piece. IgA is the main immunoglobulin used in
blood and the lymph to B-cell homing areas of lymph nodes, Peyer secretions such as milk colostrum, saliva, tears, and respiratory
patches, and the spleen. Naïve follicular B cells residing in the “fol- and intestinal mucus. IgA prevents the attachment of microor-
licular niche” may thus present T-dependent antigens to activated ganisms to mucous membranes. It is secreted as a dimer with the
T cells. The “follicular niche” therefore represents the major site at monomeric forms joined by a J chain and a secretory piece called
which re-circulating B cells mediate T-dependent immune responses sIgA, which is added during the passage through the mucosa. This
to protein antigens. Apart from homing in on their “follicular niche,” secretory piece protects IgA from proteolysis.
follicular B cells also migrate to the bone marrow where they form ⦁⦁ IgE is present in very low concentrations in serum because its Fc
discrete collections around vascular sinusoids (Cariappa et al. 2005, region can bind avidly to mast cells and basophils and trigger
2007). This “perisinusoidal niche” is made up of the same re-circulating the release of their granules. The binding of antigen to these IgE-
B cells that reside in follicles. Perisinusoidal B cells can be activated sensitized cells triggers the release of vasoactive amines (mainly
by blood-borne microbes in a T-cell-independent manner, and dif- histamine). This can result in a local (hives) or systemic reaction
ferentiate into IgM-secreting, antibody-forming cells (AFCs), but they (anaphylaxis). IgE provides protection against parasites but is also
are unable to induce antibody immunodeficiency, possibly because response for immune hypersensitive (allergic) reactions in some
they are not architecturally configured to readily interact with helper individuals.
T cells which are relatively scarce in this compartment. ⦁⦁ IgD is found on the membranes of 15% of newborns and 5% of adult
MZ B cells are considered to be innate-like cells that can be induced peripheral blood lymphocytes together with IgM. IgD is very low
to differentiate into short-lived plasma cells (Allman and Pillai 2008). in serum and is known to function in antigen recognition because
MZ B cells can also mediate the transport of antigen in immune com- it is primarily found bound to the membrane of mature B cells.
plexes into splenic follicles, may be involved in T-dependent B-cell
responses, and may participate in immune responses to lipid antigens.
MZ B cells can also transport antigen in immune complexes from the
■■THE INNATE IMMUNE RESPONSE
vicinity of the marginal sinus to follicular B cells in the splenic follicle An innate immune system can be found in all animal and plants. It
(Ferguson et al. 2004, Cinamon et al. 2008). In human lymph nodes, B responds in a uniform, reproducible way to the same stimulus and
cells located in the outer extrafollicular rim have also long been called is not capable of building a memory like the adaptive system. The
MZ B cells. These human cells with an IgM+ memory B-cell phenotype key factor in the innate immune system is the recognition of certain,
could potentially also play a role in antigen capture and transport into common molecular patterns, the DAMPs, which derive directly from
 The innate immune response 41

pathogens (PAMPs), or are released from host cells upon tissue injury by monocytes and lymphocytes. In addition, the activation of the
(alarmins) as an indirect sign of danger. These DAMPs are recognized complement and coagulation system supports the inflammation pro-
by PRRs (see Table 3.4). The response of the cells of the innate system cess. The complement system can be activated in two ways, the classic
lead to a whole cascade of events, which aim to clear the infection and and alternative pathways. The activated complement can opsonize
repair damaged tissue. The importance of the innate immune system bacteria for more efficient phagocytosis, act as chemoattractants for
is underlined by the fact that there are very few survivable gene defects leukocytes, or destroy bacteria directly by formation of the membrane
in this system. The barrier function of skin or mucosa and other passive attack complex (MAC). The injury of blood vessels leads to the initia-
defense mechanisms such as tears or cilia movements are an impor- tion of the coagulation cascade, which results in clotting arteries and
tant first line of defense and help prevent the invasion of pathogens capillaries. Both systems support the overall goal of bacterial clearance
into tissues. Besides the cellular part of the innate immune response, synergistically. The coagulation system contains the infection and
the complement system also contributes to clearance of pathogens prevents the spreading of bacteria by occluding the blood flow from
by directly killing bacteria, increasing phagocytosis, or attracting ad- the tissue; the complement system kills bacteria and attracts immune
ditional leukocytes to the site of infection. Of note, there are several cells (de Jong et al. 2010). It is now known that there is a considerable
intersections between the innate and adaptive system, which lead to cross-reactivity between the complement and coagulation system, but
enhancement of the response of both systems. also PRRs and cells of the innate and adaptive immune system, mean-
ing that activated proteinases of the complement system can activate
■■Sequence of events the coagulation cascade and vice versa (Amara et al. 2010, Ricklin et
al. 2010). This allows the activation of both systems at the same time
The response of the innate immune system has two aspects. The first by one stimulus and therefore a faster coordinated response.
focuses on containment and clearance of the local infection; the All these different events are together responsible for the clinical
second aspect is to focus the body’s metabolism on supporting the picture of inflammation of swelling, redness, heat, and pain. Derivates
clearance of infection. The local control of the infection is discussed of arachidonic acid such as prostaglandins and leukotrienes are
first. An overview of the different steps and processes in the local innate produced during inflammation and lead to vasodilation and platelet
immune response at the site of infection is given in Figure 3.6. The activation at the site of infection (Basu 2010). The increased blood flow
first step is recognition of DAMPs by PRRs, which are mainly found on is responsible for the heat and redness, which is seen clinically, but
macrophages, monocytes, and dendritic cells. The activation of these it also brings a higher number of leukocytes to the tissue. Increased
cells leads to the secretion of cytokines and chemokines. At the site of permeability of the endothelium leads to exudation of plasma proteins
infection, cytokines activate the endothelium, which is the principal and facilitates the transmigration of leukocytes trough the endothe-
signal for leukocytes in the blood to exit the bloodstream. The influx lium. This increased permeability is visible as swelling of the infected
of cells at the infectious site follows a typical and reproducible pattern. site. Pain results from the activation of nerve endings by several of the
The first cells are the PMNs such as granulocytes, which are followed secreted substances such as leukotrienes and others.

Figure 3.6  The innate immune

LPS system can be activated by
either pathogen-associated
molecular patterns (PAMPs)
DAMPs
Toll-like receptors such as lipopolysaccharide
Danger associated (on monocytes) (LPS) or by endogenous
Tissue
molecular patterns proteins (alarmins) such as
HMGB1 HMGB1 or heat shock proteins.
destruction HSP These danger-associated
molecular patterns (DAMPs) are
E. coli Signaling pathways recognized by innate immune
(NF-kappaB, MAPK)
receptors (pattern recognition
Systemic Effects: receptors [PRRs]), which are found
- Fever in high density on monocytes,
- Endothelium activation Cytokines Chemokines macrophages, and dendritic
Complement
activation
- Vasodilation cells. Activation of these cells
- Coagulation activation leads to the production of
- Acute phase response (liver) cytokines (TNF-α, IL-1α, IL-6) and
Adaptive immune chemokines (CCL2, MIP), leading
Leukocyte attraction
response to attraction of other immune
(granulocytes and others)
Bacterial clearance cells such as granulocytes and
Phagocytosis lymphocytes via endothelium
activation. The interplay of
these cells, supported by the
complement system and
coagulation system, leads to
the clearance of the pathogen.
Cytokines are also responsible for
the systemic response of the body
such as fever and the induction
of the acute phase response by
the liver.
42 SURGICAL IMMUNOLOGY

■■Role of endothelium they seem to be capable of phagocytosis, which was believed to be an

exclusive feature of cells of the myeloid lineage such as granulocytes
The trigger signals for leukocytes to enter a site of infection are the and monocytes (Wu et al. 2009).
expression of adhesion molecules on activated endothelial cells,
as previously described. The endothelium is activated by cytokines
leading to the expression of several different adhesion molecules
■■Resolution of inflammation
such as selectins and integrins, allowing migration to occur along The resolution of the inflammatory process is now known to be an ac-
a chemokine gradient. There are several subgroups of these adhe- tive process. In this concept, granulocytes and especially macrophages
sion molecules described and it seems that they are specialized for produce lipid mediators, which inhibit the influx of granulocytes but
a certain step in leukocyte transmigration (see Figure 3.1). However, attract monocytes, which are non-phlogistic (non-inflammatory)
there is a certain degree of redundancy among these molecules and (Serhan et al. 2008). These monocytes differentiate into macrophages
blocking of one subgroup alone is usually not sufficient to prevent with a high phagocytic capacity, but they do not produce proinflam-
extravasation of leukocytes. Selectins and other adhesion molecules matory cytokines or chemokines. Instead they secrete high amounts
such as ICAM-1 and -2 or VCAM-1 are mainly expressed on the endo- of IL-10 and TGFβ. In addition, the efflux of immune cells through the
thelium, whereas integrins such as LFA-1 or CD11a/b are expressed lymphatic systems in increased. The lipid mediators involved in this
on leukocytes. Chemokines are a large group of proteins, which serve process are mainly derived from essential omega-3 fatty acids. Only
as attractants for immune cells. They are divided into two groups of one of the described lipid mediators, lipoxin, is derived from a non-
CC and CXC chemokines, based on their amino acid sequence at the essential fatty acid (arachidonic acid). Intravenous administration of
N-terminus (Laing et al. 2004). Examples of chemokines are MIF and these lipid mediators has been shown to increase survival in a sepsis
monocyte chemoattractant protein 1 (MCP-1), also known as CCL2. model and might offer an avenue for future therapeutic interventions
The nomenclature for chemokines and their receptor is standardized. (Spite et al. 2009).
CC or CXC stands for the type of chemokine, R stands for receptor, and
L for ligand. Therefore, CCR2 is the receptor for CCL2. ■■Regulation of innate response
■■Role of granulocytes All these above-mentioned processes are tightly regulated with a wide
variety of cytokines and other mechanisms such as the autonomous
and macrophages nervous system. The initiation of the immune response is based on
Granulocytes are the first cells entering an infected site and their proinflammatory cytokines such as TNFα, IL-1β, and IL-6. These cy-
main role is phagocytosis and microbial killing. The fluid consisting tokines are initially secreted primarily by monocytes, macrophages,
of bacteria and dead neutrophils is clinically described as pus. Tissue and dendritic cells, but later reinforced by Th cells. The differentia-
macrophages and mainly monocytes from the bloodstream, which tion of naïve T cells to Th cells relies on IL-12, which is produced by
differentiate into macrophages, are responsible for the phagocyto- monocytes, macrophages, and dendritic cells. HMGB1 is a recently
sis of neutrophil debris and remaining bacteria. Macrophages and described protein that has cytokine-like properties (de Jong et al. 2010).
monocytes form a wall of mononuclear cells around the pus and an It was first discovered as a DNA-binding protein but is now considered
abscess is generated, which has a collagen wall and its own blood to be a crucial signaling molecule. It is released from necrotic cells,
supply via angiogenesis. Resolution of this structure is often via ex- but, more importantly, actively secreted and then recognized by
trusion in animals, but requires drainage in humans. The initial goal several receptors (TLR-2, -4, and RAGE). It seems that the release of
of the inflammatory process is to contain the infection that occurs by HMGB1 is the key activator of the systemic response to tissue injury
clotting of outflowing vessels, as well as abscess formation. There is a after trauma (Levy et al. 2007), but it is also increased during sepsis,
continual replacement of PMNs via neovascularization of the abscess. probably due to phagocytosis of increased apoptosis of lymphocytes
in the spleen by macrophages, which then release HMGB1 (Huston et
■■Other cell types al. 2008). Of note, HMGB1 alone without co-stimulatory factors such
as cytokines or PAMPs seems to be incapable of inducing a cytokine
In addition to phagocytes such as granulocytes and monocytes/ response, but it strongly amplifies the production of proinflammatory
macrophages, which are mainly responsible for the defense of bac- cytokines (Hreggvidsdottir et al. 2009).
teria, certain lymphocyte subsets are also considered to be part of the Besides proinflammatory cytokines, there are also anti-inflammato-
innate immune system. NK cells play an important role in first-line ry cytokines such as IL-10 and TGFβ, which have an inhibiting effect on
antiviral and anti-tumor response. NK cells are an exception among immune cells. Production of these cytokines are delayed, and produced
immune cells because they do not need to be activated by DAMPs or after stimulation of the cells within a few hours. The main purpose of
cytokines. NK cells check the expression of inhibitory receptors on this counterinflammatory response is to avoid damage to the host by
host T cells, such as MHC-I. If the appropriate amounts of inhibitory an exaggerated proinflammatory immune response. Despite being
receptors are expressed, NK cells do not lyse the host T cell or induce important to the counter-regulatory response, the mechanisms that
apoptosis. Virally infected cells and tumor cells fail to express MHC-I lead to the production of IL-10 are not very well understood.
and are therefore lysed by patrolling NK cells. Besides the first-line
defense against virally infected cells and tumor cells, NK cells produce
also large amounts of cytokines when stimulated by cytokines. A rare
■■Autonomic nervous system
subtype of T cells, γδ T cells, is also believed to have surveillance and and sex hormones
early response capabilities. The TCR of these cells consists of a γδ chain The autonomous nerves system clearly influences the immune
instead of αβ chains with a limited capacity to recognize antigens. response and the overall effect is similar to other effects of the sym-
These cells are believed to recognize alarmins such as heat shock pathetic and parasympathetic system: The sympathetic system has
protein and other uncommon antigens such as lipids. In addition, proinflammatory properties whereas the parasympathetic system has
 The adaptive immune response 43

anti-inflammatory actions. Immune cells are equipped with adrenergic systems, in which these processes have been clinically well described
and acetylcholine receptors. Catecholamines from the adrenal medulla and remain major challenges, are ARDS and liver injury. Several
are also produced from macrophages, and enhance the production of cytokines such as TNFα mimic the clinical picture of sepsis when
proinflammatory cytokines via NF-kB-dependent mechanisms (Flierl given systemically and the blockade of TNFα was shown to improve
et al. 2007). Exhaustion of the adrenal glands during sepsis may also, survival in experimental sepsis (Tracey et al. 1987). However, blockade
therefore, affect the immune response. In contrast, the vagal system of several cytokines or their receptors in septic patients did not lower
has anti-inflammatory properties via acetylcholine receptors (Tracey 30-day mortality (Abraham et al. 1995). Therefore, new approaches
2009). Stimulation of the vagus nerve has been shown to reduce the pro- were investigated. The close and largely not understood interactions
duction of proinflammatory cytokines and HMGB1, but also increases of the immune cells, complement, and coagulation system make the
survival. The main effector organ of this neuroinflammatory reflex in discovery for new drugs very challenging.
animal models seems to be the spleen; however, vagal stimulation of
the gut abrogates burn-induced (sterile) lung injury, which is mediated
by TLR-4 (Krzyzaniak et al. 2011a, 2011b). In addition, sex hormones,
■■Acute phase response
mainly estrogen, also modulate the response to infection and tissue Local infections also have systemic effects, which are induced mainly
injury. It is a well-described phenomenon that women of reproduc- by cytokines. The whole body response to infection is called the acute
tive age have a better survival and fewer complications after trauma phase response. The function of this acute phase response is to sup-
and sepsis (Wichmann et al. 1996, Zellweger et al. 1997, Angele 2000). port the clearance of infection. Acute phase proteins are secreted by
In humans, the data are controversial. It seems that premenopausal the liver and opsonize bacteria such as C-reactive protein (CRP) and
women have fewer infectious complications than men, but the mor- serum amyloid A (SAA); others, such as coagulation factors, aim to
tality in women is higher once the complication has occurred (May et contain the infection localized and should prevent the spread of the
al. 2008). Of note, estradiol levels in both genders are associated with infection. CRP and SAA can also be considered PRRs because they
mortality in critically ill and trauma patients. recognize phosphorylcholine, a very common part of bacterial cell
walls. Other proteins such as albumin or transferrin have decreased
■■Apoptosis of immune cells production. In addition, the metabolism shifts to a catabolic state,
which supplies the immune cells with necessary substrates such as
A very effective way to regulate the immune response is the induc- glucose and amino acids. This catabolic state typically manifests as
tion of apoptosis of effector cells. The deletion of self-recognizing weight loss in patients with chronic infections.
T cells in the thymus is the principal way by which the immune
system selects non-self-attacking T cells. However, uncontrolled
apoptosis or even necrosis of immune cells gained interest in recent
■■THE ADAPTIVE
years and seems to contribute to immune-dysfunction in sepsis. IMMUNE RESPONSE
The increased apoptosis of lymphocytes subsets and monocytes
is believed to contribute to the unresponsiveness of the immune Adaptive immunity consists of all responses that lead to the devel-
system in late sepsis (Hotchkiss et al. 2005, Pelekanou et al. 2009). opment of specific antibodies and antigen-specific lymphocytes.
The reason for the increased apoptosis is not clear. Several cytokines To fulfill this, many cells work together to produce this complex
such as TNFα and other cytokines, Fas ligand, and intracellular immune response (Figure 3.7). This includes antigen-presenting
events can induce the activation of the caspase system, leading to cells (APCs), T cells, and B cells that interact together in the central
apoptosis. Recently, an unknown, early, circulating factor, which has lymphoid (thymus and bone marrow) and the peripheral lymphoid
higher levels in non-survivors of sepsis, has been shown to induce (e.g., spleen, lymph nodes, tonsils) organs to produce the two main
apoptosis in monocytes and lymphocytes. As apoptosis is believed types of adaptive immunity, humoral and cell-mediated immunity.
to contribute heavily to the immune dysfunction in sepsis, the re- Humoral immunity is primarily mediated by antibodies, which neu-
duction of apoptosis in immune cells offers interesting therapeutic tralize microorganisms and toxins and remove antigens in the body
possibilities (Ayala et al. 2008). fluids through phagocytosis or lysis. Cell-mediated immunity (CMI)
is mediated by cytotoxic T cells, NK cells, and macrophages, and is
■■Systemic effects of responsible for killing microorganisms inside body cells as well as
eradicating abnormal host T cells (e.g., cancer cells). Cells of the
inflammatory mediators adaptive immunity (both humoral and cell mediated) include the
All these different processes such as vasodilation, increased perme- B and T lymphocytes, which represent 30% of the circulating leuko-
ability, adhesion, and transmigration of leukocytes, activation of the cytes. Adaptive (acquired) immunity takes several days to become
complement and coagulation cascade, as well as production of ROS protective, is designed to remove a specific antigen, and is the specific
together are essential for local control of an infection. However, if these immunity that one develops throughout life.
processes do not remain locally and spread through the whole organ-
ism, they are detrimental and can kill it. The clinical picture associated
with uncontrolled systemic inflammation is described as the systemic
■■Humoral immunity
inflammatory response syndrome (SIRS) and all the symptoms can This response to specific pathogens involves the production of an-
be attributed to the same mechanisms, which are locally very helpful tibody molecules in response to an antigen and is mediated by B
to control infections but systemically cause problems. Systemic va- lymphocytes, which circulate throughout the host including body
sodilation leads to hypotension, increased endothelial permeability fluids. The production of these antibodies takes place in several
leads to interstitial fluid, ROS formation leads to tissue damage, and stages. If antigen entry is intravenous, the antigen is phagocytosed
activation of the coagulation systems leads to microthrombi, which or pinocytosed in the spleen. However, if antigen entry is other than
ultimately lead to hypoxia of the tissue followed by necrosis. Two organ intravenous, the antigen moves to the lymph node draining the site
44 SURGICAL IMMUNOLOGY

Figure 3.7  Schematic summary outlining the

Exposure to microorganisms or humoral and cell-mediated arms of the adaptive
vaccines immune response.

Antigen processing in the lymph

nodes or speen

Antigen presenting cell (APC)

uptake

Intracellular Proteins
organisms

Antigen processed to
Antigen synthesized in peptides in phagocytic
APC cytoplasm and vacuoles
processed to peptides

Peptide-class ll MHC
Peptide-class I MHC complex forms and
complex forms and migrates to APC
migrates to APC membrane
membrane

CD8+ TCR binds to

CD8+ TCR binds to peptide class ll MHC
peptide class I MHC complex on APC
complex on APC

Th1 cells Th2 cells

IL-2 induces expansion
of Tc

IL-2 secretion IL-2 induced proliferation

Tc clone contacts
infected cell
TNF-, interferon- Release of IL-4, IL-5, IL-
10 and IL-13
Perforin and cytokine
release Macrophage activation With the help of antigen
activation, B-cell
activation, differentiation,
Microorganism and cell
IL-2 secretion and cytotoxic and division takes place
killed
T cell proliferation leading to
cell mediated immunity
Development of plasma
B-cells and eventually
the secreted antibodies
will lead to lysis of
microorganism through
either: Phagocytosic
respiratory burst or
complement fixation

of entry. In the lymph nodes or spleen, the antigen encounters the and migrate to the APC membrane, where they are presented to
T cell, B cell, APC triad, and is initially processed by the APC. As CD8+ cells. For exogenous protein antigens, these antigens are
a result, antigen processing brings about the activation of T cells. phagocytosed by the APCs from the extracellular environment
For viruses and intracellular parasite antigens, these antigens are by pinocytosis and are processed in acidic endosomal vacuoles.
synthesized endogenously within the APC cytoplasm and endocyto- The processed peptides will eventually bind to the cleft in MHC-II
plasmic reticulum, and then processed to peptides by proteasomes. molecules and are transported into the cell membrane, where they
The resulting peptides bind to the heavy chains of MHC-I molecules are presented to CD4+ T cells.
 References 45

■■Activation of T and B cells ■■Cell-mediated immunity

Exogenous protein antigens This type of response involves the production of cytotoxic T lympho-
After being transported to the APC cell membrane, the antigenic cytes, activated macrophages, activated NK cells, and cytokines in
peptide–MHC-II complex is presented to CD4+ Th cells. The Th-1 response to an antigen and is mediated by T lymphocytes. CMI is
cell response then develops as the specific CD4+ Th-1 cell clone directed against intracellular microorganisms and aberrant, endog-
differentiates, divides logarithmically, and secretes IL-2, IFN-γ, and enous cells (tumor cells). Immune reactivity is affected by cytotoxic
TNFa. IL-2 is necessary for T- and B-cell transformation, whereas T cells, macrophages, and NK cells on direct contact with the target T
IFN-γ is a potent macrophage and NK-cell activator and also en- cell. This reactivity is transferable to normal, non-sensitized hosts with
hances cell-mediated immunity. IFN-γ also triggers HLA antigen sensitized effector cells. No antibodies are involved except in ADCC
presentation by endothelial cells and downregulates IL-4 synthesis reactions. The effector cells, in these cases, are linked to the target T
by Th-2 cells; thus, it can also suppress antibody formation. TNFa cells by an antibody bridge, with the Fab protein binding to the specific
activates macrophages, stimulates the acute phase response, and membrane antigen on the target T cell, and the Fc portion binding to
synergizes with IL-1 in inducing this response. The Th-2 cell response the Fc receptor on an activated effector cell. There are multiple types of
develops after antigen activation and stimulation by IL-2, and the CMI and these include reaction to infectious agents (tuberculin test),
CD4+ Th-2 cell responds by transforming, differentiating, and divid- granulomatous reactions, and contact dermatitis. Although CMI is
ing logarithmically, while secreting IL-4, IL-5, IL-10, and IL-13. IL-4 basically a defense mechanism against foreign substances, cells in the
promotes the development of antibody synthesis by stimulating vicinity of antigen deposition, as well as those harboring microorgan-
B-cell differentiation and downregulates IFN-γ by Th-1 cells, thus isms, are damaged if the inflammatory response induced is excessive.
suppressing cell-mediated immunity. In addition, IL-4 is significant This is caused by the magnified inflammatory response induced by
in the switch to IgE production. IL-5 functions in synergy with IL-4 activated macrophages, cytotoxic T (Tc) lymphocytes, and NK cells.
and IL-2 to help B-cell differentiation, facilitate IgA synthesis, and
stimulate the growth and differentiation of eosinophils. IL-10, similar
to IL-4, inhibits Th-1 cell release of IFN-γ and IL-2, thereby negat-
■■CONCLUSION
ing macrophage activation by IFN-γ. IL-13 mimics IL-4 actions and The immune system is a complex and highly redundant system of
inhibits Th-1 cytokine release. cells and proteins working together to defend the body from invading
pathogens. It is made up of two distinct parts, the innate and adaptive
B-cell response systems, which overlap considerably to protect the body from infec-
Antigens are recognized by B cells with the appropriate membrane- tions. For surgical infections, the innate system seems to be of more
bound IgM that is specific for that antigen. The binding of antigen importance because of the fast and immediate response to a very
along with stimuli from the T-cell cytokines IL-2 and IL-4 triggers broad variety of pathogens. The adaptive system needs several days
differentiation of that specific B-cell clone into large blast cells, and to be engaged. However, it provides a very good protection against
logarithmic division follows. IL-5 continues the process, during re-infection with the same pathogen because of its memory cells.
which the B cell acquires the cytoplasmic machinery necessary for Major trauma and surgical stress can compromise the immune
antibody synthesis. The heavy and light chains are then synthesized, system, with patients becoming anergic and unable to respond to im-
assembled, and promoted by IL-6, and will undergo terminal dif- munological insults post-surgery (immune paralysis) due to cellular
ferentiation into a plasma cell and secrete IgM. Subsequent gene dysfunction. The mechanisms of this unresponsiveness (anergy) are
rearrangements result in a switch to IgG, IgA, and IgE synthesis and unclear, but involve defects in cell-mediated adaptive immunity. Modu-
secretion. IL-4 and IFN-γ influence the switch to IgG, TGFβ influ- lation of signaling pathways by micro-RNAs in cells of the innate system
ences the switch to IgA, and IL-4 influences the switch to IgE. The such as monocytes, macrophages, and dendritic cells or counterinflam-
binding of CD40 on the B cell to its ligand on the Th cell (CD40L) is matory cells of the adaptive system such as Treg cells might play a role.
necessary for switching to occur. Memory B cells of all classes are Influencing the immune response by a variety of strategies includ-
generated independently of the plasma cell lineage and migrate to ing anti-TNFα antibodies and stimulation by IFN-γ has not lead to
various lymphoid tissues, where they have an extended survival. improvement of clinical outcomes thus far. This finding reinforces the
A secondary response occurs when further exposure to the same complex nature of the immune system and our lack of understand-
antigen results in a shorter induction period to antibody synthesis, ing of the principal mechanisms. There are several new avenues of
more rapid class switching from IgM to IgG, increased IgG with research, which might improve the care of surgical patients with in-
antibodies of higher affinity, and a predominant IgA synthesis in fections such as the modulation of lymphocyte apoptosis, micro-RNA
mucosal tissues. expression, and strategies to promote resolution of inflammation.

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 Chapter 4 Surgical site infections
Donald E. Fry

Infection at the surgical site (SSI) continues to be a major problem. environment conditions that are present within the contaminated
With the introduction of the germ theory of disease, Joseph Lister, in wound tissues. The innate and adaptive immune responses of the host
the 1860s, introduced antiseptics into surgical practice in the hopes of (see Chapter 3) are designed to eradicate the bacterial contaminants of
killing bacteria that might contact the open wound. As the twentieth the wound, and prevent SSI as an outcome. Each of the determinants in
century emerged, surgeons developed dedicated operating rooms Figure 4.1 is individually discussed. It must be understood that there are
within hospitals and adopted a code of infection control behaviors to additive and synergistic relationships among these major determinants.
reduce the likelihood of SSI. Surgical gowns and drapes, facemasks,
hand scrubbing, and surgical gloves were all introduced in the hopes
of minimizing infection. Sterilization of surgical instruments and
■■Inoculum of contamination
sophisticated air-handling systems were similarly introduced to Among all of the clinical variables associated with SSI, the inoculum
avoid environmental introduction of potential pathogens. Although of bacteria in the incision and soft tissues of the operation is the best
the infection control practices of the operating room have favorably recognized. Most of the preventive strategies that are subsequently
impacted rates for most operations, the complexity of surgical discussed are designed to reduce the quantity of bacteria that access
interventions and the vulnerability of patients due to an expanded the surgical site. The clinical variables that govern the inoculum
array of comorbidities make the frequency and severity of SSIs a of bacteria at the surgical site are the intrinsic colonization of the
continued complication of care. In addition to patient morbidity, anatomic structure that is being entered at the time of surgery, and the
preventable SSIs are a recognized major economic cost of surgical presence of contamination or infection that may already exist within
care (Fry 2002). the patient at the time of the procedure. The microbial burden that
Bacteria are ubiquitously distributed in our environment. They can be anticipated with a given operation is the basis for the American
colonize the skin of patients and healthcare providers alike. The human College of Surgeons’ wound classification system (Culver et al. 1991).
aerodigestive tract is a rich source of bacteria. The air and floor in the
operating room are a source of bacteria. It is likely that bacteria can Clean operations
be cultured from every open surgical wound at the completion of the A clean operation does not enter a normally colonized anatomic
procedure. Yet every wound does not get infected. structure, nor is there any pre-existent infection. Although the skin is
SSI is the result of a complex interaction of the microbes that penetrated by the surgical incision, under elective circumstances the
contaminate the wound, the local environment of the wound, and number of cutaneous bacteria to enter the wound from this source is
the multifaceted components of the human host defense. In most manageable. This presumes that cutaneous colonization can be reduced
circumstances the effectiveness of host defense and the preventive by antibacterial skin preparation before the start of surgery and that
measures that are employed result in the absence of infection. In a appropriate infection control practices are employed. Clean operations
minority of cases infection occurs for reasons that are suspected by include elective breast surgery, cutaneous level operations, and even
the clinician. In an occasional case SSI occurs without any plausible inguinal hernias. Inguinal hernias are in close proximity to the groin and
clinical explanation. This chapter explores the multiple interactions perineum with heavier cutaneous colonization, but elective surgery with
of the pathogen and the host to provide a context for understanding adequate local skin preparation should have observed infection rates
and preventing SSI. that are commonly reported as less than 2%. Craniotomies, total joint
replacements, and vascular procedures are more complex examples
■■PATHOPHYSIOLOGY OF SSI of clean operations. As coronary artery bypass procedures may have
additional groin incisions with increased local colonization, infection
An SSI is the sustained local activation of the human inflammatory rates may be higher than in other clean procedures.
response due to the proliferation of microorganisms at the site of a
surgical procedure. The determinants that are responsible for SSI are Clean-contaminated operations
illustrated in Figure 4.1. The clinical variables that favor the emergence Clean-contaminated operations are elective operations that enter
of an SSI are the inoculum of bacteria in the surgical site, the virulence into normally colonized anatomic areas. Elective resections of the
characteristics of the bacterial contaminant, and the local tissue and colon, hysterectomy, and oropharyngeal resections are prototypical

Figure 4.1  A simple equation of the

Inoculum of Virulence of Adjuvant determinants of infection of a surgical site.
Plus Plus
bacteria bacteria effects
Probability of
=
infection
Intrinsic host Acquired host
Minus
defense defense liabilities
50 SURGICAL SITE INFECTIONS

Figure 4.2  The relationship between the inocula

of bacteria in the wound and the probability of
infection.

clean-contaminated operations. The human colon has about 106–107 derived from laboratory experiments where variable inocula of
bacteria per gram of content at the cecum, and this increases to nearly bacteria have been introduced into the soft tissues of healthy animals
1012 organisms per gram in the rectum (Ahmed et al. 2007). Vaginal (Robson et al. 1973). In Figure 4.2, the experimental curve in a normal
colonization may be 108 bacteria/ml during hysterectomy (Redondo- host for a hypothetical bacterial pathogen (e.g., Staphylococcus aureus)
Lopez et al. 1990). Although the density of microbial colonization is is illustrated by the line labeled A0. When the inoculum of bacteria is
less in the upper gastrointestinal and biliary tract, oropharynx, and <104, no infection occurs. When the bacterial density approaches 106,
lung, these are all considered clean-contaminated procedures. SSIs infection is almost uniformly present. Thus, the wound classification
have been correlated with the microbial density in the anatomic area adopted by the American College of Surgeons is a descriptive effort to
entered by the procedure. Reported infection rates vary from 3% in open estimate the wound inoculum by identification of the primary source
biliary procedures to 20% in open colon resections (Itani et al. 2006). of contamination. Clean wounds have a low inoculum and a low
infection rate. Operations with gross spillage or active infection have
Contaminated operations high concentrations of bacteria and higher infection rate.
Contaminated operations have overt contamination during the
conduct of an elective procedure, or are emergency procedures where
the conventional control of the elective surgical setting is lost. Spillage
■■Virulence of contamination
of intestinal contents during an elective colon operation is an example. As discussed in Chapter 1, there are many secreted and structural
A trauma laparotomy, any abdominal reoperation, emergency elements that account for the virulence of bacteria. Different strains
cesarean sections, and emergency open heart procedures constitute within a species can have vastly different virulence profiles. These
circumstances where the urgency of surgical intervention results in different virulence characteristics modify the number of microbial
higher SSI rates. SSI rates commonly exceed 20% in contaminated contaminants in a surgical incision that result in infection. In Figure
procedures. Infections are often polymicrobial and include cutaneous 4.2, line B0 illustrates an organism with unusual bacterial virulence
and enteric pathogens. (e.g., Streptococcus pyogenes). Clinical infection rates are observed
with an inoculum less than a conventional pathogen, illustrated
Dirty operations in A0. Conversely, line C0 in Figure 4.2 illustrates the infection-to-
Massive contamination may be present to give the presumption that inoculum relationship of a very low virulence bacterial organism, such
infection is eminent, or infection may already be present. A perforated as Enterococcus faecalis. Very high inocula are usually necessary for
viscus, a penetrating injury of the colon with fecal contamination, or infections with low virulence pathogens.
repair of a perforated esophagus are all dirty procedures. The density
and diversity of microbes at the surgical site are great. The surgical
sites are likely to have an SSI at the completion of the procedure
■■Environment of the surgical site
without specific and dramatic preventive measures (e.g., delayed At the time of his death, Louis Pasteur is alleged to have said: “the
primary closure). microbe is nothing, the terrain is everything.” So it is with the surgical
The traditional threshold for the microbial inoculum to result in site. Every incision has bacteria that can be cultured, but the conditions
infection has been defined as 105 bacteria/g tissue. This has been of the surgical site dramatically affect whether infection occurs.
 Diagnosis and surveillance of SSI 51

The surgeon and the techniques employed in handling the tissue of C1 could be ascribed to increased susceptibility of the host to SSI
the incision dictate whether wound contaminants result in SSI. from acquired immunosuppression as a result of the aforementioned
Hematoma and free hemoglobin enhance the virulence of bacteria. conditions and diseases.
Hemoglobin is a substrate to support the proliferation of microbes.
The ferric iron is a key element for supporting bacterial growth (Polk
and Miles 1971), and the metabolism of selected organisms in a
■■DIAGNOSIS AND
hemoglobin environment may actually create a degradation product SURVEILLANCE OF SSI
that retards specific leukocyte function (Pruett et al. 1984).
Other adjuvant effects are numerous. Tissue trauma, dead tissue,
and foreign bodies within the surgical site promote infection. Crushed
■■Diagnosis of SSI
tissue from over-exuberant retraction or indiscrete use of tissue SSI occurs when the microbes at the surgical site are proliferating and
clamps leaves dead tissue where bacterial contaminants may reside invading the adjacent normal host tissues. The host inflammatory
and proliferate. Inappropriate use of electrocautery similarly leaves responses to invading microbes are the classic signs and symptoms
islands of dead tissue. Foreign bodies such as suture (especially of redness, warmth, swelling, and pain at the surgical site. For most
non-absorbable braided materials), meshes, and other prostheses surgeons, the defining moment of an SSI is the discharge of pus at
serve an important purpose in the operation, but represent surfaces the incision.
for microbial attachment that are poorly handled by host defense However, many issues surrounding the diagnosis and interpretation
mechanisms. Obesity and incisional dead space yield poorly perfused of an SSI remain poorly defined and controversial. An infection can be
adipose tissue and reservoirs of serum, blood, and bacteria in the declared from the above criteria, but be of trivial clinical consequence
dependent portion of the incision that foster infection. with no increase in the duration of hospitalization or costs of care (Fry
The net effect of adjuvant variables is illustrated in Figure 4.2. Line et al. 2012). A single stitch sinus may innocently drain a small amount
A1 represents a complete shift to the left of the relationship between (<1–2 ml) of turbid fluid, the suture is spontaneously expelled, and
the required inoculum of bacteria and the probability of infection due the small site of disruption heals spontaneously without additional
to an adverse local environment from adjuvant factors for a given level sequelae or clinical intervention. In another setting, a wound seroma
of bacterial contamination. Line C1 illustrates the shift to the left in the is spontaneously discharged from the wound, only to have it cultured
infection:inoculum relationship and its impact upon low virulence and a small number of Staphylococcus epidermidis are recovered.
organisms. It is obvious that the primary responsibility of the surgeon This wound proceeds to uneventful healing, but such events are
in the prevention of SSI is effective intraoperative management of local labeled an SSI. A third setting may be the marked erythema about the
environmental variables. incision with some palpable induration in the subcutaneous tissue.
The erythema may relate to foreign body reaction due to staples in
■■Innate and acquired host defense the skin and not bacterial infection. No wound discharge is identified.
The patient is started on oral antibiotics and sent home. Are these
Effective or suboptimal host responses are poorly defined but real described conditions an SSI?
determinants of SSI. There is genetic variability in the efficiency of To provide some direction, the Centers for Disease Control (CDC)
the host response among patients. Chronic granulomatous disease of Atlanta have provided detailed definitions for SSI (Box 4.1). An
of childhood illustrates the genetic absence of intracellular killing important consideration in the CDC definitions is that SSIs are
capacity of the neutrophil. Although this example is an extreme one, categorized into three types: Superficial, deep, and organ/space
it is more likely that pathogen recognition, leukocyte responsiveness, (Mangram et al. 1999). In general, little controversy exists about the
cytokine responses, and other innate elements follow a pattern occurrence or clinical significance of a deep or organ/space infection.
of normal variation that result in selected individuals being more Most of the debate surrounds the occurrence and the relevance of the
vulnerable to infection when compared with the population mean. superficial SSIs. The CDC definitions allow the frequency of SSIs to
Although the pursuit of methods to enhance the responsiveness of the be standardized for evaluation by surgeons and hospital surveillance
host to resist postoperative infection continues, the reality is that we personnel.
cannot efficiently measure the genetic predisposition of the patient to
develop an infection. It is likely that the hypothetical relationship of the
infection:inoculum ratio (see line A0, Figure 4.2) should actually have
■■Surveillance
a 95% confidence interval for each point to illustrate the variability of Effective surveillance is a critical component of any quality improve­
the population under this theoretical ideal circumstance. ment program in surgical care. Only with effective surveillance can
However, acquired conditions can be measured and monitored, rates of SSI be known, and progress in prevention occur or outbreaks
and evidence demonstrates that the host is more vulnerable to be identified. Surveillance methods are controversial because the
postoperative infections when specific conditions exist (Anderson more intense the effort, the more expensive the process and the higher
2011). Shock, hypoxemia, anemia, and multisystem trauma have the rates of SSI. As an increasing number of SSIs are not identified
an acute suppressive effect upon the innate host response, with until after discharge, the post-discharge surveillance program is
increased rates of SSI and other infections. Hypoalbuminemia, chronic costly and logistically difficult. As a result of the expense and logistical
renal failure, acute and chronic alcoholism, chronic lung disease, issues, many hospitals use surveillance nurses or wound managers
chronic tobacco use, and chronic liver disease each increase the risk for inpatient evaluation, and then depend on self-reporting either by
for infection. Diabetes increases infection risk probably due to the patients or physicians for post-discharge events.
systemic immunosuppression of hyperglycemia. Steroid treatment An important part of any surveillance program is risk assessment,
and transfusion are clearly associated with increased SSI rates. and the SSI rates need to be correlated with the patient risk profile.
Advancing age is an independent factor in a suboptimal host response. Overall SSI rates without classification of patient risk become an
With reference to Figure 4.2, the shift to the left seen with line A1 and incomplete assessment. Hospital-wide infection rates without
52 SURGICAL SITE INFECTIONS

Box 4.1 Details the recommended definitions of surgical site a

National Nosocomial Infection Surveillance definition: A non-human-
infection by the Centers for Disease Control (Horan et al. 1992). derived implantable foreign body (e.g., prosthetic heart valve, non-human
vascular graft, mechanical heart, or hip prosthesis) that is permanently
Superficial incisional surgical site infection (SSI): Infection occurs placed in a patient during surgery.
within 30 days of the operation and infection involves only skin or b
If the area around a stab wound becomes infected, it is not an SSI. It is
subcutaneous tissue of the incision and at least one of the following: considered a skin or soft tissue infection, depending on its depth.
1. Purulent drainage, with or without laboratory confirmation,
from the superficial incision
2. Organisms isolated from an aseptically obtained culture of fluid
or tissue from the superficial incision stratification are not of value because gross rates are dictated by the
3. At least one of the following signs or symptoms of infection: risk profile of the patients.
pain or tenderness, localized swelling, redness, or heat, and Several different classification systems have been used to stratify
superficial incision is deliberately opened by surgeon, unless risk. The American College of Surgeons’ (ACS’s) classification
incision is culture negative system identified previously uses only the likely quantity of bacterial
4. Diagnosis of superficial incisional SSI by the surgeon or attend- contamination and does not employ any patient risk assessment.
ing physician In 1985, the Study of the Efficacy of Nosocomial Infection Control
Do not report the following conditions as SSI: (SENIC) project was undertaken to bring more variables into the
1. Stitch abscess (minimal inflammation and discharge confined prediction model (Haley et al. 1985). Four variables were found to be
to the points of suture penetration) of significance for SSI prediction:
2. Infection of an episiotomy or newborn circumcision site 1. Abdominal operations
3. Infected burn wound 2. Operations lasting >2 h
4. Incisional SSI that extends into the fascial and muscle layers 3. Surgical sites that were the ACS classification of contaminated or
(see deep incisional SSI) dirty
Deep incisional SSI: Infection occurs within 30 days of the opera- 4. More than two discharge diagnoses at the conclusion of hospital-
tion if no implanta is left in place or within 1 year if implant is in ization.
place and the infection appears to be related to the operation and A further modification of the SENIC model was undertaken by the
infection involves deep soft tissues (e.g., fascial and muscle layers) CDC in the early 1990s as part of the National Nosocomial Infection
of the incision and at least one of the following: Surveillance (NNIS) system (Culver et al. 1991). The NNIS system
1. Purulent drainage from the deep incision but not from the used only three clinical variables and developed a point system of 0–3
organ/space component of the surgical site for classification of infection risk. A point is assigned for each of the
2. A deep incision spontaneously dehisces or is deliberately three variables. Those patients with none of the three risk factors are
opened by a surgeon when the patient has at least one of the assigned a score of zero. The three variables are (1) ACS contaminated
following signs or symptoms: Fever (>38°C), localized pain, or or dirty classification, (2) the American Society of Anesthesiology (ASA
tenderness, unless site is culture negative 2012) score ≥3, and (3) patients where the operation lasted longer
3. An abscess or other evidence of infection involving the deep than the 75th percentile for operations of that type. The ASA score is a
incision is found on direct examination, during reoperation, subjective scale from 1 to 6 by anesthesiologists for overall assessment
or by histopathological or radiological examination of the patient risk. An ASA score of 1 is a patient with no comorbidities
4. Diagnosis of a deep incisional SSI by a surgeon or attending and ASA 2 is a patient with mild systemic disease. ASA 3 and above all
physician have major systemic disease or diseases that pose a major threat for
Notes: complications or death. Operations exceeding the 75th percentile in
1. Report infection that involves both superficial and deep incision duration are illustrated in Table 4.1 (Edwards et al. 2008). NNIS has
sites as deep incisional SSI been renamed the National Healthcare Safety Network (NHSN) but
2. Report an organ/space SSI that drains through the incision as the scoring system for risk of SSI remains much the same (Centers for
a deep incisional SSI Disease Control 2012).
Organ/space SSI: Infection occurs within 30 days of the opera- Despite all of the discussion about risk stratification and
tion if no implanta is left in place or within 1 year if implant is in surveillance, there remain problems with the interpretation of SSI
place, and the infection appears to be related to the operation and surveillance data. First, NNIS (now NHSN) risk categories are lacking
infection involves any part of the anatomy (e.g., organs or spaces), in detail. There are many details of the patient (e.g., age, selected
other than the incision, which was opened or manipulated during chronic diseases, selected laboratory studies) that could enhance
an operation and at least one of the following: the accuracy of the prediction model. The variables of NNIS risk
1. Purulent drainage from a drain that is placed through a stab assignment were derived by incomplete modeling. Second, the
woundb into the organ/space transformation of all disciplines in surgery to minimally invasive
2. Organisms isolated from an aseptically obtained culture of fluid strategies has reduced SSI rates. This means that any decline in SSIs
or tissue in the organ/space may not reflect improvements of infection control, but are rather the
3. An abscess or other evidence of infection involving the organ/ consequences of changes in surgical strategy. NHSN now recommends
space that is found on direct examination, during reoperation, that 1 point be removed from the risk score if the procedure is done by
or by histopathological or radiological examination a minimally invasive technique. Third, post-discharge rates of infection
4. Diagnosis of an organ/space SSI by a surgeon or attending escape surveillance and are commonly not accurate.
physician A better system is needed that reports SSI as a function of patient
risk and the severity of the SSI. We cannot interpret the results of
 Prevention of SSI 53

Table 4.1 Identifying the cut point in minutes of the 75th percentile and cancer care without knowing the stage of the patient at the time of
the respective surgical site infection (SSI) rates for operations in National treatment! Why should we not apply the same criteria to SSI? If the
Healthcare Safety Network categories 0 and 1, and the infection rates in NNIS classification of risk were paired with the CDC definitions of
categories 2 and 3.
infection severity in Box 4.1, then a 3 × 4 matrix of SSIs with true
Procedure Cut point (min) SSI infection SSI infection clinical meaning could be generated (Table 4.2). Reporting of SSIs
rate (0 or 1) rate (2 or 3) at present by simply counting all events the same without regard for
(%) (%) risk or severity cannot be interpreted and provides little foundation
Abdominal aortic 217 2.1 6.5 for improvement strategies.
aneurysm repair
Appendix surgery 81 1.2 3.5 ■■PREVENTION OF SSI
Bile duct, liver, or 321 8.1 13.7
pancreatic surgery SSIs are always viewed as preventable infections in patient care.
Preventive methods are employed before, during, and after the
Cardiac surgery 306 1.1 1.8
surgical event.
Colon surgery 187 5.0 7.3
Craniotomy 225 2.2 4.7 ■■Preoperative methods
Cesarean section 56 1.8 3.8
Prehospitalization cleansing
Kidney transplantation 237 3.7 6.6
Reduction of the cutaneous colonization at the surgical incision
Ovarian surgery 183 0.4 1.4 site is commonly initiated before the patient enters the hospital or
Thoracic surgery 188 0.8 2.0 ambulatory surgical center. A common practice has been to have the
patient scrub the surgical site with antiseptic soap on one or multiple

Table 4.2 The types of clinical scenarios that would be identified by combining the National Healthcare Safety Network (NHSN) classification of patient
risk with the Centers for Disease Control (CDC) measure of severity of surgical site infection (SSI).
NHSN risk CDC defined severity of infection
index
Superficial (S1) Deep (S2) Organ/Space (S3)

0 (N0) N0S1 N0S2 N0S3

A 35-year-old patient (ASA 1) has transient A 55-year-old man (ASA 2) has a wound abscess 64-year-old (ASA 2) patient has an infected
serous discharge that is culture positive from of hernia incision requiring complete opening hip replacement prosthesis 4 days after a 2.5-h
an inguinal hernia procedure that lasted 60 min. of the wound 3 days after 78 min elective repair total hip arthroplasty. The prosthesis has to be
Local drainage is all that is required of inguinal hernia removed

1 (N1) N1S1 N1S2 N1S3

A 60-year-old (ASA 2) patient has a superficial A 57-year-old man (ASA 2) has an emergency A 63-year-old patient (ASA 4) with severe
surgical wound infection 4 days after a 6-h sigmoid colectomy for fecal peritonitis chronic lung disease has a large pelvic abscess
laparotomy for small bowel obstruction. The secondary to perforative diverticulitis. The requiring drainage and prolonged antibiotics
wound is spontaneously closed 72  h after incision is opened for a wound abscess to the on postoperative day 5 after a 2-h total
local drainage fascia on postoperative day 7 abdominal hysterectomy

2 (N2) N2S1 N2S2 N2S3

A 63 year old (ASA 3) has a superficial SSI 10 days A 64-year-old patient (ASA 4) has the whole A 48-year-old (ASA 3) morbidly obese (480 lb,
after a multilevel laminectomy which requires incision opened to the mesh after a 5-h 216 kg) patient has a wound evisceration from
drainage only and no antibiotics ventral hernia repair. The cultures grow MRSA. a subfascial abscess after an elective 4.5-h roux-
An additional 12 days of hospitalization and en-Y gastric bypass
antibiotics are required

3 (N3) N3S1 N3S2 N3S3

A 37 year old (ASA 5) has an exploratory An 83 year old (ASA 4) undergoes subtotal A 68 year old (ASA 4) with severe congestive
laparotomy for a gunshot wound to the colon, gastrectomy for perforated gastric carcinoma hear t failure, aor tic insufficienc y, and
pancreas, and left renal vein/artery; profound that has a deep SSI requiring opening of the staphylococcal endocarditis has a postoperative
shock. He has a 5-cm area of locally drained, entire wound on day 6 after a 5.5-h subtotal sternal infection with mediastinitis 5 days after
superficial wound infection on day 5 gastrectomy a 7-h aortic valve replacement
ASA, American Society of Anesthesiologists.
54 SURGICAL SITE INFECTIONS

occasions preoperatively. Chlorhexidine, povidone–iodine, or Hence, nursing home patients harbor resistant profiles of bacterial
isopropyl alcohol applications to the site are also used. None has been colonization. Elective or emergency operations for these patients
clearly documented to reduce the frequency of SSIs. Whole body baths require consideration for preventive antibiotic choices (discussed
and showers with conventional soaps or any of the aforementioned subsequently) that are different from those conventionally employed.
antiseptics have also been advocated, but the most recent analysis
has not shown a reduction in SSIs, even though cultures before the Prior antibiotics
operation have demonstrated a reduction in bacterial counts (Webster Antibiotic administration results in changes in the patient’s microbial
and Osborne 2007). Chlorhexidine has been demonstrated to bind colonization. Oral antibiotics for streptococcal pharyngitis or for a
to skin proteins and to have a sustained antibacterial action. This community-acquired urinary tract infection result in changes in the
observation has raised the issue that repeated localized scrubs or patient’s cutaneous and gastrointestinal colonization. Similar to prior
whole body bathing over several days before surgery may be preferable inpatient care, ambulatory antibiotics will likely impact the probability
to a single scrub on the day before the procedure (Edmiston et al. 2008). of SSIs. Deferral of elective procedures, if practical, because of recent
antibiotic use is appropriate.
Surveillance cultures
A very recently popularized technique in the preoperative period
is screening cultures of the nasopharynx of the patient. This method
■■Intraoperative methods
has been shown to identify patients with colonization by specific Hair removal
pathogens, particularly meticillin-resistant Staphylococcus aureus Removal of hair at the surgical site has been part of surgical lore as a
(MRSA). MRSA colonization has been associated with increased rates technique that reduces SSIs. Many patients have limited hair at the
of infection. Screening with preoperative cultures has been used for surgical site and the majority opinion would be that no hair removal is
decontamination (e.g., mupiricin) of positive patients, changing the necessary for prevention of SSIs. For cranial, inguinal, and operations
systemic antibiotics used for prevention, or deferring the actual timing on hirsute males, hair removal may be desirable because of logistical
of the surgical procedure. Some studies have demonstrated reduced issues at the surgical site.
infection rates with preoperative decontamination, and others have Although hair removal has not been shown to reduce SSIs, the
not. Consistent effectiveness has not been demonstrated (Simor 2011). methods employed in removal have been documented to increase
An interesting feature of surveillance cultures is that hospital them. Removal the night before surgery with either a razor or
workers have similar rates of MRSA colonization as the population in elective clippers has been associated with increased SSIs (Cruse
general, even when working in environments (e.g., intensive care units) and Foord 1980). Cutaneous abrasions from early hair removal are
with frequent exposure to the pathogen (Ibarra et al. 2008). Thus, an colonized with bacteria and increased wound contamination. Even
interpretation of those patients with positive MRSA colonization may straight razors used at the time of surgery have been implicated with
be that it is the phenotype of a host that carries pathogenic bacteria, increased infections (Alexander et al. 1983). Electric clippers are the
and not necessarily an environmentally acquired risk factor. MRSA preferred method but only in the operating room immediately before
decontamination may reduce MRSA SSIs, but not change rates from all preparation of the surgical site. Loose clipped-hair pieces are potential
pathogens in a vulnerable population. With the increased prevalence foreign bodies in the surgical wound and should be mechanically
of community-associated MRSA, which is approaching 20% of elective removed. Depilatory creams have been used for hair removal but
patients, the effectiveness of this surveillance methodology deserves little evidence supports this practice. Hypersensitivity reactions to
continued evaluation. depilatory creams may be a legitimate reason to not use them.

Preoperative hospitalization Skin antiseptics

The duration of preoperative hospitalization is associated with The mechanical cleansing of the skin at the surgical site is performed
increased rates of SSIs. Cruse and Foord (1980) identified a twofold with a number of antiseptic soaps. No evidence favors one over
increase in SSIs with 4 days of preoperative hospitalization and a another, nor is there a scientific basis for defining the duration of
fourfold increase with 7 preoperative days. More recently, Vogel et the scrub. The traditional mechanical scrub is initiated at the central
al. (2010) have similarly noted increases in SSIs with the duration of area of the proposed incision and the scrubbing action continues in
preoperative hospitalization in cardiac, colon, and lung operations. a concentric fashion. The scrub is repeated with the circular action
Several hypotheses explain these observations. Hospitalization is always moving from the cleanest area toward the more contaminated
associated with colonization of the patient with hospital-associated perimeter.
microflora, and these organisms are more resistant to conventional A topical antiseptic solution is then applied over the mechanically
preventive antibiotics. Days of preoperative hospitalization are scrubbed area. Isopropyl alcohol, chlorhexidine gluconate, and
probably a surrogate marker for the severity of the patient’s medical povidone–iodine solutions all have antibacterial action and have
and surgical condition, because routine surgical cases are usually been used. Isopropyl alcohol is a potent antiseptic but presents a risk
on the same or first day of admission to the hospital. Extended of flammability. Povidone–iodine must be permitted to dry to have
preoperative inpatient assessment is a risk factor for increased optimal antibacterial action. Chlorhexidine has been a preferred
surgical morbidity. Similarly, the patient who has been hospitalized, topical antiseptic in other skin preparation studies.
discharged, and then re-hospitalized has both exposure to hospital A recent clinical trial compared a hybrid antiseptic solution of
microflora and likely complications of prior care that will increase SSI chlorhexidine and isopropyl alcohol together with povidone–iodine
rates for subsequent surgery. alone. A statistically significant reduction (p = 0.004) in SSIs was seen
with the hybrid solution (9.5%) when compared with povidone–iodine
Preoperative nursing home patients (16.1%) (Darouiche et al. 2010). It is unclear whether the addition of
Nursing homes are a concentrated collection of chronically ill patients isopropyl alcohol to the chlorhexidine solution is better than either
who have high rates of clinical infections and antibiotic utilization. chlorhexidine or isopropyl alcohol alone. The addition of isopropyl
 Prevention of SSI 55

alcohol may have similar effects to povidone–iodine. Future studies perspiration and a “green house” effect beneath the synthetic drape.
to examine the choice of topical antiseptics will be required to answer The antiseptic-coated drapes need objective study.
these questions. As skin colonization is only one variable to account for An alternative to the adhesive drape is the wound sealant (Towfigh
SSIs, such studies will likely require rigorous control, standardization et al. 2008). This cyanoacrylate preparation is applied over the
of case selection (e.g., only clean operations), and large numbers of proposed surgical site after scrubbing and antiseptic application. The
cases. sealant is permitted to dry and then the operation commences. This
process seals residual bacteria in the skin. Unlike the adhesive drapes
Air-handling systems discussed above, the sealant does not have microbial proliferation
Air-borne bacteria exist in the operating room. Although air-borne under the cyanoacrylate. Actual microbial counts within the wound
bacteria have been a concern for causing SSIs, there are no solid have been reduced with use of the sealant, but actual reductions in
scientific data to demonstrate whether significant contamination of SSIs remains to be documented. Importantly, adhesive drapes and
the surgical site occurs from this source. Air-handling systems are used sealants have value only for those procedures where the skin is the
in all hospitals and guidelines require that the operating room air must major source of surgical site contamination.
be exchanged and filtered at specified intervals of time.
The ultraviolet (UV) light clinical trial of the 1960s provided insight Technical considerations
into the role of air-borne contaminants and SSIs (Ad Hoc Committee As identified above, adjuvant factors at the surgical site increase SSIs.
of the Committee on Trauma 1964). UV light was demonstrated to Control of many of these adjuvant factors is by the surgeon. Effective
reduce bacterial fall out in the operating room but did not impact hemostasis, parsimony in the use of suture materials in the wound, and
on SSI rates except for refined-clean surgical procedures. This study the avoidance of excessive use of the electrocautery are all important
concluded that conventional air-handling systems were sufficient to considerations. Avoidance of excessive local tissue trauma to the
control air-borne bacteria. wound edges can also be of value. Adherence to accepted principles
Nevertheless, concern remains in those clean operations of technique in the operating room can be easily forgotten, with dire
where infection is infrequent but the consequences are especially consequences for the patient.
catastrophic (e.g., total joint replacement). Charnley (1972) Topical antibiotics at the surgical site have been an attractive
popularized laminar-flow air management for the operating room and method to potentially reduce SSIs (Lord et al. 1983). Experimental
provided personal experience of its efficacy. However, clinical trials methods in the laboratory have demonstrated benefits of topical
have not demonstrated benefit. Although some continue to advocate antibiotics, but clinical trials demonstrating superiority to the use
and use laminar flow, the expense and lack of documented efficacy of systemic antibiotics have not been identified. Recently Alexander
have limited general use. et al. (2009) have reported effectiveness of a topical application of
antibiotic solution into the surgical wound of patients undergoing
Operating room traffic bariatric surgery. The antibiotic solution is introduced via a closed
Personnel movements in and out of the operating room are an suction catheter system at the completion of the procedures, retained
expected event during procedures. Circulating nurses, technicians, within the surgical wound for 2 h, and then completely evacuated.
anesthesiology personnel, and surgical spectators are anticipated in Compared with historical controls, the improvement in SSI rates has
most cases. Bacterial “fall out” can be documented by placing culture been dramatic. This or similar methods deserve additional clinical
plates about the operating room, and seeing the increased number evaluation.
of bacteria that are recovered as a function of people entering and
leaving the operating theater (Adams and Fry 1984). Contaminants Drains
may be on the footwear and clothing of those entering, and air currents No one area of surgical practice defies any meaningful analytical
are created which render floor contaminants “air borne.” Restricting evaluation such as the use of drains in the surgical incision at
operating room traffic has not been scientifically proven to reduce the end of the procedure. There are passive drains, sump drains,
SSIs, and selected movements into and about the operating room and closed suction drains. The patient populations who have
environment are necessary. In clean operations, a low-cost method of received drains have been heterogeneous and are usually selected
reducing air-borne contamination is to restrict unnecessary operating based on the biases of the operating surgeon. Drains that exit the
room traffic. wound through the incision itself are likely to increase SSI rates
(Cruse and Foord 1980). Closed suction drains exiting via a separate
Adhesive drapes/wound sealants stab wound have the intellectual appeal of removing the residual
Even with vigorous scrubbing of the surgical site and use of topical bloody drainage that collects in the dependent portion of the wound,
antiseptics, residual bacteria remain within the hair follicles and pores especially in obese patients. The use of drainage systems at the
of the skin. Furthermore, the number of bacteria on the skin surface surgical site requires more scientific rigor before recommendations
will increase as lengthy procedures unfold. As it is impractical to re- in practice can be made.
scrub and re-apply antiseptics at intervals during lengthy procedures,
alternative methods have been explored to partition the residual Delayed primary closure
colonization of the skin from accessing the open wound. In selected operations, the surgeon is confronted with severe
Adhesive drapes placed over the surgical site have been used for contamination or pyogenic infection during the procedure. These
>40 years. More recent modifications of the adhesive drape have circumstances have the clinical appearance of virtual certainty that
antiseptics (e.g., povidone–iodine) on the cutaneous surface. Two infection will occur at the surgical site because of the magnitude of
studies have demonstrated that the traditional adhesive drape actually the contamination. Delayed primary closure is a potentially useful
increases SSIs (Paskin and Lerner 1969, Cruse and Foord 1980). method to avoid invasive infection of the surgical site (Bernard and
Increased SSIs are likely due to increased microbial proliferation from Cole 1963).
56 SURGICAL SITE INFECTIONS

■■Preventive antibiotics infections are frequent (e.g., colon surgery) or when the consequences
of infection are particularly severe such as total joint replacement, heart
The introduction of antibiotics into the clinical practice of medicine valve replacement, and peripheral vascular procedures. In terms of the
and surgery brought the expectation that antibiotics for prevention inoculum and the probability of infection, preventive antibiotics shift
would reduce SSIs. Expectations lapsed into disillusionment as early the relationship to the right in Figure 4.2 from A0 to A1 for conventional
clinical trials of preventive antibiotics failed for several reasons. First, pathogens, and B0 to B1 for pathogens of increased virulence.
surgical cases were poorly stratified. Clean and clean-contaminated
cases were indiscriminately mixed and no limits were placed on the risk Principle 1: The antibiotic must be in the
profile of patients entered into the clinical trials, e.g., inguinal hernia tissues of the surgical site at the time of
repairs were randomized with colon resections. Second, the timing
of antibiotic administration was not standardized. The drugs were contamination
generally given after the operation and for a sustained period of time into This is a foundation principle that has been repeatedly confirmed.
the postoperative period. By the end of the 1950s, preventive antibiotics The antibiotic needs to be at appropriate concentrations throughout
were viewed as not having any clinical value for surgical patients. the duration of the whole procedure. If the antibiotic has a short
The reason for the failure of preventive antibiotics in these early half-life (t½) and is administered too early before the incision is
trials was elucidated by experimental studies of cutaneous infection. made, the patient may have insufficient antibiotic through the entire
Miles et al. (1957) demonstrated that the antibiotic needed to be in procedure. Short t½ antibiotics, such as cephalothin (t½= 30  min),
the tissue at the time of microbial contamination if effectiveness was are rapidly eliminated and have been shown not to prevent SSIs in
to be seen. Burke (1961) similarly demonstrated the importance of longer procedures such as colon resection (Burdon et al. 1977). Early
pre-incisional administration of the antibiotic in a surgically relevant administration before the incision may result in a reduced period
animal model to achieve drug presence at the time of the surgical of antibacterial coverage for the surgical site (Shapiro et al. 1982).
incision. From these experimental models it was demonstrated that Hence, it has been recommended that the preventive antibiotic be
the antibiotic had to be in the incised tissue before contamination, it administered within 60  min of the surgical incision (Bratzler et al.
needed to have activity against the likely pathogens to be encountered, 2005). Of course, if a long t½ antibiotic is used then administration 2
and systemic antibiotics given after contamination had little or no h preoperatively will be less of a liability than a short t½ drug would
impact on the natural history of infection. be. The appropriate preventive antibiotic choices based on the
Clinical trials then followed that documented the principles recommendations of Bratzler et al. (2005) are identified in Table 4.3.
that were defined in the experimental studies. Bernard and Cole The duration of the operation is also a variable in maintaining
(1964) used benzylpenicillin, meticillin, and chloramphenicol in adequate antibiotic in the tissues of the surgical site. Antibiotic is
three intravenous doses, given preoperatively, intraoperatively, and being eliminated during the course of the operation and procedures
postoperatively in abdominal surgery patients. Two-thirds of the longer than 4 h will exceed 1–2 h t½ antibiotic concentrations at the
patients were gastric and pancreaticobiliary operations and a third surgical wound. Although not well studied, it is advisable to redose
were intestinal operations. Patients receiving the antibiotics had the preventive antibiotic at an interval of about 2 t½ (Fry and Pitcher
an 8% infection rate at the surgical site whereas placebo managed 1990). Thus, cefazolin with a t½ of 1.8 h should be re-dosed at about
controls had a 27% SSI rate. Polk and Lopez-Mayor (1969) used 3.5 h after the time of the initial dose. Better studies are needed for
cephaloridine (intramuscularly) preoperatively with two postoperative the issue of re-dosing preventive antibiotics during the procedure.
doses compared with placebos in only gastrointestinal resection, of The body mass of the patient is another important consideration
which 50% were colon operations. Placebo patients had a 29% SSI rate, in maintaining adequate antibiotic concentration at the surgical site.
whereas patients receiving antibiotics had only 6% SSIs. Almost all studies have used a single dose for all adult patients with
The principles proposed in the early studies were further validated little or no consideration for the patient’s size. Patients with a body
by Stone et al. (1976) in two separate studies. In a four-arm clinical trial, mass index (BMI) ≥30 kg/m2 will have larger volumes of distribution
multiple preoperative doses of the preventive antibiotic (cefazolin) than smaller patients, and this will likely influence the concentration
yielded the same result as a single preoperative dose in patients of drug at the surgical site (Pevzner et al. 2011). Large BMI patients
undergoing gastric, biliary and colon surgery. Antibiotics not started should receive larger preoperative antibiotic doses.
until after the operation had the same infection rate as those receiving Multiple trauma patients requiring emergency surgical intervention
only the placebo. Furthermore, in a subsequent study with a different with blood loss and an expanded volume of distribution will likely have
antibiotic (cefamandole), the same types of surgical patients as in the increased requirements for antibiotic dosing to maintain appropriate
previous study received only the perioperative three doses, but were tissue concentrations during operations (Reed et al. 1992).
compared with patients who received an additional 5 postoperative
days of the antibiotic (Stone et al. 1979). No improvement in SSI rates Principle 2: The antibiotic must have
was seen by extending the preventive antibiotic duration into the antimicrobial activity against the
postoperative period.
Gastrointestinal, biliary, and colonic procedures were the focus pathogens likely to be encountered
of the above-cited early studies because SSI rates were highest in Different operations are at risk for infections from different bacteria
these cases. Subsequent studies followed in hysterectomy, trauma, encountered at surgery. Skin incisions by definition mean that the skin
peripheral vascular surgery, orthopedic surgery, and even hernia microflora of Staphylococcus aureus and Staphylococcus epidermidis
and breast surgery. Some procedures such as coronary artery bypass are likely pathogens. For clean operations, the skin colonists are
grafting have limited placebo-controlled evidence to validate the use the major bacterial risk; nafcillin or cefazolin is the logical choice
of preventive antibiotics, but the principles appear to apply across all for preventive antibiotics. Biliary tract operations will most likely
patients and all surgical procedures. The general philosophy has been encounter Escherichia coli or Klebsiella pneumoniae, and these
that preventive antibiotics should be used in surgical procedures where pathogens make cefazolin or a synthetic penicillin/β-lactamase
 Prevention of SSI 57

inhibitor combination a good choice. Female genital tract operations infections, (2) the patient has documented colonization with MRSA,
require coverage for enteric Gram-negative bacteria and obligate (3) the patient has had treatment with a β-lactam antibiotic in the
anaerobes. The human colon harbors E. coli and Bacteroides fragilis period of timing leading up to the procedure and colonization with
as target organisms for coverage. The microbiology of SSIs reflects the MRSA is presumed, or (4) the patient has had a significant exposure
colonization of the transgressed anatomic structures and the selected to the healthcare environment before the procedure (hospitalization
antibiotic must target those potential pathogens. or nursing home). This potentially leaves the patient vulnerable
Patients exposed to the healthcare environment before elective to infection from MSSA. Some are recommending that additional
operations can be expected to have colonization with resistant antibiotics (e.g., cefazolin) for coverage of MSSA be used with
microbes not ordinarily seen. Prior antibiotics will increase the vancomycin in the clinical settings identified above. There are no
presence of S. epidermidis on the skin and will replace ordinary species clinical trials to validate the addition of MSSA coverage to vancomycin.
with resistant Gram-negative rods on mucous membrane surfaces. The
selection of a preventive antibiotic regimen must be expanded into the Principle 3: Continued antibiotic
Gram-negative range for patients from nursing homes or those with administration after wound closure has
prolonged preoperative hospitalization. Without surveillance cultures
of the patient from the nursing home environment, the selection of no impact on the frequency of SSIs
an antibiotic(s) can be very difficult to predict. It has been counterintuitive for surgeons to accept that antibiotics
The emergence of the community-associated MRSA (CA-MRSA) given after wound closure do not reduce infection rates. Yet all
has also changed the selection of suitable antibiotics for prevention, the clinical studies have failed to demonstrate any benefit from
especially in clean operations. MRSA has traditionally been of extending the duration of drug administration. In general surgery,
concern in SSIs only when patients have recently or currently been McDonald et al. (1998) have demonstrated no reduction in SSI rates
hospitalized. However, the CA-MRSA is currently responsible for most by extending postoperative antibiotics beyond the time of surgery
S. aureus infections that occur in the community, and the frequency in an extensive meta-analysis of 25 clinical trials. Song and Glenny
of colonization with this organism creates concern about whether (1998) have confirmed the same observation in an extensive review
conventional preventive antibiotics (e.g., cefazolin, nafcillin) are of elective colon surgery. Similar studies have been done in total joint
adequate. replacement, cardiac surgery, hysterectomy, trauma laparotomy, and
Finkelstein et al. (2002) examined vancomycin versus cefazolin open fractures with no benefit demonstrated from extension of the
for the prevention of SSIs in cardiac surgical patients in an institution postoperative antibiotics.
that was deemed to have high rates of MRSA infections (3% of The lack of benefit of postoperative preventive antibiotics is
cardiac admissions). In a randomized trial of 885 patients, 9.2% of all illustrated in Figure 4.3. First, during the operation the human
patients had SSI. Patients that received vancomycin had higher rates inflammatory cascade is activated within the surgical site, which
of meticillin-sensitive S. aureus (MSSA), whereas patients receiving includes the coagulation cascade and the formation of tissue edema.
cefazolin had higher rates of MRSA infection. Comparison of the The acute endproduct of the inflammatory response is the formation
overall SSI rate was no different between the two study groups. The of fibrin over the wound surface. Fibrin deposition begins at the start
results indicate that patients in high MRSA infection environments of the operation and continues throughout. As bacteria contaminate
are colonized with both sensitive and resistant strains of S. aureus, the surgical site from all potential sources, these microbes are encased
and that infection in the vulnerable host occurred with the pathogen within the dynamically forming fibrin matrix. A critical consideration
not covered by the preventive antibiotic used. It also appears that in antibiotic effectiveness is that the antibiotic be present and is
vancomycin is less effective against MSSA than cefazolin, which entrapped within the matrix as the fibrin is formed. The density of the
poses a real problem in the use of vancomycin for the prevention mature fibrin matrix is poorly penetrated if at all by antibiotics given
of clean wound infections. Unfortunately, vancomycin is currently after it has formed. Subsequently administered drugs will not access
the only drug with evidence for prevention of MRSA infections after the bacterial contaminants within. Then as the wound surfaces are
clean operations. closed, the potential interface between the apposed wound surfaces
Thus, coverage of MRSA in major elective clean operations appears is promptly filled with fibrin. This fibrin serves as the scaffolding for
to be warranted when (1) the hospital has a high prevalence of MRSA the subsequent deposition of collagen as part of wound healing.

Table 4.3 The recommended prophylactic antibiotic regimens by the Surgical Care Improvement Project.
Procedure Approved antibiotics Approved for β-lactam allergic patients
Coronary artery bypass graft, Cefazolin, cefuroxime, or vancomycin Vancomycin or clindamycin
other cardiac surgery, or
peripheral vascular surgery
Hysterectomy Cefotetan, or cefazolin, or cefoxitin, or cefuroxime, or ampicillin/sulbactam Clindamycin or metronidazole
Hip or knee arthroplasty Cefazolin, or Cefuroxime, or Vancomycin Vancomycin, or Clindamycin
Colon resection Cefotetan, cefoxitin, ampicillin/sulbactam, or ertapenem Clindamycin with aminoglycoside
Drug Combinations Clindamycin with quinolone
Cefazolin or cefuroxime with metronidazole Aminoglycoside with metronidazole
Clindamycin with aminoglycoside Quinolone with metronidazole
Clindamycin with quinolone
Clindamycin with aztreonam
Aminoglycoside with metronidazole
Quinolone with metronidazole
58 SURGICAL SITE INFECTIONS

Unfortunately, microbes wedged into this wound matrix will not make since the 1930s, there has always been the intuitive idea that purging
contact with systemic antibiotics given after closure, and systemic the colon of stool should prevent infection after colon resection.
antibiotics administered after wound closure do not make contact Studies from the 1930s demonstrated no reduction in SSIs with
with the potential microbial pathogens within the surgical site. mechanical preparation alone.
A second consideration in the failure of postoperatively When antibiotics emerged as potential therapy for patients in the
administered antibiotics is that edema continues in the tissues after late 1930s, there was considerable interest in using oral antibiotics to
wound closure. Edema can be viewed as an obligatory response of the reduce infection after colon surgery. This concept was to give poorly
host to provide aqueous conduits for leukocytes to navigate through absorbed oral antibiotics after a complete MBP of the colon in the
the dense extracellular tissues and access would-be pathogens. preoperative period to reduce the microbial contamination of the
Millions of years of evolution did not anticipate that surgeons would surgical site. The major impetus for adding oral antibiotics to the MBP
be closing wounds, and accordingly the continued formation of edema was because mechanical preparation alone has been recognized since
after wound closure creates increased hydrostatic pressure about the the 1930s not to reduce SSI rates after colon surgery.
wound. Thus, not only is the fibrin matrix of the wound interface poorly The early efforts to use oral antibiotics failed to demonstrate
penetrated by antibiotics, but also the wound itself is functionally efficacy of this method. Numerous sulfanilamide derivatives and
ischemic from increased hydrostatic pressure about its perimeter. oral aminoglycosides were initially used, but none demonstrated
Simply stated, postoperatively administered antibiotics do not access in prospective trials a reduction in SSIs through three decades of
the microbial contaminants of the surgical site! clinical research. During this entire period of time, improved MBP
A common justification for the continuation of postoperative was explored because complete colonic evacuation was considered
antibiotics is coverage of various tubes and interventions that are essential for the reduction of stool bulk, but also to facilitate antibiotic
used in patient care. Wound drains, chest tubes, mediastinal tubes, delivery to the mucosal surface of the colon.
intravenous catheters, Foley catheters, endotracheal tubes, and others Finally, in 1974 a randomized clinical trial demonstrated
are recognized as potential avenues for microbial entrance into the significance in the use of the oral antibiotic bowel preparation
host. Some surgeons insist on the continuation of systemic antibiotics (Washington et al. 1974). Patients were randomized to three groups
to “cover” these alternative routes for microbial contamination despite after complete MBP. One group received oral neomycin alone, a
no evidence to support this use. second group received oral neomycin plus tetracycline, and a third
Continuing antibiotics to cover drains and tubes ignores the group received only oral placebo. No patients received systemic
concept of the “decisive period” as proposed by Miles et al. (1957). antibiotics. The combination of oral neomycin and tetracycline
Antibiotics can provide prevention only if the period of bacterial reduced SSI rates by nearly 90%. Neomycin alone resulted in no
contamination at a site is temporally limited, e.g., the duration of a reduction in SSI rates. The rationale of the antibiotic combination
surgical procedures. During this decisive period, the colonization of was that the neomycin covered the aerobic gut bacteria, whereas
the host is stable and the pathogens have a stable and predictable tetracycline covered the anaerobic species.
sensitivity to the antibiotics that are employed. However, if systemic A subsequent study evaluated the use of neomycin and
antibiotics are administered across multiple generation times of the erythromycin versus a placebo in elective colon surgery within
bacteria, then the character of the colonization of the patient changes. Veterans Administration hospitals (Clarke et al. 1977). Erythromycin
Sensitive bacteria are eliminated and the proliferation of resistant was chosen because of superior anaerobic coverage compared
species remaining, from either the original colonization of the patient with tetracycline which was used previously. All patients received a
or species acquired from the hospital environment, results in resistant complete 3-day MBP before the oral antibiotics were started. SSI rates
bacteria. The charade of using prolonged preventive antibiotics is were 35% in placebo patients but only 9% in those patients receiving
not only ineffectiveness in the prevention of infection, but also the the oral antibiotics.
substitution of resistant colonization for subsequent pathogens. Thus, during the 1970s the concept of preventive systemic antibiotics
The negative consequences for the patient of extending preventive and the oral antibiotic bowel preparation evolved independently as
antibiotics into the postoperative period are real. Needless antibiotics strategies to reduce SSI rates after elective colon surgery. Conceptually,
are expensive to purchase and expensive to deliver. As noted above, systemic preventive antibiotics provided a “safety net” to control
multiple days of postoperative systemic antibiotics change the patient’s bacterial contaminants within the surgical wound, whereas the oral
colonization to resistant forms and also create epidemiological antibiotic bowel preparation reduced the number of contaminants
resistance in the hospital environment. Finally, excess preventive that escaped from the colon and into the surgical site.
antibiotics result in increased drug complications, especially with As the two preventive strategies had different mechanisms of
the epidemic increase in Clostridium difficile infections (see Chapter prevention, several studies examined the utility of both methods
11). Prolongation of systemic antibiotics after wound closure cannot together. In 2002 (Lewis 2002), a definitive study had patients who
be justified. were randomized to receive the oral antibiotic bowel preparation
of oral neomycin and metronidazole versus MBP alone, with the
■■Preoperative colon preparation patients in both arms of the clinical trial receiving the systemic
antibiotics amikacin and metronidazole preoperatively. The results
The colon is the largest repository of bacteria in the human body. demonstrated that patients receiving only the systemic antibiotics
Elective colon surgery is associated with higher infection rates than (and MBP) had an SSI rate of 16%, whereas patients receiving both
elective procedures at any other anatomic site. In a review, Poth (1982) systemic antibiotics and the oral antibiotic bowel preparation had an
identified that before the use of contemporary preventive measures, SSI rate of 7%. Furthermore, a meta-analysis of 13 individual studies
an SSI rate of >80% and a perioperative mortality rate >10% were seen demonstrated a significant reduction of SSI rates (p <0.0001) in favor
in elective colon surgery in the 1930s. of oral antibiotics and systemic antibiotics together versus systemic
Early surgical efforts to reduce SSIs in colon surgery included the antibiotics alone. Similarly, separate studies have demonstrated that
use of the mechanical bowel preparation (MBP). Although the full the combination of oral and systemic antibiotics is superior to just
magnitude of the microbial density has not been fully appreciated oral antibiotics (Englesby et al. 2010).
 Prevention of SSI 59

The evidence indicates that the oral antibiotic bowel preparation before the operation. Oral antibiotics must not be given until the MBP
with MBP is a significant method to reduce SSIs, in addition to the use is complete or undissolved drug will pass through the colon with no
of systemic preventive antibiotics. However, this method continues to antimicrobial effect. Oral antibiotics given too close to the time of
have many unanswered questions that need to be addressed. the operation (e.g., <8 h before the incision) will not have had ample
time to reach the entire length of the colon and not had sufficient
What is the optimal MBP? time to reduce microbial concentrations on the mucosal surface. In
Very different mechanical preparations have been used individually the original study by Washington et al. (1974), the antibiotics were
and in concert to clear the colon of all fecal content. Clear liquid diets given >48 h before the incision and it should be noted that the SSI
(commonly for many days preoperatively), castor oil, magnesium salts, rates in the antibiotic arm of the trial were quite low (5%). Studies
sodium phosphate, and other oral cathartics or purgatives have been in the early years of investigating oral antibiotics started the drugs
used. Sequential enemas with multiple agents have also been used for 2 days before the operation, based on experimental observations
usually together with various oral cathartics. The ongoing issues have of the duration necessary to achieve optimum antimicrobial effect.
been the duration necessary to cleanse the colon preoperatively, the Thus, additional investigation is necessary to define the timing and
thoroughness of the result, and the necessity for significant patient duration of oral antibiotic administration. The timing and duration will
discomfort to achieve effective MBP. also need to be determined by the specific antibiotic strategy that is
In recent years the use of polyethylene glycol solutions has been employed because the total administration may need to be adjusted
popular for MBP. The polyethylene glycol solution can give a rapid for the specific drug that is used.
and complete cleansing of the colon, but requires patient compliance
and perseverance in the ingestion of 4 l of solution over a 4- to 6-h Is C. difficile infection increased with the
period of time. Poor compliance and suboptimal colon preparation oral antibiotic bowel preparation?
are issues, especially among elderly patients undergoing preparation
as an outpatient. Thus, dissatisfaction with available MBP regimens The emergence of C. difficile infection (CDI) as a complication of
means that improved alternatives need to be developed. inpatient care is associated with the administration of systemic
Although MBP itself has not been shown to reduce SSIs, a further antibiotics. This is thought to be in large part the disruption of the
consideration is whether the composition of the MBP may actually have normal microflora of the colon (see Chapter 11). One retrospective
an influence. Itani et al. (2007) have shown an apparent reduction of study has demonstrated an increased rate of CDI with the oral
SSIs when sodium phosphate MBP was compared with polyethylene antibiotic bowel preparation (Wren et al. 2005), whereas another
glycol. Experimental research studies by Long et al. (2008) have did not (Krapohl et al. 2011). Additional studies need to examine
demonstrated that maintenance of normal phosphate concentrations the frequency of CDI after the oral antibiotic bowel preparation, and
modulate the virulence of Gram-negative bacteria. Hypophosphatemia particularly focus on its association with the specific antibiotics used.
enhances Gram-negative bacterial virulence. Mobilization of Prolongation of systemic preventive antibiotics into the postoperative
phosphate from the mucosal surface of the colon to the extracellular period becomes especially problematic when the oral antibiotic bowel
reservoir may be an important consequence of the physiological stress preparation has been used because this will impact the recolonization
response. Although not conclusively proven, phosphate-containing process postoperatively. The use of postoperative probiotics or
MBP may be an important addition to the oral antibiotic preparation prebiotics needs to be evaluated in the postoperative colon resection
and needs further clinical evaluation. The concept that electrolyte patient who has received both the oral antibiotic bowel preparation
and macromolecules that are not antibiotics could have attenuation and systemic antibiotics for prevention.
effects on microbial virulence opens an entirely new direction in MBP.

What is the best oral antibiotic choice? ■■Physiologic/Metabolic methods

The basic premise of the oral antibiotic bowel preparation is that the Supplemental oxygen
drug(s) have activity against the target pathogens of the colon, and that A substantial volume of experimental studies has demonstrated
they be poorly absorbed or not at all to achieve intraluminal effects. the benefits of increased oxygen availability in the prevention of
Neomycin has been commonly used but is suspect as to the extent infection after soft-tissue contamination with bacteria. Molecular
of its antimicrobial activity because of the anaerobic intraluminal oxygen availability is a critical variable in the intracellular killing
environment of the colon, and the requirement for aminoglycoside function of phagocytic cells and enhanced synthesis of reactive oxygen
antibiotics to have oxygen availability for biological activity. intermediates, and may be beneficial for other cellular pathways (e.g.,
Erythromycin does have very good anaerobic activity and significant chemotaxis efficiency).
aerobic Gram-negative activity as well. It does have some systemic Greif et al. (2000) demonstrated a 50% reduction in SSI rates when
absorption, and is also associated with gastrointestinal motility supplemental oxygen was administered during and immediately
disorders. Tetracycline has less anaerobic activity than erythromycin after elective colon surgery. The supplemented patients received 80%
and is also absorbed to a greater degree. Metronidazole has superb inhaled oxygen and had documented partial O2 pressure (PO2) of
anaerobic activity but is also absorbed. As vast numbers of antibiotics 40 kPa (>300 mmHg) during and after the operation. Control patients
have been evaluated for parenteral use, it is likely that minimally had 30% inhaled oxygen and normal intraoperative PO2 values.
absorbed oral alternatives can be identified. Importantly, supplemented patients received a vastly larger amount
of crystalloid solution (7 l versus 2 l) to expand the extracellular water
What is the best timing for volume to facilitate oxygen delivery.
oral antibiotic administration? Pryor et al. (2004) reported a randomized clinical trial with
supplemental oxygen in general surgery laparotomy patients,
Current evidence indicates that the oral antibiotics should be which had exactly the opposite effect. Supplemented patients had
administered in three divided doses over the 10- to 20-h time span a statistically significant increase in SSIs. Supplemented patients
60 SURGICAL SITE INFECTIONS

received 80% inhaled oxygen during the procedure whereas control remain to be defined. Can other types of operations benefit from
participants received 35%. No supplemental perioperative crystalloid glycemic control? Finally, an important feature of glycemic control is
solutions were used. A third trial by Belda et al. (2005), with many having real-time methods to measure blood glucose rather than the
of the same investigators from the Greif study and using the same episodic measurement and insulin response method that currently
protocol, again demonstrated a 40% reduction in SSIs in general characterizes management. Safe blood glucose management <200 mg%
surgery patients. is problematic at present, and future applications of lower thresholds
Thus, there are conflicting clinical data about supplemental will require better quantitative methods for glucose monitoring.
oxygen and many questions remain. How could increased oxygen be
deleterious in the short term? What is the percentage of inhaled oxygen
necessary to achieve a beneficial effect? What should be the time span
■■Postoperative prevention
for oxygen delivery. Should it be only during the procedure, or should Prevention, before and during the surgical procedure, has been
it be extended after the operation? Oxygen supplementation remains documented as of value in the prevention of SSIs. However, there
of uncertain value until additional clinical trials have been completed. is little that can be identified to change the outcome of the surgical
site after the operation. Once closure of the surgical site has been
Normothermia completed, a fibrin matrix seals the wound space very promptly
Maintenance of core body temperature has been a desired goal (Figure 4.3). Wound dressings offer limited if any protection. Topical
in surgical patients. Intraoperative hypothermia is a commonly salves and antibiotic creams influence colonization only around the
recognized event from conduction heat loss during open thoracotomy skin of wound closure, not where infection will occur. Continuation
and laparotomy procedures. The major concern has traditionally of postoperative systemic antibiotics is certainly not of any value!
focused on the association of coagulopathy with the decline in core Optimization of the physiology of the patient may offer an
body temperature. The threshold for intraoperative hypothermia has opportunity for postoperative prevention. Oxygen supplementation,
been poorly defined, but it has generally not been a source of concern core body temperature control, and glycemic control extended into
in elective operations until the core temperature declines <35°C. the postoperative period may offer benefit. There is a lack of current
Kurz et al. (1996) reported on the effects of a reduced core body evidence. Restoration of homeostasis in the surgical patient is likely to
temperature in patients undergoing elective colon surgery. The have some benefit and not have downside risks. Future investigations
intervention group of patients had core temperatures ≥36.5°C whereas need to explore the postoperative benefits of physiological control
control patients had no body temperature intervention until the and SSI rates.
temperature reached ≤34.5°C. The final difference between groups was
1.8°C. Maintenance of core body temperature ≥36.5°C resulted in a 70%
reduction in SSIs. Of interest, patients with the higher core temperature
■■MANAGEMENT OF SSIs
nearly had a lower probability of receiving a transfusion (p = 0.054). Despite application of preventive measures, SSIs still occur. Each
It is likely that maintenance of physiological core body temperature infection will have unique characteristics with respect to the patient
is of value to the patient undergoing surgical intervention, although and the bacteriology of the infection. Therapy of an SSI must be
this solitary study has not confirmed this conclusion. Experimental individualized to the specifics of each event. The foundation principles
evidence would identify global effects of hypothermia on leukocyte for management of these infections include drainage and debridement
migration and other biochemical processes of the innate host response. of the focus of infection, removal of foreign bodies, antibiotic
Additional studies in other surgical procedures are necessary. management if needed, and local wound care.

Glycemic control Drain and debride the Infection

Decades of diabetes research have led to the conclusion that The staples or sutures of the infected area of the wound are removed.
hyperglycemia is associated with increased infections. Hyperglycemia Visible pus is evacuated. Pus that extends the length of the incision,
appears to have a host of different effects on the innate host defense or the presence of erythema and induration across most of the wound
mechanisms and correcting the hyperglycemic state restores the length, requires complete opening. If sinus tracts are present, additional
normal host response. This negative effect on leukocytes and opening of the tissues will be required. Initial assessment dictates
potentially other components does not appear to be specific to the
patient with diabetes but applies to hyperglycemia secondary to any
clinical cause in patient care.
The benefits of glycemic control in the prevention of infection
in surgical patients have been demonstrated in open-heart cardiac
surgical patients (Furnary et al. 1999). These authors demonstrated
that maintenance of blood sugar during and after operation <200 mg%
resulted in a statistically lower rate of sternal infections. This benefit
was true for patients who were either diabetic or non-diabetic. Latham
et al. (2001) confirmed an increasing odds ratio of SSIs in cardiac
surgical patients because the blood sugar increased above the 200 mg%
threshold.
Multiple issues now confront the desirability and benefit of glucose
control for the prevention of SSIs and other surgical infections. The
Figure 4.3  The fibrin layer on the wound interface and the presence of
Furnary study has demonstrated benefits by keeping the blood glucose the fibrin matrix in the closed wound. Note the “halo” of edema about the
below the 200  mg% threshold. Whether additional improvements closed wound and the potential consequences of increased tissue hydrostatic
in SSI rates can be achieved with lower thresholds of blood glucose pressure and ischemia of the interface.
 References 61

the need for local or even general anesthesia to achieve complete Evidence of severe inflammation, tissue necrosis, presence of
drainage. All necrotic tissue and fibrinous debris should be removed, prosthetic materials, and immunosuppression of the host justifies
often by sharp dissection. Dark eschar and cutaneous necrosis must systemic antibiotics. Empirical choices of antibiotics are based on
be removed. The wound will require careful daily inspection after suspected pathogens, and therapy is de-escalated as culture results
the initial drainage because specific pathogens and specific patient are available or clinical resolution of the infection is observed.
comorbidities may make additional drainage necessary. MSSA infections are best covered with nafcillin or a first-generation
Cultures of pus and infected tissue are necessary. Although cephalosporin (e.g., cefazolin). CA-MRSA may be treated with
drainage without cultures was reasonable for those localized trimethoprim–sulfamethoxazole in most cases, and hospital-
staphylococcal infections in the past, the era of CA-MRSA makes acquired MRSA will require vancomycin, linezolid, or daptomycin.
cultures a requirement to guide antibiotic therapy. Polymicrobial infections will require Gram-negative coverage and
suspected infections after colonic contamination may benefit from
Removal of foreign bodies metronidazole for anaerobic coverage. In general, the effectively
Suture materials in the wound are generally removed, except for those drained and debrided wound may require only a short course (e.g.,
at the fascial level. If necrotic fascia is present, then the associated 48 h) of antibiotic coverage, although MRSA infections in particular
sutures will need removal. Infected mesh is debrided and removed may require longer duration.
with only that mesh that is firmly incorporated into adjacent tissues
preserved. The removal of orthopedic hardware or vascular grafts is Wound management
usually required in most of these infections, and efforts to salvage The infected wound that has been opened requires daily, bedside
these prostheses require clinical judgment by the treating surgeon. debridement. Loosely packed, coarse gauze that is moist with saline
is preferred, with the frequency of dressing changes as necessary (at
Antimicrobial management least daily). Dressings should not be permitted to completely dry
Antimicrobial treatment of the open, infected wound may be required. because this creates neoeschar in desiccated tissues and fosters the
It must be emphasized that drainage and debridement of most SSIs will continuation of local infection. Wounds should not be packed tightly,
be sufficient. Topical agents are commonly employed but have not been lest this functionally converts an open wound to a closed one.
well studied for efficacy (Drosou et al. 2003). Topical povidone–iodine, Negative pressure-assisted closure devices are often deployed
Dakin solution, and others have been employed. Topical antiseptics in in the large open wound. These have generally been useful for
open wounds may be toxic to the host tissues and to phagocytic cells secondary closure and preparing large surfaces for skin grafting. A
(Lineweaver et al. 1985). Use of topical agents commonly employed in secondary benefit has been to protect the open wound from secondary
burn wound management, such as silver sulfadiazine and mafenide, contamination in circumstances such as abdominal wall stomas. It can
may be useful in the opened wound where evidence of invasive infection be said that support for negative pressure devices is largely anecdotal
exists about the perimeter tissues. and little has been determined by clinical trials.

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 Chapter 5 Skin, skin structure, and
Skin, skin soft-tissue infections
Donald E. Fry

Skin, skin structure, and related soft-tissue infections (SSSTIs) are membrane of the epidermis, and are the cell population that
common clinical problems. SSSTIs are the most common cause for undergoes active mitosis to replace losses from skin injury and
emergency department visits by patients, and these infections are one sloughed superficial layers of the epidermis. Mature daughter cells are
of the most common causes for outpatient and inpatient antibiotic progressively displaced toward the surface and undergo progressive
administration. They are secondary to bacteria that normally colonize desiccation until they become the stratum corneum layer of the
the skin or bacteria that are carried into the underlying tissues by superficial epidermis. Effete cells are then sloughed as part of the
penetrating injury. The spectrum of infections may vary from limited dynamic replacement of skin. Beneath the basement membrane of
areas of spontaneous cellulitis to widely invasive and life-threatening the epidermis is the dermal layer of the skin, which contains the hair
necrotizing soft-tissue infection. Understanding the full scope of these follicle, cutaneous vasculature, and sensory nerves, all of which are in
infections is very important for correct diagnosis and treatment of a dense collagen matrix that gives the overall skin its tensile strength.
SSSTIs. Beneath the dermis is the subcutaneous tissue, which exists between
the inferior surface of the dermis and extends for a variable depth to
■■ANATOMY OF THE SKIN the anterior surface of the investing muscle fascia.
Skin has structures and functions other than being a barrier that serve
Human skin is a water-impervious envelope that constitutes the the host. Hair follicles arise from the dermis via specialized pores, and are
primary barrier between the host and noxious challenges from the abundant on the head or absent on volar surfaces. Small muscle fibers
environment. It consists of the epidermis, dermis, and subcutaneous are attached at the base of the follicle for piloerection. Sebaceous glands
layers (Figure 5.1). The basal cells of the skin rest on the basement communicate into the pores of the hair follicle, and provide lubrication
for the hair follicle and epidermal surface. Apocrine sweat glands share
the pore of the hair follicle. A separate pore structure exists for the
eccrine sweat glands which originate in the dermis and communicate
to the surface of the epidermis for purposes of sweat production and
thermoregulatory control for the host. The dermis also contains the
sensory nerves that recognize pain and other noxious stimuli. The rich
arteriolar, venular, and lymphatic channels in the dermis deliver nutrients
and provide exit channels for the perfusion of the total skin structures.
Skin Beneath the dermis is the subcutaneous layer which is primarily made
of adipocytes and a loose collagen structure. The subcutaneous tissue is
largely a warehouse for fat stores, but may also have a secondary role in
providing thermal insulation. A larger physiological and metabolic role
Subcutaneous of the subcutaneous adipocytes is being identified (Frayn et al. 2003).
tissue The subcutaneous fat tissues rest on the surface of the dense collagen
layer of investing fascia. Although the fascia is not part of the skin, the
Perifascial space blood and lymphatic channels that serve the skin penetrate through and
course over the surface of this investing fascia.
An important cell population that should be considered as part of
Deep soft tissue the “anatomy” of the skin is the microbial colonization (Table 5.1). The
(fascia and skin has up to 106 bacteria per gram of tissue (Greene 1996), although
muscle)
specific environmental conditions may increase or decrease microbial
colonization (Table 5.2). These microbial colonists are present on the
surface of the stratum corneum, and within the various pores and
crevices of the skin. Anaerobic colonists are present which reflects the
Organ/space low oxidation–reduction potential in selected areas of the cutaneous
histology. Indigenous bacteria are present in all humans, but the
microflora in any host will reflect those transient microbes acquired
from environmental exposure. The composition and concentration of
the colonization of the skin at the time of an injury of the epidermis are
Figure 5.1  A cross-section of the human abdominal wall with skin, clinical variables that assume major importance in whether infection
subcutaneous tissue, muscle, and abdominal contents. The perifascial or uneventful healing will be a consequence.
space is that potential space on the surface of the investing muscle that
A symbiotic relationship ordinarily exists between skin colonization
anteriorly contacts the subcutaneous fat, and posteriorly contacts the
underlying muscle. and host cells. Bacteria provide a “housekeeping” function by digesting
64 SKIN, SKIN STRUCTURE, AND SOFT-TISSUE INFECTIONS

Table 5.1 Normal skin microflora.

Normal skin microflora Commentary
Staphylococcus aureus Have demonstrated an increased tendency to be community-associated meticillin-resistant organisms. Cutaneous
colonization has been correlated with nasopharyngeal carriage
Staphylococcus epidermidis S. epidermidis is one of many coagulase-negative staphylococcal colonists of the skin, but of these it is most commonly
associated with clinical infection but also as a contaminant of blood cultures
Peptococci Includes Peptococcus anaerobius, P. saccharolyticus, P. constellatus, P. magnus. Also a colon and genitourinary colonist.
Periodically appears in polymicrobial soft tissue infections
Corynebacterium spp. C. lipohilicus and C. minutissimum are species among many of the skin. These are anaerobic Gram-positive rods. They are
common colonists of sebaceous glands and are collectively referred to as diphtheroids on cultures
Micrococci A common Gram-positive coccus of the skin that is rarely seen in clinical infection. It has the unique quality of an
extraordinarily thick cell wall that may represent half of the mass of the cell
Brevibacterium spp. Numerous species that colonize the skin and are associated with foot odor
Gram-negative rods E. coli, and Klebsiella, Enterobacter, Proteus, and even Acinetobacter spp. are colonists of the perineum and intertriginous
areas
Transient colonization Streptococci and all flora of the mouth and gastrointestinal tract can be transient colonists of the skin. Hospital
environments promote the acquisition of highly resistant hospital-based microflora on the skin of patients

Table 5.2 The numerous environmental factors that influence the qualitative and quantitative character of human skin colonization.
Environmental factor Commentary
Climate Higher environmental temperature and increased humidity of the environment together increases bacterial density. Different
geographic areas will have different qualitative and quantitative cutaneous colonization
Occlusive dressings The “green house” effect may increase bacteria counts by 104 organisms/g (Aly 1982)
Body location Intertriginous areas have higher counts. Head and neck with oral colonists; perineum with colonic colonization. Hands and feet
with transient flora. Upper arms with lowest colonization
Hospitalization Transient colonization with healthcare-associated pathogens, commonly resistant gram positive and gram negative species.
Antimicrobial Systemic antibiotics quickly eliminate colonization by sensitive species that are replaced by other resistant or transient
colonization
Medications Estrogens, corticosteroids and others affect the composition and quantity of microbial colonization
Age Infants and children carry more potentially pathogenic bacteria; adults higher Propionibacterium spp. reflecting higher skin lipid
content (Somerville 1969)
Gender Males have higher skin counts and larger numbers of species likely due to greater sweat production
Occupation Sun exposure, hospital workers, and other occupations with unique environments will influence colonization
Soap and detergent exposure Medicated soaps will reduce microbial counts as does the mechanical process of cleansing
Ultraviolet light Reduces surface colonization
Bacterial adherence Unique adherence properties of randomly encounter bacteria will affect the transient skin colonization (Nobbs et al. 2009)

unwanted surface debris and eliminating dead cells. The density responses are slow to respond. Another vulnerability is the potential
of microbial colonization is regulated by the sloughing of the space that exists between the subcutaneous fat and the surface of the
cornified layer of skin, but also by the dynamic movement of sweat muscle fascia. This potential “perifascial” space permits the rapid
and sebaceous products that prevents excessive colonization of the dissemination of bacterial infection but also exposes vascular inflow
pore structures of the skin. The sequestration of bacteria within to the overlying tissues to the potential of thrombosis and necrosis of
the pore structure of the skin, due to excessive sebaceum, external tissues dependent on these nutrient routes (see Figure 5.1).
contaminants, clusters of exfoliated cells that have not been expelled,
and epidermal/dermal edema that narrows pore diameter, creates
a situation for microbial accumulation, proliferation, and invasive
■■COMMON SKIN AND SKIN
infection. STRUCTURE INFECTIONS
Other anatomic peculiarities of the skin are important in
understanding the genesis of specific infectious events. Disruption of
the dermal vascular structures from penetrating or crush injury will
■■Cellulitis
create ischemic islands of skin tissue. Remote radiation treatment Cellulitis is the most common SSSTI. Cellulitis may occur following
impairs the efficiency of lymphatic function and will be associated superficial cuts, abrasions, and small burns. It may occur in areas of
with increased spontaneous infections due to cutaneous edema. lymphedema and of prior radiation therapy. Cellulitis may occur as
Penetrating injury into the subcutaneous fat tissues will introduce a spontaneous event without any local injury or provocation. This
bacteria into an environment of poor vascularity where inflammatory infection is known to affect the skin at any anatomic site on the body.
 Common skin and skin structure infections 65

Cellulitis affects the full thickness of the skin and extends into the sometimes difficult to discern. The extremities and the head/neck are
subcutaneous tissues the most common anatomic sites of erysipelas. Predisposing factors
The diagnosis of cellulitis is a clinical one and thus appreciation of include diabetes, alcoholism, and lymphedema secondary to venous
its clinical appearance is vitally important. Cellulitis is a superficial insufficiency or prior surgical interventions (e.g., mastectomy). This
spreading infection that is characterized by advancing erythema from infection is most often due to Strep. pyogenes but may be caused by
an epicenter of origin. The epicenter is commonly the injury site that other streptococci.
has disrupted the integrity of the epidermis, or the epicenter may be The diagnosis is made by the identification of the typical advancing
an infection originating from one of the anatomic pores of the skin. red rash with a clear line of demarcation about the perimeter. It has
The infection involves both the epidermis and the dermis, with the the typical signs of inflammation and is quite painful. A peau d’orange
attendant inflammatory response of the host causing vasodilation appearance can be seen from the skin edema. Lymphadenitis and
of the microcirculation, and the resultant characteristic blanching lymphangitis may be observed. The patients will usually demonstrate
erythema. The infection has palpable tenderness over the clearly a systemic toxemia from the infection, although blood cultures are not
defined areas of erythema, but palpable induration is usually identified dependably positive for diagnosis. In advanced cases, blistering and
only around the epicenter of the infection. The central site of injury bullae will be observed in the central areas of the infection.
or puncture may appear clinically innocent, may have a serous-to- Antibiotic therapy alone is the treatment for erysipelas. Penicillin,
purulent drainage, and local skin necrosis or sloughing may be seen. clindamycin, or even quinolones have been used for treatment. Severe
Bullae indicate an especially severe cellulitis infection or may indicate infections or those occurring with compromised hosts may require
that a deeper necrotizing infection is actually present. hospitalization and parenteral therapy.
Gram-positive organisms predominate as the pathogens of
cellulitis. Most are secondary to Streptococcus pyogenes, and a
smaller number to Staphylococcus aureus (Gunderson and Martinello
■■Pyogenic SSSTIs
2012). Only a very small percentage is due to other bacteria when Pyogenic infections of the skin and skin structures cover a broad
the infection originates from a community source. Wounds from collection of different infections. Impetigo, furuncles, and carbuncles
rural or farm environments will demonstrate Gram-negative or are the various terms employed to cover the array of differently
polymicrobial pathogens. When infections are due to staphylococci or presenting infections that have the common feature of being abscesses
Gram-negative organisms, the central infection about the injury site is involving the skin structures. They have the common denominator of
usually pyogenic with only a limited perimeter of cellulitis identified. having Staph. aureus as the most frequent pathogen.
In general, streptococci are the pathogens of the typical spreading Impetigo is the skin infection of children that arises from non-
erythematous infection of cellulitis. follicular, small abscess collections of the skin. The disease begins
The merits of cultures remain a problematic issue in the as cutaneous blisters which suppurate, drain, and form cutaneous
management of these infections. Blanching erythema with minimal crusts. The infections are commonly cause by staphylococci, but may
drainage at the injury site is most always Streptococcus pyogenes and be secondary to Strep. pyogenes. Effective treatment for many cases is
most clinicians will provide treatment in the absence of culturing to cleanse the skin and remove crusts, and then use topical antibiotics
the injury site. However, genuinely purulent drainage or evidence (e.g., bacitracin). More extensive disease is treated with systemic
of necrosis/eschar at the injury site raises the issue of community- antibiotics that cover staphylococci. CA-MRSA has been implicated
associated meticillin-resistant Staphylococcus aureus (CA-MRSA) as and may need coverage based on clinical suspicion.
the pathogen. Cultures are important in this setting and tissue biopsy The more common pyogenic infection of the skin begins in the
for culture may be required to obtain accurate identification of the hair follicle due to stasis of sebum and microbial proliferation. This is
pathogen. SSSTIs receiving antibiotic therapy that do not promptly usually Staph. aureus. These infections are commonly referred to as
respond should also have cultures of available drainage. boils or furuncles. Local inflammation and edema may result in the
The treatment of cellulitic infections is oral antibiotics. Penicillin occlusion of adjacent follicular units, and a carbuncle is the result
has maintained activity against Strep. pyogenes and is the appropriate of multiple confluent furuncles. Regardless of nomenclature, these
choice for non-allergic patients. Clindamycin is an appropriate choice cutaneous abscesses can reach several centimeters in diameter. The
for the penicillin-allergic patient. The broad sensitivity of streptococci diagnosis is purely a clinical one with a fluctuant central area, apparent
allows any number of antibiotics as choices for a successful outcome in pus beneath the intact epidermis, and a perimeter of induration and
treatment. Occasionally, a limited area of infection may be drained or erythema. Spontaneous drainage may have already begun at the time
debrided with superficial cellulitic streptococcal infections. Antibiotic of presentation.
choices for staphylococcal infections are dictated by the sensitivity Drainage of the abscess is the treatment. In most cases, this will
of the pathogen. Meticillin-sensitive Staph. aureus (MSSA) is treated be sufficient (Rajendran et al. 2007). Anti-staphylococcal antibiotic
with an oral penicillin (dicloxacillin) or cephalosporin (cephalexin). therapy is reserved for only the most severe infections when the
CA-MRSA is commonly treated with trimethoprim–sulfamethoxazole pathogen is MSSA. The prevalence of CA-MRSA now makes cultures
or clindamycin. Patients with severe CA-MRSA infections may be necessary, and antibiotic therapy is unavoidable in this circumstance.
hospitalized and require parenteral vancomycin therapy. The cutaneous lesions of CA-MRSA infection are commonly associated
with a black eschar which may have limited or no suppuration, and is
■■Erysipelas commonly reported by patients to be an insect bite. Treatment is with
trimethoprim–sulfamethoxazole or clindamycin. Severe CA-MRSA
A unique variant of a superficial spreading infection of the skin cutaneous infections may require hospitalization and vancomycin
is erysipelas. As opposed to those infections defined as cellulitis, treatment.
erysipelas is confined to the epidermis and dermis of the skin. This Other variations on this theme may be the inoculation of the skin
infection typically occurs in those aged >60 or in very young children. and adjacent soft tissues from scrapes, puncture wounds, or even
It follows a cutaneous injury that may be very minor in nature and is infected bites. Infections from wounds or self-administration of drugs
66 SKIN, SKIN STRUCTURE, AND SOFT-TISSUE INFECTIONS

are likewise seen. These pyogenic infections will have characteristics and abscess are the result. The process can be viewed as similar to that
that are shared with furunculosis but may have an extensive associated of facial acne, except that the sebaceous glands of the face do not have
degree of cellulitis, lymphadenitis, and lymphangitis. The treatment the apocrine sweat gland apparatus. Acne also has a typical pathogen
remains local drainage and antibiotic therapy for most cases. CA- of Propionibacterium acres as an inciting pathogen, which is also
MRSA infections are common in these infections and cultures are different from HS. HS seldom occurs before adolescence and occurs
necessary. Unusual clinical circumstances such as farm-associated most commonly over the ages 25–40. It is more common in women. It
soft-tissue injuries will have Gram-negative and even anaerobic has been clinically associated with obesity, tobacco use, and tropical
pathogens involved in the soft-tissue infection. Cultures are essential climates. It affects 1% of adults.
with unusual mechanisms of injury. Pathogens associated with HS have been Staph. aureus, non-
group A streptococci, and an array of Gram-negative rods. Pathogens
■■Human and animal bite infections are commonly Gram-positive skin colonists in the axilla and Gram
negatives in the groin, perianal region, and perineum. Repeated
Animal bites are common events and are a potential source of courses of antibiotics may change the identified pathogen over
infections of the extremity (Talan et al. 1999). Acute wounds are best time. Although infectious pathogens are associated with the disease,
handled by local cleansing and irrigation. Continued cleansing and many feel that the disease represents a functional impairment of the
occlusive dressings are employed to avoid secondary contamination, epithelial cells of the pilosebaceous unit which leads to the abnormal
and perhaps topical antibiotic ointment may be of value. A single sinus tracts of the illness (Kurokawa et al. 2002).
parenteral antibiotic dose at the time of presentation and injury Tissue damage and local scarring result in fibrotic occlusion to
management makes practical sense. However, sustained systemic apocrine and sebaceous glandular products, which in turn results in
antibiotics for post-injury prophylaxis have not worked in any other chronic recurrent infections and soft-tissue disfigurement. Sinus tracts
clinical setting of surgical or traumatic injury of the soft tissues and develop as alternative drainage passages for glandular secretions that
are not likely to be of any benefit in this circumstance (Medeiros and have normal egress routes obstructed. Sinus and fistula tracts develop
Saconato 2001). between adjacent glands and lead to the large fibrous abscesses that
When patients present with established infection after animal are seen in advanced disease. The spectrum of HS can be mild and
bites, the same principles of local debridement and drainage apply effectively managed medically whereas advanced diseased with
as would be uses for any other soft-tissue infection. Dog and cat matted clusters of interdigitated abscesses, sinus tracts, and chronic
bites are associated with Pasteurella spp. infection, but are identified drainage require the surgical option.
with multiple other pathogens. Staph. aureus, and Bacteroides, The diagnosis of HS is made by recognition of the typical physical
Fusobacterium, Capnocytophaga, and Porphyromonas spp. are also findings. Typically there is a delay in patient presentation so initial
recognized pathogens. Treatment for these infections should be with assessment may not reflect the duration of disease. Inflammatory
oral amoxicillin–clavulanate. Patients with β-lactam allergy may receive intradermal lesions are palpable and occur in clusters. They have
doxycycline, trimethoprim–sulfamethoxazole, or a combination variable tenderness and may be only a few millimeters to several
of a fluoroquinolone and clindamycin. Severe infections requiring centimeters in diameter. The inflammatory lesions are cutaneous
hospitalization may need intravenous cefoxitin, ampicillin–sulbactam, abscesses that are in variable states of evolution and eventually
or even a carbapenem to effectively cover all pathogens. suppurate and drain. Fluctuance is not common because of the
A related infection from domestic animals is cat-scratch infection. chronic fibrosis and loss of tissue elasticity that occur in the skin and
The pathogen is a Bartonella spp., usually B. henselae. Infections are adjacent subcutaneous fat. The lesions become chronic with periodic
identified from 3 days to 4 weeks after injury. Culture documentation exacerbations from acute infection.
of the pathogen is difficult and frequently assumed to be present with a As the HS occurs across a continuum of mild to extremely severe
suggestive clinical history. Four weeks of oral therapy is recommended disease, treatment needs to be individualized for each patient.
with azithromycin (Bass et al. 1999). Sitz baths, heating pads, maintenance of a dry local environment,
Human bites or hand lacerations from tooth injuries during fist- avoidance of tight-fitting clothing, and antibiotic therapy are
fights pose another unique microbial challenge (Talan et al. 2003). components of medical management. Antibiotic therapy commonly
Streptococci, Staph. aureus, and Eikenella corrodens are the most consists of tetracycline, clindamycin, or a combination of clindamycin
common pathogens. Fusobacterium, Peptostreptococcus, Provotella, with rifampin (Jemec 2012). Tobacco cessation and weight reduction
and Porphyromonas spp. are also seen. Oral antibiotic therapy for are recommended. Local incision and drainage of individual abscesses
established infection is with amoxicillin–clavulanate. Inpatient are commonly employed, but recurrent local infection is then generally
treatment with cefoxitin or ampicillin–sulbactam is recommended. observed.
Other treatments have been employed. Intralesional injection of
■■Hydradenitis suppurativa steroids, systemic isotretinoin, and anti-androgenic therapies has been
used. Laser treatments and even external beam radiation have also
Hydradenitis suppurative (HS) is a chronic bacterial and inflammatory been used. Recent trials have examined anti-tumor necrosis factor,
disease of the apocrine sweat glands (Jemec 2012). The apocrine sweat monoclonal antibody treatments with mixed results.
glands drain into the pilosebaceous unit, as opposed to the more Surgical management is the option for advanced disease and
common eccrine sweat glands which open independently on to the is usually chosen when disease is far advanced and patients are
skin. The apocrine glands occur in selected areas, especially in the fatigued from sustained and poorly successful conservative measures.
axilla, perineum, and pubic areas, and about the areola of the breast. Adequate excision of all affected tissues is essential. Retained, diseased
The apocrine glands are in a deeper location within the skin structure glands will result in recurrence. Wound management is problematic.
than eccrine glands. Occlusion of the drainage system of the apocrine Primary closure with split-thickness skin grafts is commonly used.
sweat gland leads to stasis, microbial proliferation within the gland– Flap closures are used for large tissue defects. Staged procedures
follicle complex, and a local inflammatory response. Local infection have been used when extensive excisions are required and chronic
 Necrotizing soft-tissue infection 67

suppuration is present. The role of negative pressure dressings is not

well defined for these cases, but may have a role in preparation of the Box 5.1 Risk factors for necrotizing soft tissue
excised wound for subsequent closure.
Infection
■■NECROTIZING SOFT-TISSUE Diabetes
Age >65 years
INFECTION Alcoholism/Cirrhosis
Cardiac disease
SSSTIs infrequently evolve in rapid order into a life-threatening Chronic lung disease
necrotizing soft-tissue infection (NSTI). NSTI occurs when either Cancer diagnosis
the infection in a conventional SSSTI progresses vertically toward Chronic renal failure
the investing muscle fascia, or the injury itself penetrates to the level Intravenous drug abuse
of fascia, or through the fascia, and carries contaminants into deep Postoperative status
tissues. Areas of skin with shallow subcutaneous tissues (olecranon HIV disease
or patellar surfaces) can be especially vulnerable to vertical extension Chronic corticosteroid therapy
of infection to the fascial level. Established infection at the level of Clinical immunosuppression
the perifascial space (see Figure 5.1) progresses laterally in a rapid APACHE score ≥15
fashion. The relative avascularity of the perifascial space and the Pre-existent shock or sepsis
minimal perfusion of the overlying fat tissue and underlying collagen
of the fascia permit rapid progression of the infection. When injury
violates the muscle fascia, infection within and over the surface of
the muscle may similarly extend in a lateral direction. Usually either reduced oxygen delivery to tissues will be associated with NSTIs after
necrotic muscle from the initial injury, or hematoma, or introduced skin or soft-tissue injury (Mills et al. 2010, Huang et al. 2011, Tunovic
foreign bodies are present to allow the initiation of the infectious et al. 2012). Congestive heart failure, chronic lung disease, and
event. Toxin-producing pathogens such as Clostridium perfringens peripheral vascular disease are the most notable associations. Other
or Strep. pyogenes are cytotoxic and result in direct tissue necrosis chronic diseases of renal failure, liver failure, and HIV infections are
or thromboses of the microcirculation. Dead muscle tissue becomes associated conditions. Diabetes and obesity are identified as risks in
the nutrient resource for sustained microbial replication, additional virtually every published series of NSTI cases. Corticosteroid treatment
toxin production, and extended necrosis. The extension of infection is noted for both an association with NSTI, but also with delayed
above the fascia results in thrombosis of the perforating nutrient symptoms in the evaluation of the disease. Nevertheless, 30% or more
blood vessels to the overlying skin and subcutaneous tissues. The of NSTIs appears in patients without apparent immunocompromise
progression of infection is far greater than the physical evidence or predisposing risk factors, and likely reflect pathogens of unusual
indicates on observation. With deep myofasciitis, muscle necrosis virulence characteristics.
may be extensive and the patient will manifest extreme toxemia from The microbiology of NSTIs has high variability between reports.
the systemic inflammatory response syndrome but not have dramatic In a report consistent with this author’s experience, polymicrobial
external visual evidence of NSTI. infections were 2.5 times more common than monomicrobial
The characteristic finding of the NSTI patient is pain and tenderness infection (Bernal et al. 2012). However, another recent report from a
that is out of proportion to the inciting injury. Minor cuts, punctures, geographically different area of the USA demonstrated a nearly equal
abrasions, or burns that result in severe complaints of pain in a wider frequency of polymicrobial to monomicrobial infection (Kao et al.
perimeter (5–10  cm) about the injury, and similarly have palpable 2011). As a general rule, monomicrobial infections seem to complicate
tenderness within this described perimeter, must be considered as lesser injuries to the skin and soft tissues, whereas polymicrobial
being NSTI. In patients with a relatively shallow depth of subcutaneous infections are more commonly seen after major tissue injuries and at
tissue and an infection superficial to the investing muscle fascia, the surgical site of major operations. Mortality rates of monomicrobial
there will be induration that is palpable, and the discriminating infections appear to be higher with clostridial myonecrosis at >50%,
examiner may even be about to palpate the leading edge of the streptococcal at 20–30%, and polymicrobial infections in the 10% range
advancing induration. However, if the infection is beneath the fascia, (Das et al. 2011, Tunovic et al. 2012). An effort to aggregate all reported
then induration cannot be appreciated. Severe pain with passive series of necrotizing fasciitis over nearly 30 years has identified a 24%
movements will be evidence of muscle necrosis, which will evolve overall mortality rate (May et al. 2009). As discussed, mortality rates
into signs of extremity compartment syndrome. Soft-tissue crepitus for general description of any one subgroup of NSTIs are very difficult
leads to the diagnosis of ‘gas gangrene.’ Soft-tissue crepitus is often because each case has a unique risk and microbiology that make
associated with C. perfringens, but may exist with streptococcal NSTI generalizations very difficult (McHenry et al. 1995).
and even with infections where aerobic Gram negatives or obligate Regardless of risk factors, microbiology and other issues in care,
anaerobes are present. Conventional radiographs of the soft tissue may it is essential that debridement must remove all necrotic tissues
demonstrate the presence of air¸ and computed tomography (CT) or and those perimeter tissues that have striking evidence of invasive
magnetic resonance imaging (MRI) may identify evidence of severe infection (Wong et al. 2008). The surgical field should have clearly
edema within the muscle. The most critical issue in the diagnosis of viable and bleeding tissues at the time of completion. Efforts to
NSTI is that the clinician has a high index of suspicion. Exaggerated save marginally viable tissue or those that may appear viable but
clinical symptoms within 24–48 h of an apparently minor wound must have evidence of induration and erythema will result only in major
stimulate thoughts of NSTI. necrotic tissues on subsequent debridements. Patients should be
NSTIs are associated with common risk factors (Box 5.1). Any returned for daily debridements until a completely viable wound
comorbid condition that is associated with reduced perfusion or has been identified.
68 SKIN, SKIN STRUCTURE, AND SOFT-TISSUE INFECTIONS

■■Clostridial NSTIs
Clostridial myonecrosis is the least common but most deadly of the
NSTIs. It is commonly associated with C. perfringens as the responsible
pathogen, although C. septicum, C. sordellii, and other clostridia have
been identified with NSTIs (Stevens et al. 2012). The wounding process
can lead to clostridial NSTIs when the wounding device is laden with
clostridial spores. Clostridial spore colonization of human skin is
a very unlikely source to lead to this clinical infection. Local tissue
necrosis and/or hematoma provides the substrate and environment
for the obligate anaerobe to transform into the vegetative state from
the spores. Exotoxins result in necrosis of adjacent muscle tissue,
microbial replication in invasion of the dead (and very anaerobic)
muscle, and microbial replication produces additional toxin. Fatal
infection can evolve within 24 h of injury because the toxic products of
inflammatory cytokines, necrotic tissue, and the systemic distribution
of clostridial toxins generate a profound clinical syndrome of systemic
inflammatory response syndrome (SIRS) and septic shock.
Among clostridial SSSTIs, an occasional infection will be seen Figure 5.2  A photomicrograph of Clostridium perfringens, 1000 x
magnification. (From the Public Health Image Library, Centers for Disease
that is confined to the skin and subcutaneous fat and is superficial
Control – courtesy of CDC/Don Stalons.)
to the muscle fascia. These infections are far less virulent than
those characterized by myonecrosis. These lesser infections result
when spore contamination is confined to the subcutaneous fat, successful initial intervention (defined as patient survival for 24 h)
and associated hematoma/non-viable tissues are superficial to requires reoperation within 24 h for re-debridement and cleansing
the muscle fascia. Subsequent toxin production does not have the of fibrinous debris. Re-debridement in the operating room every 24
same pathological consequences in adipose tissue as is seen in h is necessary until all tissue is identified as viable at reoperation.
muscle. These superficial “clostridial cellulitis” infections will usually Systemic antibiotics will not manage the infection that is established
have more common clinical evidence of cutaneous erythema and in dead tissue and has not been successfully debrided. However,
induration than is seen with the true myonecrosis infection. Palpable aggressive systemic antibiotics may slow the advance of the pathogens
crepitus is usually present and therapeutic intervention is far more into uninfected tissues and hopefully provides some benefit for the
easily achieved. The patients exhibit a far less severe picture of systemic attendant clostridial bacteremia of these cases (Table 5.3). High-dose
inflammation. As infection within the subcutaneous tissue commonly intravenous benzylpenicillin (24 MU/24 h) and clindamycin (1200–
accompanies the more severe myonecrosis, only exploration of the 1500 mg/8 h) are the antibiotic combination of choice. C. perfringens
area will clearly define the limits of the infection. and the other clostridia are sensitive to the cell wall activity of penicillin,
When the clinical criteria of pain and tenderness are present about and clindamycin as a protein synthesis inhibitor is considered effective
the injury site, timely clinical intervention is essential. Streptococcal in the inhibition of toxin production.
myonecrosis has a clinical picture that is very similar to clostridial An important aspect of care for these patients is the use of
NSTIs and, in the immunosuppressed host, other pathogens can aggressive support measures. The patients all have an expanded
mimic the clostridial infection syndrome. When NSTI is present, volume of distribution and sequestered extracellular water in systemic
preoperative definition of the specific organism is not as important edema. Intravascular volume expansion with crystalloid solutions
as surgical debridement. (e.g., lactated Ringer solution) is important, and the hemolytic
Typical findings of clostridial myonecrosis are important to and blood loss consequences of the disease and its management
recognize but all are seldom present. Palpable crepitus is commonly may require red blood cell replacement. Colloidal solutions are
present. Drainage at the site of injury will often have the “dish water” ordinarily withheld until there is evidence that “third spacing” of
appearance of an anaerobic infection. Leukocytosis or leukopenia fluids has stopped. As coagulopathy is a usual accompaniment to
may be present with white cell counts being very high or very low, clostridial NSTI, coagulation factors may be necessary even during
leukopenia of <2000/mm3 being a poor prognostic finding. Laboratory the hyperacute phases of management. Supportive management
evidence of an increased serum creatinine and elevated hepatic of cardiac output (catecholamines), renal output (volume support),
enzymes is a common finding. Respiratory failure and coagulopathy and systemic oxygenation (ventilator support) is essential for patient
emerge rapidly. Cultures of the drainage, excised tissue, and blood survival.
will usually demonstrate clostridial bacteremia, but results will not be Hyperbaric oxygenation has been proposed and advocated for
available until after the patient’s fate has been dictated by therapeutic the treatment of clostridial NSTIs (Kaide and Khandelwal 2008).
intervention. The identification of Gram-positive rods by the Gram Thorough oxygenation of all tissues will presumably kill or retard
stain of wound drainage provides ample evidence to identify this the advance of this aggressive NSTI. Despite testimonial evidence,
organism prospectively (Figure 5.2). studies of hyperbaric oxygen have many shortcomings, not the least
The treatment for clostridial NSTIs is prompt and aggressive of which is that control patients have not received increased oxygen
debridement of necrotic tissues. Black muscle is completely excised as delivery under normobaric conditions (Fry 2005). Dead tissue remains
is the overlying dead fascia. Muscle that does not bleed or contract is dead tissue and it is unlikely that hyperbaric oxygen reaches or has
presumed to be dead and debrided. Overlying skin and subcutaneous therapeutic effect within dead necrotic muscle. Hyperbaric oxygen has
tissue may or may not be viable, and excision of these superficial severe vasoconstrictive effects, and will result in increased ventricular
tissues requires clinical judgment. In this author’s judgment, afterload for the patient with tenuous cardiac reserve. Finally, the
 Necrotizing soft-tissue infection 69

Table 5.3  The antibiotic choices, doses, and rationale for each of the pathogens of necrotizing soft tissue infection.
Target pathogen Antibiotic choice Rationale
Clostridium myonecrosis Penicillin 2 MU every 2 h; clindamycin 1200–1500 mg every Aggressive dosing necessary because of the expanded
6–8 h. If penicillin allergic, use vancomycin 30 mg/kg daily in volume of distribution identified with the systemic
two doses inflammatory response of these patients. Clindamycin reduces
toxin production
Streptococcus pyogenes Penicillin 2 MU every 2 h; clindamycin 1200–1500 mg every Aggressive dosing necessary because of the expanded
6–8 h. If penicillin allergic, use vancomycin 30 mg/kg daily in volume of distribution identified with the systemic
two doses inflammatory response of these patients. Clindamycin reduces
toxin production
Meticillin-sensitive Nafcillin 1–2 g every 4 h or cefazolin 1–2 g every 6–8 h Aggressive dosing is recommended because of the expanded
Staphylococcus aureus (MSSA) volume of distribution seen in these patients. Dosing should
be de-escalated once the systemic inflammatory response is
improving
Meticillin-resistant Vancomycin 30 mg/kg per day in two doses; or linezolid Presumptive coverage of MRSA is employed if sensitivities are
Staphylococcus aureus (MRSA) 600 mg every 12 h, or daptomycin 6 mg/kg daily not known and then de-escalated if MSSA.
Polymicrobial infection: Use all three if cultures are not available
Gram-positive coverage Vancomycin 30 mg/kg per day in two doses; or linezolid Presumptive coverage of MRSA is employed if sensitivities are
600 mg every 12 h, or daptomycin 6 mg/kg daily not known and then de-escalated if MSSA
Gram-negative coverage Piperacillin/Tazobactam 3.375–4.5 g every 6 h; or imipenem Treatment will need modification after culture and sensitivity
1 g every 8 h; or meropenem 1 g every 8 h results are available
Anaerobic coverage Clindamycin 1200–1500 mg every 6–8 h This is the preferred choice because of anaerobic coverage,
but because of toxic inhibition if Gram positives are present

hyperbaric chamber becomes logistically problematic for the patient violates the fascia, a rapidly advancing myonecrosis can be seen
on ventilator support. Hyperbaric oxygen remains of controversial that has visual features in common with the clostridial myonecrosis
value, and requires more evidence to support its routine use. described earlier. Whether the infection is within the perifascial space
Other therapies have been proposed for C. perfringens infections. or in the muscle itself, the progression of the infection is rapid and
Some consideration has been given to a vaccine not unlike the one requires prompt recognition by the clinician if intervention is to be
that has been successfully used for the prevention of tetanus infection effective.
(Titball 2009). Efforts at vaccine development have been unsuccessful. Any breech or injury to the epidermis has the potential to result in
The scope of an immunization program cannot be justified when streptococcal NSTIs. ”Paper cuts” of the finger and tangential abrasions
considering the infrequency of this infection. Immunoglobulin for of the skin at any site can yield streptococcal NSTIs. Scratching of
neutralization of the cytotoxins of clostridia has been considered but pruritic chickenpox vesicles by children, with presumed streptococci
has not been successfully employed in patient care. from the mouth, have been associated with streptococcal NSTIs
Finally, some special consideration should be given to clinical (Waldhausen et al. 1996). Inguinal hernia incisions (Sistla et al. 2011)
circumstances that are unique to C. septicum and C. sordellii infections and trochar sites from laparoscopic procedures have also been seen
(Stevens et al. 2012). C. septicum bacteremia and NSTIs have been (Bharathan and Hanson 2010). Anatomically, streptococcal NSTIs
identified without any physical injury present at the site of the occur most commonly on the extremities and the truck. Similar to all
infection. These C. septicum metastatic infections are associated with NSTIs, they occur least frequently in the head–neck areas, although
colon cancers, diverticulitis, and other pathological circumstances these latter infections are often spectacular in severity and appearance,
in the gastrointestinal tract. Spontaneous myonecrosis should be a and are reported in the literature. Why most SSSTIs due to streptococci
consideration in patients that develop acute and painful soft-tissue prove to be innocuous, and selected others become life-threatening
illnesses with systemic toxemia, but no injury at the location. Those NSTIs remains an unanswered question. The answer lies in either the
patients fortunate enough to survive these C. septicum infections impaired effective of the host, or the random encounter of an unusually
need to have a gastrointestinal evaluation to define the source of the virulent strain of Strep. pyogenes.
bacteria. Similarly, one may see a metastatic myonecrosis infection Streptococcal NSTIs can occur via metastatic seeding of an injury
in association with severe myometrial infection after medical or self- site from a remote source. Soft-tissue contusions, subcutaneous or
induced interruption of pregnancy with infections due to C. sordellii. muscle hematomas, and chronic joint effusions can all be receptive
sites for blood-borne seeding and NSTIs without any disruption of
■■Streptococcal NSTIs the skin over the site of the acute or chronic injury. Remote sites of
innocent cellulitis or even asymptomatic pharyngeal colonization is
Strep. pyogenes is a common pathogen for soft-tissue infections thought to result in hematogenous seeding of a distant location. This
after relatively minor skin injuries. Most pursue an indolent course author has witnessed metastatic NSTIs when the patient has presented
and require minimal or no treatment. A very select minority of these with infection at one site, only to develop metastatic streptococcal
infections result in streptococcal NSTIs, which may be the result infection at a distant infiltrated intravenous catheter location.
of rapidly invasive infection within the perifascial space and cause Streptococcal NSTIs can be a difficult diagnosis to appreciate in
necrosis of the skin and subcutaneous tissues, but leave the muscle the early phases, and are commonly not recognized by inexperienced
fascia and underlying muscle viable. When the wounding process clinicians. The characteristic rule of NSTIs is pain and tenderness out
70 SKIN, SKIN STRUCTURE, AND SOFT-TISSUE INFECTIONS

of proportion to the inciting injury, and never is that rule more valid patient’s life depends on the effectiveness of the surgical intervention.
than when Strep. pyogenes is the putative pathogen. When an NSTI is The effort to conserve tissue in the interest of future reconstruction
superficial to the muscle fascia, a rapidly developing cellulitis is seen is a risky proposition. The patient is returned to the operating room
in the skin. Commonly, bullae and sloughing of skin will be seen at for additional wound inspection every 24 h until no necrotic tissue is
the wound site, although not within the first few hours of the infection. identified. Clinical deterioration after debridement may necessitate
Clinical evidence of lymphadenitis or lymphangitis may be present an earlier return to the operating room for additional debridement.
with extremity infections. The cellulitis changes can be observed to Extremity streptococcal NSTIs are the site of infection in over 50% of
advance several centimeters within a 30- to 60-min period of time. these cases, and they invariably result in questions about the necessity
Nevertheless, the extent of the advancing cellulitis underestimates the of amputation. When infection involves only the skin and subcutaneous
progression of the infection at the perifascial level. With streptococcal tissue of the extremity, then the extremity can be salvaged. When
myonecrosis, the overt findings of cellulitis, bullae, and sloughing are muscle groups of the leg or arm are necrotic, then amputation is
absent until late in the progression of the infection. Only with the rapid necessary. In questionable cases, the issue of amputation may or may
advance of pain, tenderness, and SIRS will the diagnosis be made. not be resolved until the second or third reoperation.
Crepitus may be present in a minority of cases. Dramatic leukocytosis The combination of high-dose benzylpenicillin and clindamycin
in the early phases of streptococcal NSTI evolves into leukopenia as is the antibiotic of choice in doses similar to those used for clostridial
the infection progresses. Pulmonary, renal, and hepatic failure evolves NSTIs (see Table 5.3). Streptococci are very sensitive to benzylpenicillin,
quickly. Coagulopathy is usually present and may lead to disseminated but rapidly multiplying streptococci will demonstrate the “Eagle effect”
intravascular coagulation. Cultures of infected tissues and blood are (Eagle 1949). High density of streptococci in tissue as are seen in NSTI
almost always positive but results will not be available in a clinically will be less influenced by antibiotics and may have reduced expression
relevant period of time. The Gram stain of the drainage at the injury of penicillin-binding proteins among rapidly dividing bacterial cells.
site will often identify Gram-positive cocci in chains (Figure 5.3). The addition of clindamycin reduces the rapidity of replication and
Similar to clostridial NSTIs, streptococcal NSTIs are a clinical reduces toxin production (Bisno and Stevens 1996). With penicillin-
diagnosis that requires prompt surgical intervention. Debridement allergic patients, clindamycin remains the choice and a second drug
of the infection must be liberal and aggressive. The subcutaneous fat (e.g., vancomycin or quinolone) may be added. The systemic edema
will be necrotic and the perifascial space will weep with a tan-colored, of the streptococcal NSTI patient is extensive and generalized and
thin-consistency, exudative fluid. The exudate lacks a purulent requires aggressive dosing to achieve therapeutic effect.
character except at the area adjacent to the site of injury. It has been Supportive care of the streptococcal NSTI patient is vitally
this author’s experience that the skin and subcutaneous tissue will important. Many of these patients demonstrate a toxic shock-
need to be excised in all areas above the extent of the tan exudate and like syndrome, which is felt to be secondary to the production of
induration of the fascial layer. When myonecrosis is present then all superantigens by the pathogen (see Chapter 1; Stevens 1995). Volume
obviously dead, non-contracting, and non-bleeding muscle is excised. support is essential during the acute phase of the infection, and
Debridement must proceed with the full understanding that the catecholamine support for maintenance of the systemic circulation
is commonly needed. Resolution of elevated creatinine levels and
increased concentrations of liver enzymes reflect clinical resolution of
the infection. Prolonged ventilatory support may be required for many
days after clinical resolution of the infection and for many days after
antibiotic therapy has been discontinued. Nosocomial pneumonia
becomes a risk from hospital-acquired bacteria for the NSTI patient
that requires prolonged ventilator support.
Similar to clostridial NSTI, the use of intravenous immunoglobulin
and hyperbaric oxygen has been proposed for the treatment
of streptococcal NSTIs. Some evidence supports the use of
immunoglobulin for severe streptococcal infections (Darenberg et
al. 2003), especially when administered early in the natural history
of the infection. Additional studies are needed for the evaluation of
intravenous immunoglobulin. Similar to clostridial NSTI, there is
little objective evidence to support the use of hyperbaric oxygen with
streptococcal infection.
The overall outcome for patients with streptococcal NSTIs
remains, with an overall mortality rate in the range of 25% (Davies
et al. 1996). No one institution has a large experience and this 25%
figure is certainly an estimate. The morbidity of the disease involves
reconstruction and rehabilitation for the major loss of tissue that is
necessary to achieve survival for these patients. Improved public
awareness and physician recognition of the disease are necessary for
improvement in clinical outcomes.

■■Staphylococcal NSTIs
Figure 5.3  A photomicrograph of Streptococcus pyogenes, 900 x
magnification. (From the Public Health Image Library, Centers for Disease Traditionally, Staph. aureus has been a common pathogen of
Control – courtesy of CDC.) pyogenic bacterial infections of the skin and soft tissues but an
 Necrotizing soft-tissue infection 71

infrequent pathogen of NSTIs. Even when infection occurs in the

perifascial space or muscle, the coagulase-positive Staph. aureus
infection has been largely of a pyogenic character and not the rapidly
expanding infection of NSTIs. The presence of the Panton–Valentine
leukocidin and other virulence characteristics of CA-MRSA have
changed the behavior of staphylococci, and NSTIs have become a
more frequent event (Miller et al. 2005). Since the major publication
by Miller et al., the numbers of individual cases and small series
that have identified staphylococcal NSTIs have escalated at a
very rapid rate. Staphylococcal NSTIs are usually seen in patients
with major medical comorbidities such as diabetes, hepatitis C,
intravenous drug abuse, and HIV infection. Similar to streptococcal
NSTIs, all anatomic areas appear to be vulnerable to this aggressive
staphylococcal infection. Unlike streptococcal infection, the
staphylococcal infection has a lower mortality rate but typically a
very high morbidity rate.
Staphylococcal NSTIs usually evolve from conventional SSSTIs.
The unattended pyogenic infection may become vertically invasive
into the subcutaneous fat, where the perifascial plane is entered and Figure 5.4  A photomicrograph of Staphylococcus aureus, 250 x
magnification. (From the Public Health Image Library, Centers for Disease
lateral progression of the infection proceeds. The primary infection site
Control – courtesy of CDC/Richard Facklam, PhD; http://phil.cdc.gov/phil/
will have a pyogenic character but may exhibit only the black eschar details.asp.)
that is commonly associated with CA-MRSA. An advancing cellulitis
is identified emanating from the epicenter of the infection, but it does
not characteristically have the rapidly spreading cellulitis seen in importantly give the sensitivity patterns of the specific staphylococcal
streptococcal NSTIs. The cellulitis adjacent to the area of the wound pathogen. MSSA, CA-MRSA, and healthcare-associated MRSA each
and eschar may not blanch, reflecting thrombosis of the intradermal have unique sensitivities that are important in choosing antimicrobial
vasculature secondary to the effects of coagulase. The induration of therapy. In complex infections and in the fetid foot, deep tissue
the soft tissues to physical examination is more pronounced than samples are best for yielding dependable culture results. Selected
streptococcal infection. The progression of staphylococcal NSTIs patients will have different levels of sensitivity to vancomycin, which
can still be clinically rapid, but not in the same order of magnitude is becoming an increasing problem in the selection of therapy for
seen with streptococcal or clostridial NSTIs. Similar to streptococcal these patients.
NSTIs, staphylococci have been identified with metastatic seeding The principles of treating the staphylococcal NSTI are the same as
to injured soft-tissue sites without an open injury to the soft tissue for all of these infections. Adequate local debridement, which results
(Kim et al. 2010). in only viable tissue remaining, is essential. Repeat debridements are
An important NSTI with staphylococci is seen in the diabetic often necessary depending on the severity of the infection. Bedside
fetid foot infection. These infections begin with ulceration of toes debridement on a daily basis is useful. Eradication of dead tissue is
and the plantar surface of the feet in patients with diabetes and the objective, whether done by repeated debridements under general
advanced neuropathy and peripheral vascular disease. The chronic anesthesia or debridement performed at the bedside. Many topical
neuropathic and ischemic tissue, combined with the effects of antibacterial agents have been used to treat these infections at the
hyperglycemia, results in repeated infections in these chronic ulcers. completion of debridement. Mafenide acetate solution or silver
Infection in the diabetic foot ulcer has been demonstrated initially sulfadiazine is preferred.
to be with Staph. aureus and the persistence of this infection, which Systemic antibiotics are important components for the treatment
burrows into the several soft-tissue planes of the foot, is an indolent of staphylococcal NSTIs (see Table 5.3). Although MSSA infection
variation of a necrotizing infection. These patients undergo repeated may principally respond to drainage and debridement alone, it needs
hospitalizations and multiple courses of antibiotics. Ultimately the appropriate antibiotic coverage (see Chapter 2). Staphylococcal NSTIs
infection becomes polymicrobial with Gram-negative and even will require inpatient antibiotic therapy and vancomycin remains the
anaerobic bacteria. MRSA is commonly a continued participant drug of choice for most patients. Linezolid as an inhibitor of protein
in this polymicrobial infection. Ascending infection in the lower synthesis may offer the advantages of suppressing toxic production
extremity results in severe and aggressive local necrosis, cellulitis, by these organisms. Oral agents may be used in selected patients and
lymphadenitis, and lymphangitis. Amputation is a common trimethoprim–sulfamethoxazole or clindamycin may be chosen for
outcome when distal ulcers, infection, and the diabetes itself are CA-MRSA infections that are sensitive. Antibiotics are continued until
neglected. local evidence of inflammation has resolved and granulation tissue
With staphylococcal NSTIs, establishing a bacterial diagnosis is identified in the wound. Because of risks from the complication of
is important. The clinical presentation is highly variable and these bacterial endocarditis, systemic drug therapy may be continued for
NSTIs can mimic streptococcal infections at times and appear much up to 4 weeks in those patients with bacteremia during the infection.
like the polymicrobial NSTIs discussed below. The Gram stain of the As with other pathogens of NSTIs, interest in staphylococcal
exudates will commonly be of value in the identification of the grape- vaccines and antibody treatments focused on specific virulence
like clusters of Gram-positive cocci (Figure 5.4). Blood cultures are factors (e.g., PVL) is under study. The constantly changing antigenic
infrequently positive with staphylococcal NSTIs. Cultures of the wound and virulence factors of Staph. aureus make successful immune-based
purulence and tissue biopsies will identify the pathogen, but more therapies a worthy but difficult goal (Proctor 2012).
72 SKIN, SKIN STRUCTURE, AND SOFT-TISSUE INFECTIONS

■■Polymicrobial NSTIs polymicrobial NSTIs. Among patients with large, open traumatic,
or surgical wounds, the duration of hospitalization and influence
Over 50% of NSTIs are polymicrobial infections, and may include of systemic antibiotic therapy result in healthcare-associated
any combination of Gram-positive, Gram-negative, or anaerobic pathogens such as Pseudomonas aeruginosa, Staph. epidermidis,
pathogens. Polymicrobial NSTIs are most frequently seen in major MRSA, Enterococcus spp., and Acinetobacter baumanii as resultant
soft-tissue traumatic injuries and at surgical sites where massive pathogens in the sustained infection.
contamination or active infection has been encountered. The scenario Appropriate attention to the acute injury wound and to the celiotomy
with large traumatic wounds includes devitalized tissue, foreign wound with massive contamination can reduce the frequency and
bodies, soft-tissue hematoma, and varying degrees of microbial severity of polymicrobial NSTIs. Dead tissue must be debrided, foreign
contamination from the injury. Invasive polymicrobial NSTIs bodies are removed, and hematoma is evacuated. Broad-spectrum
commonly follow when the acute debridement of the injury site has preoperative antibiotics are employed for prevention but are likely
been suboptimal, or the magnitude of the contamination makes to be of only limited value in the massively contaminated wound.
infection a probable outcome. The celiotomy incision for trauma The traumatic wound requires daily vigilance because continued
surgery or an acute perforated viscus results in the surgical site being debridement is usually necessary. Traumatic wounds should not be
subjected to a large inoculum of microbes, which reflect the character closed primarily. Similarly, delayed primary closure or secondary closure
of the viscus that was disrupted. Colon disruptions are most notable is the choice for management of the contaminated celiotomy wound.
in this regard because of the large inocula of colonic microflora that Prevention of desiccation of the large open wound requires frequent
contaminate the surgical site. dressing changes with saline-moist gauze. Evidence to support any one
The pathogens that have been identified in polymicrobial NSTIs topical antimicrobial in these wounds is not available. Negative pressure
are detailed in Table 5.4. This list is certainly incomplete because dressings can be useful in preparing large tissue defects for subsequent
virtually every human pathogen has been reported as part of reconstruction, and for secondary closure of celiotomy wounds.
these infections. Meleney’s gangrene was one of the originally The diagnosis of polymicrobial NSTI requires a high index of
reported polymicrobial NSTIs and consisted of staphylococci suspicion. Traumatic wounds can be quite complex and invasive
and anaerobic streptococci. NSTIs after colon disruption are infection along lateral fascial planes can escape immediate
commonly Gram-negative rods (e.g., Escherichia coli) and colonic recognition. Furthermore, the trauma patient or patient with a
anaerobes (e.g., Bacteroides fragilis). Four or more pathogens may perforated abdominal viscus has many reasons to have leukocytosis,
be recovered from the infection before specific antibiotic therapy fever, and evidence of systemic inflammation.
is begun (Elliott et al. 2000, Ustin and Malangoni 2011). It is likely These infections are generally indolent compared with the
that anaerobes are under-reported in several reported clinical monomicrobial NSTIs, although the rapidity of advancing infection
series because of inefficiency in culturing these organisms. The is highly variable. Careful inspection of the wound, identification of
synergistic relationship between aerobic and anaerobic bacteria evidence of new cellulitic changes, recognition of new exudates that
likely contributes to the invasive perifascial infection seen in are expressed from the fascial margins, and pain and tenderness
beyond the perimeter of the open wound are all important findings.
Crepitus can be seen in polymicrobial NSTIs but cannot be depended
Table 5.4  Pathogens of polymicrobial NSTIs on as a reliable finding. Crepitus is often evidence of advanced
infection which may have been overlooked earlier. Once the diagnosis
Aerobic species Anaerobic species
of infection has been made, good cultures at the site are essential.
Gram-positive bacteria The best cultures are actual biopsies of the infected tissues that are
Staphylococcus aureus Bacteroides spp. promptly submitted to the clinical laboratory.
Coagulase-negative staphylococci Clostridium spp. The treatment of these polymicrobial NSTIs is similar to those
infections from other pathogens. Debridement of non-viable tissue is
Enterococcus spp. Peptostreptococcus spp.
essential and reoperation to re-debride the site of infection is essential.
Streptococcus pyogenes Peptococcus spp. Antibiotic therapy is very broad spectrum because presumptive therapy
Non-group A streptococci Corynebacterium spp. will need to cover the Gram-positive, Gram-negative, and anaerobic
Gram-negative bacteria Prevotella spp. possibilities (see Table 5.3). De-escalation of therapy is important to
avoid sustained treatment that is in excess of the patient’s needs.
Escherichia coli Fusobacterium spp.
Klebsiella spp. Veillonella spp.
■■OTHER PATHOGENS
Enterobacter spp.
This discussion has focused on the four major bacterial groups that are
Serratia spp.
associated with NSTIs. It must be emphasized that, with a vulnerable
Pseudomonas spp. host and microbial contamination that reaches the critical area of
Proteus spp. Fungi the perifascial area, literally any human pathogen can be the agent
Acinetobacter spp. Candida spp. for NSTIs. Vibrio spp. after injuries in salt water (Hong et al. 2012),
Aeromonas hydrophila (Park et al. 2011), Bacillus cereus as a seemingly
Aeromonas spp. Aspergillus spp.
random event (Hutchens et al. 2010), and even fungi (Harada and Lau
Citrobacter spp. Mucor spp. 2007) have all been implicated in NSTIs. The clinical presentation
Vibrio spp. and the anatomic distribution of these unusual pathogens appear to
Eikenella corrodens follow the same pattern as those microbes that are more commonly
associated with these infections.
 References 73

■■CONCLUSION increased physician sensitivity to the diagnosis of this overall

constellation of pathogens and clinical presentations that represent
The complexity and the clinical variability of NSTIs appear to be NSTIs. A foundation has been established to help achieve the
increasing. The number of publications reporting individual or goals of more public attention to this problem and better care for
small series of cases is escalating at a rapid rate. Improvement in these patients (National Necrotizing Fasciitis Foundation – www.
the overall results of care requires greater public awareness and nnff.org).

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Bharathan R, Hanson M. Diagnostic laparoscopy complicated by group A 2002;30:131–6.
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Bass JW, Freitas BC, Freitas AD, et al. Prospective randomized double blind tissue infections. Surg Infect 2009;10:467–99.
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disease. Pediatr Infect Dis J 1998;17:447–52. mortality for necrotizing soft-tissue infections. Ann Surg 1995;221:
Bisno AL, Stevens DL. Streptococcal infections of skin and soft tissues. N Engl J 558–63.
Med 1996;334:240–5. Medeiros I, Saconato H. Antibiotic prophylaxis for mammalian bites. Cochrane
Bernal NP, Latenser BA, Born JM, Liao J. Trends in 393 necrotizing acute soft Database Syst Rev 2001;CD001738.
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European randomized, double-blind, placebo-controlled trial. Clin Infect Dis Mills MK, Faraklas I, Davis C, et al. Outcomes from treatment of necrotizing soft-
2003;37:333– 40. tissue infections: results from the National Surgical Quality Improvement
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 Chapter 6 Intra-abdominal infections
John E. Mazuski

■■INTRODUCTION AND Both primary and catheter-associated peritonitis are typically

monomicrobial infections. They are treated medically with intravenous
DEFINITIONS antibiotics or, in some cases of catheter-associated peritonitis, with
topical antibiotics administered through the device itself. Unless
Intra-abdominal infections (IAIs) are common. They arise from a catheter removal is needed, source control is not a major consideration
number of different sources. Usually, they are caused by enteric in the treatment of these forms of peritonitis. These disorders are not
bacteria and other microorganisms normally found within the lumen considered further.
of a hollow viscus.
These infections can be classified as uncomplicated or comp­
licated. Uncomplicated IAIs are those that do not extend beyond the
■■Secondary peritonitis
wall of the hollow viscus, although they are at risk of doing so if left Secondary peritonitis is the IAI most frequently treated surgically. Most
untreated. Acute appendicitis is an example of an uncomplicated cases of secondary peritonitis are polymicrobial, involving a variety
IAI. In contrast, complicated IAIs are those in which the infection of microorganisms normally found within the gastrointestinal tract.
extends into the peritoneal cavity or another normally sterile area Generally, secondary peritonitis is the result of an overt perforation
of the abdomen. Thus, perforated appendicitis is an example of a somewhere in the gastrointestinal tract, which allows direct access of
complicated IAI (Marshall 2004, Blot and De Waele 2005, Solomkin contaminants to the peritoneal cavity. However, secondary peritonitis
et al. 2010). may also occur with ischemia or necrosis of a portion of the intestine.
Management of most complicated IAIs requires an invasive In this case, microorganisms access the peritoneal cavity by invading
procedure to control the source of the infection. This has sometimes through the wall of the intestine.
been used as a surrogate definition of a complicated IAI (Solomkin
et al. 1992). However, a source control procedure may not be utilized
to treat certain localized complicated infections, such as complicated
■■Tertiary peritonitis
diverticulitis; thus, the definition of a complicated IAI should not be As opposed to primary and secondary peritonitis, there is no generally
strictly based on this operational criterion. accepted definition of tertiary peritonitis. It is often defined as any
Many complicated IAIs are characterized by inflammation of peritoneal infection observed after initial treatment of secondary
the peritoneal cavity, or peritonitis. Others are described as an peritonitis. However, tertiary peritonitis is described here as a late
intra-abdominal abscess, within either the peritoneal cavity or infection that occurs only after several serial attempts have been
the retroperitoneal tissues, or occasionally as an intra-abdominal made to control an IAI. Typically, tertiary peritonitis is a diffuse,
phlegmon. Peritonitis itself has been described as primary, secondary, poorly localized process. The microbial agents associated with this
or tertiary. disorder tend to be nosocomial organisms, which are more resistant
to common antimicrobial agents than those producing secondary
■■Primary and catheter- peritonitis (Nathens et al. 1998, Buijk and Bruining 2002). Most patients
with tertiary peritonitis have significant impairment of host defenses,
related peritonitis which allows microorganisms of relatively low pathogenic potential
Primary peritonitis is inflammation or infection of the peritoneal cavity to proliferate and produce the disease process. Tertiary peritonitis is
that occurs in the absence of overt perforation or leakage from the the most lethal type of IAI.
gastrointestinal tract (Blot and De Waele 2005). In the past, primary
peritonitis due to streptococci or pneumococci was relatively common.
In the current era, the most common type of primary peritonitis is
■■Intra-abdominal abscess
“spontaneous bacterial peritonitis,” which typically occurs in patients Intra-abdominal abscesses are localized collections of fluid containing
with ascites due to hepatic cirrhosis. The microorganisms that most inflammatory cells and microorganisms. They characteristically
frequently cause this disorder are Enterobacteriaceae (Strauss and occur in dependent areas of the peritoneal cavity such as the pelvis,
Caly 2006). It is likely that at least some of these infections occur as subphrenic spaces, subhepatic space, right and left paracolic gutters,
a result of translocation of these microorganisms through the wall of and lesser sac. Intra-abdominal abscesses may also develop at other
the gut into the peritoneal cavity. sites within the peritoneal cavity, such as between loops of bowel, as
Peritonitis associated with devices that access the peritoneal cavity, well as in the retroperitoneum (Altemeier et al. 1973).
such as peritoneal dialysis catheters, has become an increasingly As with secondary peritonitis, most intra-abdominal abscesses
common problem. As with primary peritonitis, these infections originate after perforation of a hollow viscus. An intra-abdominal
occur in the absence of any violation of the gastrointestinal tract. abscess results from localization of the peritoneal infection by the
Microorganisms colonizing the skin can produce these infections, host over a period of days. The microbiology of secondary peritonitis
with the catheter providing a portal of entry into the peritoneal cavity. and intra-abdominal abscess is generally quite similar. Abscesses
Thus, staphylococci are frequent causes of this type of peritonitis, can also develop in solid organs, such as the liver and spleen, but
although infections due to Enterobacteriaceae are also common resulting from hematogenous dissemination of bacteria rather than
(Faber and Yee 2006). from intraperitoneal pathogens.
76 INTRA-ABDOMINAL INFECTIONS

■■Intra-abdominal phlegmon microorganisms and facilitate their disposal. Fibrin production

and deposition play a key role in the development of macroscopic
An intra-abdominal phlegmon is a frequently described type of IAI, sequestration. These adhesive molecules promote the binding of
but the entity has been very poorly characterized. In general, an intra- various surfaces covered by parietal or visceral peritoneum to each
abdominal phlegmon is a solid inflammatory mass that infiltrates into other. Thus, the omentum, mesentery, bowel loops, and abdominal
adjacent tissues of the abdominal cavity. Intestinal loops and other wall all adhere together in the area of most intense inflammation.
structures may become incorporated into this inflammatory mass. This restricts the access of pathogens or other irritants to other areas
Although small collections of fluid may be present within the mass, of the abdomen. This process also may result in the sealing of some
these do not constitute most of the volume of the mass. This provides perforations of the gastrointestinal tract (Cheadle and Spain 2003).
some distinction between an intra-abdominal phlegmon and an The end result of sequestration and the inflammatory reaction
abscess, but this distinction may be somewhat arbitrary. There are may be a contained intra-abdominal abscess, with a phlegmon as a
clearly examples in which an intra-abdominal phlegmon evolves into potential intermediate stage in this evolution. The development of
an intra-abdominal abscess over time, although the frequency with an intra-abdominal abscess may actually represent a successful host
which this occurs is unknown. response, because the infection has been localized. When host defense
Similar to an intra-abdominal abscess, an intra-abdominal mechanisms are ineffective, a much more virulent infection may
phlegmon is generally the result of a hollow viscus perforation. ensue. An example of this is the highly lethal diffuse disease process
However, the result of this is an intense inflammatory and fibrotic characterized as tertiary peritonitis. Thus, standard host defense
reaction, usually confined to a discrete area within the abdominal mechanisms play a key role in promoting survival and recovery after
cavity or retroperitoneum. The reason why a phlegmon rather than peritoneal contamination.
an abscess develops in a given patient is unclear.
■■SOURCES OF IAIs
■■PATHOPHYSIOLOGY A variety of different types of infections are collectively grouped
The pathophysiology of IAIs has been studied using experimental together as IAIs. As already indicated, these infections can be
models of peritonitis developing after hollow viscus injury. These described as uncomplicated or complicated. However, some processes
experimental data relate to the pathophysiology of secondary described as uncomplicated IAIs are not initially infections, e.g.,
peritonitis and intra-abdominal abscess development, and may not acute cholecystitis is initially an inflammatory process induced by
necessarily be relevant to the pathophysiology of other types of IAIs, obstruction or ischemia, and not by microbial invasion.
such as postoperative infections. Beyond this gross division of IAIs into uncomplicated and
There is a fairly stereotypical response that follows contamination of complicated varieties, the site from which an infection develops
the peritoneal cavity with gastrointestinal content from a hollow viscus, will have a significant impact on its clinical characteristics and
which is a reaction to both the chemical irritants and microbiological management. The source of an IAI will influence its microbiology,
agents released as a result of the perforation. The various host defense because the site of perforation within the gastrointestinal tract will
mechanisms invoked serve to limit the spread of these agents and determine the quantity and type of microbial contamination that
reduce the likelihood of the development of an overt infection. occurs. Similarly, the source of infection may also determine the
First, there is rapid mechanical clearance of contaminated fluid degree to which a particular infection spreads, depending on whether
from the peritoneal cavity. Fluid within the peritoneal cavity is in the perforation is into the free peritoneal cavity, or the mesentery or
constant circulation due to diaphragmatic contraction and relaxation. retroperitoneum.
Contaminated fluid comes into contact with the undersurface of the The types of IAIs and their associated sources vary with the age
diaphragm relatively quickly. There, specialized stomata take up that of the patient. In the neonatal period, necrotizing enterocolitis is the
fluid into lymphatic vessels, where it is distributed to larger lymphatics most common entity producing an IAI (Brook 2003, Blakely et al. 2008).
and lymph nodes in the mediastinum. This mechanical clearance During childhood, appendicitis is the predominate type encountered.
results in the rapid removal of a significant portion of extravasated Appendicitis persists as the major source of IAIs throughout early
fluid and its associated pathogenic microorganisms. adulthood, although infections arising in the gallbladder become
An inflammatory reaction also develops relatively rapidly in increasingly more frequent. However, development of a complicated
response to contamination of the peritoneal cavity. Chemical and IAI due to perforation of the gallbladder is relatively unusual. During
biological irritants, particularly microbial molecules, are recognized the later decades of life, infections arising from the colon due to
by pattern recognition receptors of resident macrophages and other diverticular disease or malignancy increase progressively in numbers,
proinflammatory cells present within the peritoneal cavity. This and surpass the appendix as the most frequent cause of a complicated
results in release of signals that attract large numbers of inflammatory infection in those age groups (Podnos et al. 2002).
cells into the peritoneal cavity. Early on, these are primarily
polymorphonuclear leukocytes, but after 1 or 2 days, mononuclear
leukocytes come to predominate. These cells may directly phagocytose
■■Appendicitis
pathogenic microorganisms or other particulate matter. In addition, Overall, appendicitis is the most frequently encountered IAI. In the
this early inflammatory reaction triggers the development of the developed world, the incidence had been reported to be 75–140
specific immune response, as well as subsequent phases of wound cases per 100 000 patients per year (Körner et al. 1997, Al-Omran et
healing. al. 2003). More recent data suggest that rates have been increasing
Sequestration is another key component of the host response that over the past 10–15 years, possibly in association with increased use
serves to limit the extent of the infection. This process occurs at both of imaging studies to make the diagnosis (Livingston et al. 2007). In
the microscopic and the macroscopic level. Microscopic sequestration the developing world, somewhat lower rates have been reported, but
involves production of fibrin and other macromolecules that entrap these also appear to be increasing (Oguntola et al. 2010). There is a
 Sources of IAIs 77

male-to-female predominance of approximately 1.4–1.5:1. The peak secondary bacterial peritonitis not associated with prior surgery
incidence occurs in the second decade of life, but appendicitis occurs were due to such perforations (Mosdell et al. 1991). Although peptic
in all age groups. In association with changes in demographic trends, ulcer disease is the most common cause of an acute gastroduodenal
increased numbers of middle-aged and elderly patients are being perforation, the incidence of this is decreasing, possibly as a result
treated for this disease (Harbrecht et al. 2011). of widespread use of proton pump inhibitors and other agents for
Acute appendicitis has long been assumed to be due to obstruction reducing gastric acid production (Hermansson et al. 2009, Wang
of the appendiceal lumen, subsequent distension of the appendix with et al. 2010). The incidence of gastric perforation has not decreased
inflammatory fluid and mucus, bacterial overgrowth within the lumen, as rapidly as has the rate of duodenal perforation (Wang et al.
and eventual gangrene and perforation as the end result. This concept 2010). Gastroduodenal malignancies may present with an acute
has been challenged. Non-obstructive etiologies can clearly give rise perforation, but benign diseases are responsible for a far higher
to appendicitis, and actual obstruction of the appendiceal lumen as proportion of these perforations. Iatrogenic perforations, due to
the initiating factor may be relatively uncommon. The supposition endoscopic or surgical therapy, may also cause these infections.
that acute appendicitis, once initiated, will inexorably progress to The amount of microbial contamination of the peritoneal cavity
perforation has also been challenged. Spontaneous regression of produced by a gastroduodenal perforation tends to be quite low in
appendiceal inflammation may be a much more common process than patients with normal acid production. Arbitrarily, such patients are
is generally appreciated, making many cases self-limited (Mason 2008). considered to have peritoneal contamination, and not a complicated
Appendicitis can be considered either an uncomplicated or a IAI, if they undergo a source control procedure within 24 h of the
complicated IAI, depending on its stage. Acute, non-perforated perforation.
appendicitis is an uncomplicated IAI, whereas perforated appendicitis
is a complicated infection. Gangrenous appendicitis is somewhat more
difficult to classify; however, unless microorganisms are isolated from
■■Biliary disease
inflammatory fluid outside the appendix, it should be considered an The gallbladder and the biliary tree are frequent sources of IAI.
uncomplicated infection. Perforated appendicitis rarely results in Infections arising in the gallbladder are much more common than
generalized peritonitis; if present, this is usually seen at the extremes those developing in the bile ducts. Acute cholecystitis leads to most of
of age. More often, perforated appendicitis presents with localized the intra-abdominal infections developing from the gallbladder. Acute
peritonitis in the right lower quadrant, with the inflammatory process cholecystitis is not synonymous with an infection of the gallbladder.
being limited by the ileocecal mesentery, adjacent loops of bowel, Bacteria are isolated from the bile of only 40–50% of patients with
and omentum. If the disease process progresses for several days, an acute calculous cholecystitis (Csendes et al. 1996, Yoshida et al. 2007).
appendiceal phlegmon or periappendiceal abscess may develop. Acute cholecystitis may evolve into a complicated IAI. Perforation of
the gallbladder occurs in a small percentage of patients who develop
■■Large and small bowel perforation cholecystitis, and accounts for approximately 5% of all complicated
IAIs (Mosdell et al. 1991).
Next to the appendix, the colon is the most common source of an IAI. Acute cholangitis may develop with obstruction of the major
In developed countries, diverticular disease causes most IAIs related biliary ducts. Although biliary calculi are the most common cause
to a colonic source. Other colonic processes leading to IAIs include of this obstruction, extrinsic compression due to neoplasms or
perforated colonic malignancy, iatrogenic or traumatic injury, foreign inflammatory masses, biliary strictures, and occlusion of drains or
body perforation, ischemic colitis, inflammatory bowel disease, and stents placed into the biliary system may all lead to acute cholangitis.
stercoral perforation. IAIs from a colonic source tend to occur in older Perforation of the biliary tree is very uncommon in the absence of
patients. Not surprisingly, mortality from these infections tends to gallbladder disease, and is usually associated with leakage from a
be higher than from other types of IAIs. This is particularly true for biliary–biliary or biliary–enteric anastomosis. Acute cholangitis is
infections developing from a colonic process other than diverticular frequently associated with bacteremia or frank septicemia. The onset
disease (Mosdell et al. 1991). of disease is usually quite acute, and systemic symptoms and signs
IAIs arising from a small bowel source are much less common than such as fever, chills, and hypotension predominate over abdominal
those arising from a colonic source. There is no predominant etiology symptoms and signs.
of small bowel perforation. Crohn disease causes frequent perforations
of the small bowel, but this process may be limited to localized abscess
or fistula formation. Perforations of the small bowel due to abdominal
■■Pancreatic and
trauma may result in an IAI if not treated expeditiously within 12 h. peripancreatic infection
Necrosis of the small bowel leading to peritonitis with or without overt IAIs related to the pancreas generally develop in the setting of severe
perforation may be due to vascular compromise or a low-flow state. acute pancreatitis. There are several different types of pancreatic
Vasculitis may give rise to a discrete focus of necrosis and resultant or peripancreatic infections that can be included in this category,
perforation. Perforation may also be related to a Meckel diverticulum including infected pancreatic pseudocysts, pancreatic abscesses, or
or a primary or metastatic small bowel tumor. Certain infectious infected pancreatic necrosis (Loveday et al. 2008). Infected pancreatic
diseases, such as tuberculosis or cytomegalovirus infection, lead to necrosis is among the most lethal. The reported mortality rate is
perforations of the distal small bowel. Finally, many IAIs arising from approximately 30%, which is considerably higher than the mortality
the small bowel are postoperative infections. rate secondary to necrotizing pancreatitis alone (Banks and Freeman
2006). The high mortality may be due to the inherent difficulty in
■■Gastroduodenal perforation surgically managing these infections, but it has also been suggested
that infection is a marker for the severity of pancreatitis, and not
Gastroduodenal perforations are responsible for a minority of the necessarily an independent risk factor for mortality (Büchler et al.
complicated IAIs. In one population-based survey, 9% of cases of 2000, Bourgaux et al. 2007).
78 INTRA-ABDOMINAL INFECTIONS

■■Postoperative IAIs Box 6.1 Common pathogens in intra-abdominal infection.

The numbers of patients with postoperative IAI have increased in
concert with the number and complexity of abdominal procedures. Community-acquired infection
Approximately 15–20% of complicated IAIs occur postoperatively Gram-negative bacilli:
(Pacelli et al. 1996, Kologlu et al. 2001). Gastroduodenal and colon Escherichia coli, Klebsiella spp.
procedures are those most frequently associated with these infections. Enterobacter spp., Pseudomonas aeruginosa – infrequently
The mortality rate for postoperative IAIs is around 30% (Mulier et isolated
al. 2003). The microbial pathogens producing these nosocomial Gram-positive cocci:
infections are somewhat different to those involved with most Streptococcus milleri group
community-acquired infections. Enterococci – infrequently isolated
Anaerobic bacteria
■■MICROBIOLOGY Bacteroides fragilis, other B. fragilis group, peptostreptococci,
peptococci, eubacteria, Fusobacterium spp., Clostridium spp.
Most IAIs are caused by microorganisms normally present in the
gastrointestinal tract, whereas blood-borne pathogens may produce Postoperative infection (limited prior antimicrobial exposure)
some less common infections, such as splenic or hepatic abscesses. Gram-negative bacilli:
The types and numbers of microorganisms present within the lumen of Escherichia coli, Klebsiella spp., Enterobacter spp., Pseudomonas
the gastrointestinal tract vary greatly in different areas of the gut. As a aeruginosa
general principle, the numbers of microorganisms and the prevalence Gram-positive cocci:
of Gram-negative Enterobacteriaceae and anaerobic organisms Enterococcus faecalis
increase in frequency from the stomach to the distal colon. In the Anaerobic bacteria
normal individual, the stomach and proximal small intestine contain Bacteroides fragilis, other B. fragilis group – less frequently
fewer than 103–104 organisms per gram of contents. These are primarily isolated
streptococci or lactobacilli (Savage 1977, Tappenden and Deutsch Fungi:
2007). However, in critically ill and other hospitalized patients, Candida albicans – infrequently isolated
the stomach and duodenum may become heavily colonized with
Enterobacteriaceae, Pseudomonas spp., enterococci and other Gram- Healthcare-associated infection (significant prior antimicrobial
positive cocci, and yeasts (Marshall et al. 1993, Reddy et al. 2008). exposure)
In the more distal small intestine, Gram-negative enteric aerobic/ Gram-negative bacilli:
facultative anaerobic bacilli become increasingly prevalent, although E. coli, Klebsiella spp., Enterobacter spp., Pseudomonas aerugi-
Gram-positive cocci continue to be present. In the terminal ileum, nosa, Acinetobacter spp.
bacterial counts may reach 107–108 organisms/g contents; significant Gram-positive cocci
numbers of anaerobic organisms are present in addition to the aerobic Enterococcus faecium, including vancomycin-resistant E.
Gram-negative bacilli and Gram-positive cocci. In the colon, obligate facecium
anaerobic microorganisms come to predominate as much as 100- to Staphylococcus aureus, including meticillin-resistant S. aureus
1000-fold over the aerobic microorganisms. Bacterial counts reach Coagulase-negative staphylococci
1010–1011 microorganisms/g contents (Savage 1977, Tappenden and Anaerobic bacteria
Deutsch 2007). In the presence of intestinal obstruction or intestinal Bacteroides fragilis, other B. fragilis group – infrequently isolated
dysmotility, this pattern of colonic flora becomes prevalent in more Fungi:
proximal portions of the small intestine as well. Candida albicans
The actual pathogens responsible for an IAI reflect the Non-C. albicans spp.
gastrointestinal flora at the source of the infection. Thus, the most
common pathogens are enteric Gram-negative bacilli, Gram-positive
cocci, and anaerobic microorganisms. These infections are nearly streptococci, described as the Streptococcus milleri group (Goldstein
always polymicrobial (Box 6.1). In fact, 5–10 isolates can be obtained and Snydman 2004); species that are components of this group
from clinical samples analyzed in research laboratories; however, include S. anginosus, S. constellatus, and S. intermedius (Verrall 1986).
few of these microorganisms are actually identified by most clinical Although much attention has been paid to the role of enterococcal
laboratories (Brook 2002, Roehrborn et al. 2003, Goldstein and organisms in IAIs, these are isolated much less frequently than the
Snydman 2004). S. milleri group streptococci. Enterococci are encountered in only
The most common microorganism isolated from IAI is Escherichia 10–20% of peritoneal cultures (Waites et al. 2006). When enterococci
coli. This organism is identified in at least 50% of specimens obtained are isolated in patients with community-acquired IAIs, it is most
with these infections. (Brook 2002, Goldstein and Syndman 2004). commonly a penicillin-susceptible strain of E. faecalis (Teppler et al.
Klebsiella spp. is probably the next most common Gram-negative 2002). Enterococcus faecium, which is generally resistant to penicillins
aerobic organism found, although it is encountered much less and may become resistant to vancomycin, is increasingly encountered
frequently than E. coli. Other enteric Gram-negative bacilli, such as as a component of healthcare-associated IAIs. The pathogenic role of
Enterobacter spp. may also be identified. Pseudomonas aeruginosa enterococci, particularly in the setting of community-acquired IAIs,
is associated with nosocomial infections, but can also be isolated remains controversial.
occasionally from patients with community-acquired IAIs. Obligate anaerobic organisms are important in the pathogenesis
Along with Gram-negative bacilli, aerobic Gram-positive cocci are of most IAIs, particularly those arising from a lower gastrointestinal
commonly isolated from IAIs. These are predominately viridians-type source. Bacteroides fragilis is isolated from a third to a half of cultures.
 Diagnosis 79

Other members of the B. fragilis group, including B. thetaiotaomicron, species (Snydman et al. 1999, Aldridge et al. 2001, Mazuski et al.
B distasonis, B. vulgatus, B. ovatus, and B. uniformis, are also 2002b). However, it is uncertain if this increased resistance is of
encountered. Other anaerobic bacteria that contribute to these clinical importance except in the small subgroup of patients who have
infections include peptostreptococci, peptococci, eubacteria, and anaerobic bacteremia. MRSA is increasingly encountered throughout
Fusobacterium and Clostridium spp., among others (Goldstein 2002). the world (Chua et al. 2011), but is infrequent in community-acquired
Fungal microorganisms are isolated from less than 10% of patient infections.
IAIs. Almost all are Candida spp., most frequently C. albicans, although
non-C. albicans spp. are also encountered. These yeasts play relatively
little role in the pathogenesis of community-acquired IAIs, but have
■■DIAGNOSIS
a greater role in healthcare-associated infections. An IAI is suspected in most patients on the basis of a constellation
of abdominal symptoms and signs. The most frequent symptom is
■■Microbiology of healthcare- abdominal pain, which is present in most patients. Pain is typically of
relatively recent onset, but of variable severity, quality, and radiation.
associated IAIs Symptoms of gastrointestinal dysfunction, such as anorexia, nausea,
The standard microbial flora of IAIs is altered in patients with prior vomiting, diarrhea, or constipation, are frequently observed, but
exposure to the healthcare setting, with regard to both the microbial are generally non-specific in character. Many patients present with
species and the susceptibility profiles (see Box 6.1). There is a shift in systemic signs of inflammation, such as fever, tachycardia, and
the relative frequency of various Gram-negative isolates. E. coli tends tachypnea, but these may be absent in severely ill patients.
to be isolated less frequently, but Enterobacter and Pseudomonas spp. The abdominal exam is generally abnormal. Most often, there is
more frequently. A similar shift is seen in Gram-positive organisms. some degree of abdominal tenderness, which may range from mild and
Streptococci are less likely, but enterococci are identified more poorly localized to severe and localized to one part of the abdomen, or
frequently. Anaerobic bacteria are isolated less frequently in patients generalized to the entire abdomen. Rebound tenderness and voluntary
with healthcare-associated IAIs, and may play less of a role in these or involuntary guarding is variably elicited.
infections because of prior treatment. C. albicans and non-C. albicans Basic laboratory examinations, although non-specific, are
spp. are identified more commonly in healthcare-associated IAIs. frequently utilized in the diagnostic evaluation of patients with
Patients who have recurrent gastrointestinal perforations, e.g., after suspected IAIs. Leukocytosis with a neutrophilia is observed in many
surgical procedures or pancreatic infections, are at increased risk for patients. Blood chemistry studies, such as serum bilirubin or other
candidal infections (Calandra et al. 1989). Colonization of the upper liver function tests for patients with suspected hepatobiliary disease,
gastrointestinal tract with Candida spp. becomes more common in or amylase or lipase with suspected pancreatitis, can be valuable in
critically ill patients (Sandven et al. 2001). selected patients.
Patients with tertiary peritonitis exhibit the most resistant types It is not necessary to obtain blood cultures in suspected IAIs.
of IAI pathogens. The most common pathogens isolated in these Only 0–5% of patients will have positive blood (Solomkin et al. 2010).
patients include multiply resistant, Gram-negative pathogens, such However, higher rates of bacteremia are observed in critically ill
as Pseudomonas and Acinetobacter spp., enterococci, including patients with IAIs. It is recommended that routine blood cultures be
vancomycin-resistant E. faecium, coagulase-negative staphylococci, acquired in such patients when they present with severe sepsis or
meticillin-resistant Staphylococcus aureus (MRSA), and fungal septic shock (Wagner et al. 1996).
organisms (Trick et al. 2002, DeLisle and Perl 2003, Pfaller et al. 2005). For most patients, the history, physical exam, and basic laboratory
studies will establish the presence of an IAI. Clinical diagnoses of
■■Susceptibilities of appendicitis, cholecystitis, or diverticulitis can frequently be made on
the basis of their characteristic symptoms and signs. For the diagnosis
common pathogens of appendicitis, scoring systems have been devised that integrate
Antimicrobial resistance has become increasingly common among various symptoms, signs, and laboratory findings into a single score.
pathogens involved in community-acquired IAIs. For E. coli, in vitro Although these scoring systems appear to have good sensitivity and
resistance to ampicillin/sulbactam is commonplace, occurring in specificity, their utility for clinical practice has not been universally
at least 45% of strains cultured from IAIs. These resistant strains are accepted (Alvarado 1986, Urban and Fishman 2000, Doria et al. 2006,
recovered at approximately the same frequency in all parts of the Bundy et al. 2007).
world (Chow et al. 2005). E. coli resistance to fluoroquinolones has also Ultimately, however, clinical diagnoses will not always be accurate.
become common, particularly in Latin America and south Asia, and is More importantly, many patients will not present in a classic manner
increasing elsewhere (Hsuch and Hawley 2007, Coque et al. 2008, Ko for IAIs. The diagnosis may be particularly obscure in certain patient
and Hsueh 2009). Probably the most ominous change is the emergence groups, such as elderly people, those receiving corticosteroids or
in the community of strains of Enterobacteriaceae, including E. coli, other immunosuppressive therapies, and those with an unreliable
Klebsiella spp., and Enterobacter spp. with resistance to several β-lactam examination due to a neurological problem such as dementia or a prior
antibiotics. These strains typically carry plasmids that encode for one spinal cord injury. Thus, further confirmatory testing is employed in
of a variety of different extended-spectrum β-lactamases. Such strains many patients to establish the presence of an IAI.
have become widespread in Latin America and south Asia. Most of these A number of different imaging procedures are used. Standard
strains remain susceptible to carbapenems; however, some strains of radiographic views of the chest and abdomen may reveal free
Enterobacteriaceae, particularly those carrying the New Delhi metallo-β- abdominal air or other findings of IAIs, but these are often inconclusive.
lactamase, are resistant to essentially all β-lactam antibiotics, including Ultrasonography and computed tomography (CT) of the abdomen are
carbapenems (Dupont 2007, Coque et al. 2008, Gupta et al. 2011). the principal imaging modalities of diagnostic value. Ultrasonography
Increasing resistance to antibiotics such as clindamycin and is the technique of choice for suspected hepatobiliary disease. It is
cefotetan is frequently seen in strains of B. fragilis and other anaerobic also of use in pelvic sources of gynecological infection in women.
80 INTRA-ABDOMINAL INFECTIONS

If there is good technical expertise available, ultrasonography can also such as enterococci, has been associated with an increased risk of
be used to establish the diagnosis of appendicitis. treatment failure (Hopkins et al. 1993, Christou et al. 1996, Sitges-Serra
However, for most suspected IAIs, CT of the abdomen has become et al. 2002). Furthermore, the use of an inadequate initial empirical
the preferred imaging modality (Anaya and Nathens 2003). There is antimicrobial regimen, defined as one that did not provide coverage
a large body of literature comparing ultrasonography and CT for the of one or more of the microorganisms eventually isolated from the
diagnosis of appendicitis. In a meta-analysis of this literature, it was infected site, has also been found to be an independent predictor of
found that the sensitivity and specificity of CT was superior to that treatment failure and death (Montravers et al. 1996, Krobot et al. 2004,
of ultrasonography for diagnosing appendicitis in both children and Sturkenboom et al. 2005). Thus, the choice of the initial empirical
adults (Wacha et al. 1999). antimicrobial therapy appears to play a role in determining clinical
Other considerations play a role in the decision to use one or other outcome. Stratification of patients based on the absence of presence
of these techniques. Avoidance of ionizing radiation may be desirable of a healthcare-associated infection, and thereby the likelihood of
in the diagnostic evaluation of children and pregnant women. Also, encountering resistant organisms, has been recommended as a means
any decision on the imaging modality includes local availability of CT of selecting specific antimicrobial therapy.
and ultrasonography, as well as access to technical expertise in their
performance and interpretation. ■■Physiological resuscitation
■■MANAGEMENT OF IAIs and support
Correction of physiological abnormalities associated with IAIs is a
The three fundamental principles for managing patients with IAIs are: fundamental principle in management. The goal is to improve tissue
1. Physiological resuscitation and support perfusion, such that delivery of endogenous mediators of host defense
2. Interventional procedures to control the source of the infection as well as exogenous antimicrobial agents to inflamed and infected
3. Antimicrobial therapy to treat the residual infection remaining after tissues is optimized. Enhancement of systemic perfusion should also
a source control procedure. allow the patient to better withstand the physiological challenges
Application of these principles will vary according to the patient’s inherent in source control procedures, thereby improving outcomes.
acuity and associated underlying medical comorbidities. Thus, an None the less, physiological resuscitation and support are not an end in
assessment of patient risk factors may be useful in selecting the specific themselves, and attempts to correct these physiological abnormalities
therapeutic approach for a given patient. without also addressing source control and antimicrobial therapy will
lead to treatment failure.
■■Patient risk assessment The degree to which a patient with an IAI demonstrates severe sepsis
or septic shock can be used to assess that patient’s need for aggressive
Risk factors for treatment failure and death in patients with IAIs have physiological resuscitation and support. Criteria have been established
been evaluated in a number of multivariate analyses. Identified risk to define patients with sepsis, severe sepsis, and septic shock (Box 6.2)
factors include those related to patient characteristics as well as (Bone et al. 1992). Although these criteria are not highly sensitive or
those that are related more to the infection itself. Patient-related risk specific, they provide a basis on which to stratify patients according
factors include a higher APACHE II (Acute Physiology and Chronic to severity of illness. Another option is to use the serum lactic acid
Health Evaluation II) score, advanced age, hypoalbuminemia, concentration as a marker of severity. This measurement is usually
hypocholesterolemia, malnutrition, significant cardiovascular, readily available, and can be used not only to stratify patients according
hepatic, or renal disease, malignancy, and corticosteroid therapy to risk, but also to monitor their response to therapy (Bakker et al. 1991,
(Mazuski et al. 2002b). Among these, the APACHE II score has been Shapiro et al. 2005, Arnold et al. 2009, Jones et al. 2010).
the most consistent predictor of treatment failure and death. The Most patients with IAIs will have some depletion of intravascular
individual components of the APACHE II score include measures of volume and extracellular fluid due to poor oral intake, increased
the host response to the infection as well as underlying comorbidities. insensible water loss due to fever, extracellular fluid losses from
However, this score is somewhat problematic to calculate and subject vomiting or diarrhea, and sequestration of fluid within the bowel or
to significant interobserver variation. It is also a general marker of in the peritoneal cavity. Thus, administration of isotonic intravenous
illness, and its utility for tailoring specific therapeutic interventions fluids is generally indicated in these patients. For patients with severe
in patients with IAIs seems limited. sepsis or septic shock, more aggressive resuscitation is recommended.
Risk factors that pertain more directly to the characteristics of the IAI Early goal-directed therapy during the first 6 h of recognition of the
might be more useful for the selection of specific treatment modalities. infection is a reasonable approach for administration of intravenous
Surprisingly, the source of infection has not proven to be a reliable fluids, as well as selective use of vasopressor agents and inotropic
predictor of outcome, although one relatively large study identified a support in these patients (Rivers et al. 2001). Early goal-directed
non-appendiceal source of infection as an independent risk factor for therapy is included in the Sepsis Resuscitation Bundle, a component
severe sepsis (Anaya and Nathens 2003). The Mannheim peritonitis of The Surviving Sepsis Campaign guidelines for managing septic
index, a measure of how widespread an IAI is within the peritoneal cavity, shock (Dellinger et al. 2008).
has been found to be an independent risk factor (Pacelli et al. 1996).
However, most importantly, several studies have found that failure to
achieve adequate source control at the time of the initial intervention is
■■Source control
a very strong predictor of an adverse outcome (Wacha et al. 1999). Thus, Interventions to control the source of an IAI include drainage of
it appears important that an optimal operative or other source control infected fluid collections, debridement of infected tissue, and
procedure be performed as part of the early therapy in IAIs. procedures to contain further microbial contamination. The eventual
Risk factors may also relate to the type of microbial pathogens goal of source control is to re-establish normal anatomy and function.
involved in an IAIs. The presence of certain resistant microorganisms, In patients with uncomplicated IAIs, the source control procedure
 Management of IAIs 81

The timing of source control interventions in patients with IAIs

Box 6.2 Criteria for sepsis, severe sepsis, and septic shock (based is also a matter of controversy. It had been customary for such
on Bone et al. 1992). procedures to be carried out promptly at the time of diagnosis.
However, with the increasing use of less invasive but more technically
Systemic inflammatory response syndrome (SIRS) complex procedures, a delay in performing source control to ensure
Two or more of the following: availability of adequate technical expertise and resources has become
Temperature >38°C or <36°C more common. For patients with diffuse peritonitis or with ongoing
Heart rate >90 beats/min hemodynamic instability, source control should be undertaken as
Respiratory rate >20 breaths/min or PaCO2 <32 mmHg (4.26 kPa) soon as feasible, even if ongoing physiological resuscitation needs to
White blood cell count >12 000/mm3, <4000/ mm3, or with >10% be provided simultaneously. For hemodynamically stable patients
immature forms with localized infections, a delay in performing source control can be
considered if the availability of additional resources is likely to improve
Sepsis patient outcome. If such a delay is to be contemplated, adequate
The presence of an infection with two of more SIRS criteria antimicrobial therapy must be provided and the patient needs to be
carefully monitored for any evidence of deterioration.
Severe sepsis: Many of the details about source control procedures are determined
Sepsis associated with organ dysfunction, hypoperfusion, or by the specific organ that is involved in the infection. A full summary
hypotension of all these operative procedures and options is beyond the scope of
Hypoperfusion and perfusion abnormalities including, but not this chapter. Rather, some of the trends and controversies related to
limited to: source control will be highlighted by considering the management of
Lactic acidosis appendicitis, localized intra-abdominal fluid collections, and diffuse,
Oliguria generalized peritoneal infections.
Acute alteration in mental status
Source control for appendicitis
Septic shock The management of appendicitis has undergone significant changes
Sepsis-induced hypotension unresponsive despite adequate fluid over the past two decades. Appendectomy had been considered the
resuscitation treatment of choice for nearly all patients with suspected appendicitis
Perfusion abnormalities including, but not limited to: for nearly a century. The primary exception to this was for children
Lactic acidosis who presented with a periappendiceal abscess, in whom drainage
Oliguria followed by interval appendectomy was considered a reasonable
Acute alteration in mental status approach (Mason 2008).
In the past, nonsurgical management of acute appendicitis was
described as an option to be used only if surgical treatment was
completely unavailable (Adams 1990). However, deliberate use of this
should result in full control of the site of infection. In patients with approach in the treatment of patients with acute appendicitis has been
complicated IAIs, this procedure does not entirely eliminate the investigated in several prospective randomized controlled trials. In
infection, but should serve to sufficiently limit it such that subsequent these trials, nonsurgical management of appendicitis using antibiotics
antimicrobial therapy will lead to its complete resolution. alone was compared with mandatory surgical treatment (Eriksson and
A number of treatment modalities are utilized for source control. Granström 1995, Styrud et al. 2006, Hansson et al. 2009, Malik and Bari
Patients with circumscribed abscesses or other infected fluid 2009). Despite the availability of these data on over 700 randomized
collections can be treated with percutaneous drainage, provided that patients, various authors have come to different conclusions about
a safe route of access to the infection is available (Akinci et al. 2005, nonsurgical management (Varadhan et al. 2010, Ansaloni et al. 2011,
Theisen et al. 2005). Minimally invasive procedures are employed in Liu and Fogg 2011). The combined data indicate that appendectomy
many patients for the treatment of uncomplicated IAIs, such as acute was avoided in approximately 58% of the patients in these trials.
appendicitis (Cueto et al. 2006, Sauerland et al. 2010). Minimally Appendicitis subsequently recurred in around 14% of patients who
invasive procedures are also being increasingly used in patients with were initially managed nonsurgically. There was no apparent increase
complicated IAIs, although this is less widespread. For many patients, in perforation as a result of a delay in surgical management in the
open surgical procedures are still utilized, particularly when the patients who failed antibiotic treatment alone. Overall complication
infectious process is not well localized or there is necrotic tissue that rates were significantly higher in patients randomized to initial surgical
needs to be debrided. management (Ansaloni et al. 2011).
In patients with complicated IAIs, the source control procedure Although these data indicate that nonsurgical management of
provides the opportunity for obtaining cultures of the infected peritoneal acute appendicitis using antibiotic therapy alone is a relatively safe
fluid. There is some disagreement as to the utility of such cultures. For option, there are also extensive data attesting to the general safety
individual patients with a community-acquired IAI, routine cultures of appendectomy. The overall mortality rate in patients undergoing
appear to have relatively little value, particularly for those with surgical management of non-perforated appendicitis was estimated
perforated appendicitis (Dougherty 1997, Bilik et al. 1998, Kokoska et al. to be 0.8/1000 in a Swedish database, although the rate increased to
1999). However, even though these cultures may be considered optional >10/1000 in patients aged ≥70 years (Blomqvist et al. 2001). Another
for the individual patient, their use is recommended as part of an overall long-term study of the Swedish population found that an operation for
surveillance program for resistant pathogens within a community. As small bowel obstruction had been performed in only 0.75% of patients
a result of the greater potential for resistant organisms in patients with who had undergone appendectomy after 30 years, although this rate
healthcare-associated IAIs, routine cultures are recommended. was approximately 3.6-fold higher than that observed in matched
82 INTRA-ABDOMINAL INFECTIONS

control patients who had not undergone appendectomy (Andersson after an acute process such as appendicitis or diverticulitis, as well
2001). Currently, it would appear that both a traditional surgical and as the iatrogenic abscess that forms after an abdominal procedure.
nonsurgical approach using only antibiotics are viable options for The presence of localized extraluminal air or fluid around the site
treating patients with acute non-perforated appendicitis. of perforation or leak is not a contraindication to the placement of
The approach to perforated appendicitis has also undergone a percutaneous catheter. Overall success rates for percutaneous
significant evolution. Nonsurgical management of perforated procedures range from 80% to 92%, and complication rates are low.
appendicitis, particularly for those patients who present with a Many failures of initial percutaneous drainage can be salvaged by
periappendiceal phlegmon, has become increasingly accepted. This subsequent catheter drainage procedures (Akinci et al. 2005, Theisen
has been estimated to occur in 3.8% of patients with appendicitis et al. 2005).
(Andersson and Petzold 2007). Primary surgical therapy of such The success of percutaneous drainage is related to both the size of
patients may necessitate a larger procedure, such as a ileocecectomy the abscess and its complexity. In one study, the best success occurred
or right hemicolectomy, rather than simple appendectomy. There are with a unilocular fluid collection containing no more than 200  ml
only very small prospective randomized controlled trials evaluating fluid and with no fistulous connection to the bowel or other intra-
this approach; most of the data are retrospective and uncontrolled. abdominal organ. However, patient characteristics also influenced
In one meta-analysis comparing initial nonsurgical management of outcome after percutaneous drainage procedures; severity of illness, as
patients with a periappendiceal mass with an initial surgical approach, assessed by APACHE-III scores, increased the risk of failure, regardless
the failure rate with the nonsurgical approach was only 7.2%. of the abscess characteristics (Betsch et al. 2002).
Utilization of nonsurgical management was associated with a nearly
threefold decrease in complication rates. Recurrent appendicitis Source control for generalized peritonitis
was identified in only 7% of patients. As the risk of morbidity of It has generally been recommended that patients with generalized
routine interval appendectomy was greater than the risk of recurrent peritonitis undergo expeditious source control. However, many
appendicitis, these authors recommended against routine interval of these patients are at high risk for an adverse outcome due to
appendectomy. The finding that patients with a periappendiceal mass significant physiological compromise. Thus, there is an interest in
or phlegmon had fewer complications with an initial nonsurgical utilizing less invasive, less morbid procedures for source control in
approach was validated in a second meta-analysis as well (Simillis such patients as well, even if the intervention is just a temporizing
et al. 2010). measure (Fry 2003).
Laparoscopic appendectomy is now widely used for the treatment One example of a less invasive intervention for patients with
of appendicitis. The use of this technique has been supported by a generalized peritonitis is the use in laparoscopic lavage and drainage
large body of evidence. Compared with patients treated with open as treatment for patients with perforated diverticulitis. One review of
appendectomy, patients treated with laparoscopic appendectomy such patients, most of whom had generalized purulent peritonitis,
have a decreased rate of surgical site infection, decreased pain, a found a reoperation rate of only 2.4% during the initial treatment
decreased length of hospitalization, and an earlier return to normal period, and a mortality rate of only 1.4% (Alamili et al. 2009). As this
activities. The rate of postoperative intra-abdominal abscess is approach has not been evaluated in controlled trials, these results
higher, however, in patients undergoing laparoscopic appendectomy. should be considered preliminary.
Young female patients, obese patients, and those needing to return Damage control laparotomy is another potential approach that
to employment appear to be those who benefit most from use of the can be utilized to avoid an extensive procedure at the time of the
laparoscopic approach (Sauerland et al. 2010). initial intervention in severely ill patients with generalized peritonitis
Overall, current management of patients with appendicitis (Subramanian et al. 2010). The principles of this approach have been
exemplifies a trend toward using less invasive procedures for, and adapted from experience gained in patients with severe abdominal
even complete deferral of source control interventions in, selected trauma (Waibel and Rotondo 2010). During the initial intervention,
groups of patients. Utilization of these approaches appears to result in only the essential procedures necessary to control bleeding or
decreased patient morbidity. None the less, these approaches may not ongoing peritoneal contamination are performed. Thus, a diseased
produce similar results if applied to other patients with IAIs. Overall portion of bowel may be resected, but an anastomosis or stoma is
morbidity and mortality related to appendicitis are low because the not placed. The fascia is left open to facilitate subsequent, definitive
patients are generally young and previously healthy. In contrast, other procedures, which are undertaken after the patient has reached
types of intra-abdominal infections are more lethal and morbid than physiological stability.
appendicitis, and the patients who sustain them typically have fewer There are certain indications for which a planned, repeat
physiological reserves than patients with appendicitis (Merlino et laparotomy has gained acceptance. Planned re-laparotomy is
al. 2001). utilized when the source of the infection cannot be controlled with
a single procedure, when bowel or other hollow viscus continuity
Source control for infected cannot be safely restored at the time of the initial procedure, there is
intra-abdominal fluid collections a potential for ongoing intestinal ischemia such that re-laparotomy
is needed to establish the viability of the remaining bowel, and
The use of percutaneous drainage techniques for treating patients there is significant visceral edema that could lead to an abdominal
with localized infected intra-abdominal abscesses and other fluid compartment syndrome if primary fascial closure were performed
collections is another example where less invasive procedures (Schein 2003).
have come to be the predominant approach to source control. The For patients with generalized peritonitis who do not have one
continued advancement of techniques has made it possible to of these indications, however, there is no consensus as to the utility
approach many fluid collections that hitherto required a surgical of planned re-laparotomy. A prospective randomized controlled
procedure for treatment (Maher et al. 2004). Percutaneous drainage is trial compared patients with severe secondary peritonitis who were
routinely used for treating both the spontaneous abscess that develops treated with planned re-laparotomy versus those who underwent
 Management of IAIs 83

repeat laparotomy only if there was a clinical indication (“on-demand Antimicrobial therapy for mild-to-moderate
laparotomy”). Only 42% of patients in the latter group actually community-acquired IAIs
underwent repeat laparotomy. Overall, there was no evidence of a
clinical benefit for patients undergoing mandatory re-laparotomy, and For less severely ill patients with community-acquired IAIs, antimicrobial
this approach resulted in a longer hospital and intensive care lengths therapy should be relatively narrow spectrum, directed against Gram-
of stay as well as higher costs (Van Ruler et al. 2007). negative Enterobacteriaceae, particularly E. coli, streptococci, and
Thus, use of less invasive procedures may be an option for the usually obligate anaerobic microorganisms. In general, activity of
management of severely ill patients with IAIs, just as it is has become the regimen against Pseudomonas spp., enterococci, and fungal
for the treatment of less severely ill patients. The use of temporizing organisms is not necessary. The safety of using narrower-spectrum as
measures may be of benefit in these patients with significant opposed to broader-spectrum agents in these patients is established.
compromise of vital organs. However, these approaches need to Recommended agents for the treatment of patients with community-
undertaken with some caution because inadequate source control acquired IAIs of mild-to-moderate severity are shown in Table 6.1.
is associated with a substantially increased risk of an adverse clinical Selection of the specific antimicrobial regimen for a given patient
outcome. When managing any patient with limited or deferred source would ideally be based on considerations of efficacy and toxicity.
control, the patient should be carefully monitored. A potentially life- However, there are very few data to indicate that one regimen is more
saving procedure is undertaken expeditiously if the patient’s clinical effective than another (Mazuski et al. 2002a, Solomkin et al. 2003, Wong
trajectory declines. Carefully performed, adequately controlled et al. 2005). The relative efficacy of aminoglycoside-based regimens,
research studies are needed to better understand which patients might which at one time were considered the “gold standard” for IAIs, was
best be treated with approaches featuring limited or deferred source challenged in one meta-analysis (Bailey et al. 2002). These regimens
control interventions. are no longer considered first-line agents for empirical treatment.
Changing microbial susceptibilities would be expected to have
■■Antimicrobial therapy an impact on the efficacy of different antimicrobial regimens. This is
reflected in newer recommendations about antimicrobial regimens
Antimicrobial therapy is part of the general therapeutic armamentarium for IAIs. The widespread resistance of E. coli to ampicillin/sulbactam
for the treatment of patients with IAIs. The effectiveness of throughout the world led to this antibiotic being removed from
antimicrobial therapy is dependent on the presence of a functioning recommended agents. Resistance of E. coli to fluoroquinolones
host defense system, which is ultimately responsible for the clearance has led to caution in their use if the local prevalence of resistance is
of microbial pathogens and toxins. >10–20%. The emergence of Enterobacteriaceae in the community
Antimicrobial therapy is used for both prophylactic and thera­ with extended-spectrum b-lactamases will also limit the choice of
peutic purposes when managing an IAI, although it may be difficult antibiotics in certain locales. Thus, local patterns of resistance among
to distinguish between these two purposes. Prophylactic use of common pathogens should be taken into consideration when selecting
antimicrobial agents is generally advocated for the prevention of specific antimicrobial regimens.
surgical site infection in patients undergoing surgical procedures Beyond efficacy considerations, the toxicity of a given regimen
classified as clean contaminated, contaminated, or dirty infected. and its propensity for creating collateral damage will influence
This applies to virtually every patient with an IAI. For patients with antimicrobial selection. In the individual patient, a history of an allergic
complicated IAI, the therapeutic aim of antimicrobial agents is to or other reaction to a specific antibiotic may lead to the selection of an
eradicate pathogenic microorganisms that remain after a source alternative agent. In the local community, overuse of certain antibiotics
control procedure. For selected patients in whom a primary source may lead to collateral damage due to outbreaks of superinfecting or
control is not performed, the antimicrobial regimen is purely resistant organisms (Paterson 2004). Thus, if a given antimicrobial agent
therapeutic, since it plays a definitive role along with the host response had been implicated, e.g., in a local outbreak of Clostridium difficile-
in controlling the infection. associated disease, the use of an alternative agent would be prudent.
The general principle underlying antimicrobial therapy for IAIs
is to use agents effective against the aerobic/facultative anaerobic Antimicrobial therapy for severe
Gram-negative bacilli and aerobic Gram-positive cocci. For most community-acquired IAIs
IAIs, except for some that arise in the upper gastrointestinal tract or
hepatobiliary tree, the antibiotic regimen should also cover obligate Patients with community-acquired IAIs who present with severe sepsis
anaerobic organisms (Wong et al. 2005, Solomkin et al. 2010). Several or septic shock are at a substantial risk for a poor clinical outcome.
studies have shown that failure rates increase if anaerobic coverage is
not included (Edelsberg et al. 2008).
Selection of a specific antimicrobial regimen should be based on Table 6.1 Recommended antimicrobial agents for patients with
stratification of the patient according to risk of an adverse outcome. community-acquired intra-abdominal infections of mild-to-moderate
Different regimens have been recommended for patients with severity (based on Solomkin et al. 2010).
community-acquired and health care-associated IAIs. In addition, Single agents Combination regimens
within the category of community-acquired infections, different agents
Cefoxitin
are recommended according to the severity of the illness (Solomkin Cephazolin, cefuroxime, cefotaxime, or
Ertapenem
et al. 2010). Thus, no single antimicrobial regimen is preferred for all ceftriaxone plus metronidazole
Moxifloxacina
Ciprofloxacina or levofloxcina plus
patients. Use of a regimen that inadequately covers the pathogens may Ticarcillin/clavulanic acid
metronidazole*
result in treatment failure, but use of an excessively broad regimen Tigecycline
may lead to collateral damage through selection of resistant bacteria aAsa result of increased resistance of E. coli to fluoroquinolones, local susceptibility
and superinfecting pathogens. profiles should be considered before prescribing these agents.
84 INTRA-ABDOMINAL INFECTIONS

Although there are few data suggesting that the microbiology in such
patients differs from that of lower-risk patients with community- Box 6.3  Recommended antimicrobial agents for empirical treat-
acquired IAIs, use of inadequate antimicrobial therapy could potentially ment of patients with healthcare-associated intra-abdominal
have much more deleterious consequences. This hypothesis is based infections (based on Solomkin et al. 2010).
on outcome studies of other critically ill patients, e.g., inadequate
antimicrobial therapy in patients with ventilator-associated ⦁⦁ Utilize one of the regimens listed in Table 6.2
pneumonia has been associated with a twofold increase in mortality ⦁⦁ If there is a possibility of significant resistance among the
(Chastre and Fagon 2002). Moreover, a delay in the administration likely Gram-negative pathogens, add a second agent with activ-
of appropriate antimicrobial therapy has also been associated with ity against Gram-negative aerobic bacilli (an aminoglycoside,
increased mortality in a population of patients presenting with septic colistin, a fluoroquinolone, tigecycline), according to local
shock (Kumar et al. 2006). As a result of this potential for suboptimal susceptibility profiles
outcomes with community-acquired IAIs receiving inadequate ⦁⦁ Add vancomycin or ampicillin if a cephalosporin or fluoroqui-
antimicrobial therapy, broader-spectrum antimicrobial regimens nolone-based regimen is being used and the patient has not
are recommended for the initial empirical treatment (Table 6.2). received extensive prior antimicrobial therapy. If the patient has
The planned use of broader-spectrum antimicrobial agents for initial received extensive prior antimicrobial coverage, add vancomycin
therapy should also have a de-escalation plan to a narrower-spectrum to all regimens to provide activity against Enterococcus facecium;
regimen once definitive culture results are available. There is no need if there is a high risk or known colonization with vancomycin-
to continue a broad-spectrum regimen if more resistant pathogens, resistant E. faecium, substitute linezolid
such as Pseudomonas spp. or enterococci, are not isolated. ⦁⦁ Add vancomycin if the patient is colonized with methicillin-
resistant S. aureus (MRSA) and thought to be at significant risk
Antimicrobial therapy in for an intra-abdominal infection due to this organism
healthcare-associated IAIs ⦁⦁ Add an echinocandin (anidulafungin, caspofungin, micafungin)
if the patient is critically ill and at risk for an infection due to
As a result of changes of the microbial flora that are associated with Candida spp. Fluconazole should be used in less critically ill
the healthcare setting, and particularly with prior treatment with patients; an echinocandin or voriconazole can be used in pa-
antimicrobial agents, resistant pathogens are frequently involved. As tients infected with non-C. albicans spp. resistant to fluconzaole
with other healthcare-associated infections, resistant microorganisms
make empirical antimicrobial choices very difficult.
Antimicrobial therapy for healthcare-associated IAIs needs to
be individualized, according to both the patient’s history of prior infected with resistant pathogens. This is based in part on knowledge
antimicrobial therapy and the resistance patterns of the microbial of the frequency with which certain pathogens are encountered in the
pathogens in the local environment. The initial empirical regimen local environment, as well as their likely resistance patterns. Additional
should include coverage against a relatively broad range of Gram- Gram-negative coverage is recommended if more than 10% of the
negative bacilli and anaerobic organisms. Recommended regimens strains of the expected pathogen or pathogens would be resistant to
are similar to those described for treatment of high-severity the standard antimicrobial regimen. This approach is analogous to that
community-acquired infections. However, empirical treatment recommended for the treatment of ventilator-associated pneumonia.
regimens for patients with healthcare-associated infections frequently Additional agents that might be considered, depending on the types
need to be expanded to include additional agents directed against and susceptibilities of local pathogens, include an aminoglycoside, a
specific Gram-negative pathogens. In addition, the regimen may fluoroquinolone, a glycylcycline, or even the antibiotic colistin if highly
be broadened to provide coverage of enterococci, resistant Gram- resistant strains of Pseudomonas or Acinetobacter spp. are present
positive cocci, and yeast. Some of these recommendations have been locally. The empirical antimicrobial regimen should be narrowed once
summarized in Box 6.3. definitive culture results are available. Continued use of two agents
When deciding whether or not to utilize additional antimicrobial against Gram-negative organisms in an effort to provide synergy is
therapy directed against Gram-negative aerobic pathogens, an not recommended, and has not been shown to be effective (Cometta
assessment needs to be made of the likelihood that the patient will be et al. 1994, Dupont et al. 2000).
As a result of the frequency with which enterococci are isolated
in patients with healthcare-associated IAI, empirical coverage of
Table 6.2 Recommended antimicrobial agents for patients with this microorganism should generally be provided (Sotto et al. 2002,
community-acquired intra-abdominal infections of high severity (based Harbarth and Uckay 2004). In patients with an initial postoperative
on Solomkin et al. 2010). infection who have not received subsequent courses of antimicrobial
Single agents Combination regimens therapy, E. faecalis, is the usual enterococcal pathogen that will be
isolated. Piperacillin/tazobactam and broad-spectrum carbapenems,
Doripenem
Ceftazidimeb or cefepimea plus metronidazole including imipenem/cilastatin, and doripenem have reasonable
Imipenem/cilastatin
Ciprofloxacina,b or levofloxcina plus metronidazole activity against this organism. Ampicillin or vancomycin can also
Meropenema
Aztreonamc plus metronidazole plus vancomycin be added to a regimen that lacks such anti-enterococcal activity.
Piperacillin/tazobactam
aAs a result of increased resistance of E. coli to fluoroquinolones, local susceptibility Patients with healthcare-associated IAIs who have received more
profiles should be considered before prescribing these agents. extensive antimicrobial therapy are at risk for enterococcal infections
bAddition of ampicillin or vancomycin to the regimen should be considered to provide due to E. faecium. Under these circumstances, vancomycin is the
anti-enterococcal activity. The need for additional anti-enterococcal activity when preferred agent for enterococcal coverage, because this organism
using meropenem is controversial. is generally resistant to penicillins and carbapenems. Increasingly,
cThe recommended regimen for patients with a significant allergy to β-lactam antibiotics.
vancomycin-resistant E. faecium is being encountered in patients with
 Clinical outcomes 85

IAIs who have received extensive prior antibiotic therapy. Linezolid, iatrogenic bowel injuries operated on within 12 h of the injury and
daptomycin, quinupristin–dalfopristin, and tigecycline have activity those undergoing laparotomy for upper gastrointestinal perforations
against this microorganism, and are potential choices (Torres-Viera operated on within 24 h should be treated with no more than 24 h
and Dembry 2004, Eliopoulos 2005). Linezolid is the antibiotic for of antimicrobial therapy. In addition, patients with non-perforated
which most clinical experience has been reported. Empirical use an appendicitis, cholecystitis, bowel obstruction, or bowel infarction,
agent effective against vancomycin-resistant enterococci has not been in whom the focus of inflammation or infection has been eliminated
extensively studied, but could be considered in patients known to be by the source control procedure, should receive perioperative
colonized with vancomycin-resistant enterococci or considered to be antimicrobial therapy for no more than 24 h (Mazuski 2002a).
at very high risk for an infection due to that microorganism. Shorter courses of antimicrobial therapy are warranted for most
Staphylococcus aureus is occasionally found as a component of complicated IAIs. Limiting the duration of antimicrobial therapy to
a healthcare-associated IAIs, most commonly with postoperative 3–5 days has been shown to be effective in both retrospective and
infections, pancreatic infections, and tertiary peritonitis (Rotstein prospective studies (Andåker et al. 1987, Schein et al. 1994). An
et al. 1986, Torres-Viera and Dembry 2004). Treatment of IAIs alternative approach is to discontinue antimicrobial therapy once the
involving staphylococci follows the principles used for treating other patient has defervesced, has a normalizing white blood cell count, and
staphylococcal infections (Solomkin et al. 2004, Eliopoulos 2005). has had return of gastrointestinal activity (Wilson and Faulkner 1998,
If methicillin sensitive S. aureus is isolated, an anti-staphylococcal Taylor et al. 2000). This approach also leads to decreased utilization
penicillin or cephalosporin can be used. For patients with MRSA, of antimicrobial agents without adverse effects on patient outcome.
vancomycin has generally been used. Linezolid, daptomycin, Some patients with IAIs do not respond optimally to the initial
quinupristin/dalfopristin, and possibly tigecycline are potential empirical antimicrobial regimen. Patients with persistent signs of
alternatives. Very limited experience has been reported regarding the infection, such as ongoing fever or leukocytosis, may have an ongoing
use of any of these agents in IAIs. Empirical therapy directed against or recurrent IAI, or an infection at an extra-abdominal site (Lennard
MRSA is not generally warranted. However, it might be considered et al. 1980, 1982). The recommended approach for these patients is to
in a patient who has had extensive prior antimicrobial therapy and is perform diagnostic imaging or other investigations to localize a source
known to be colonized with this organism. of the abnormal physiological parameters. Prolonged, non-directed
Fungal microorganisms, particularly Candida spp., are frequently antimicrobial therapy, with either the same or different agents, is
components of healthcare-associated IAIs (Rotstein et al. 1986, strongly discouraged.
Montravers et al. 2004, 2006). Antifungal therapy directed against Patients in whom adequate source control cannot be achieved
Candida spp. should be used in patients who have a confirmed constitute an exception to the general rule of using short-duration
infection due to this microorganism. Identification of yeasts on the antimicrobial therapy for the treatment of IAI. An example of such
Gram stain of infected peritoneal fluid should also prompt inclusion a patient is a critically ill individual with tertiary peritonitis, who has
of antifungal therapy in the empirical regimen selected for these and ongoing clinical evidence of sepsis. Antimicrobial therapy should
other higher-risk patients (Bochud et al. 2004). Pre-emptive antifungal most likely be continued for a longer period of time, because early
therapy in patients who are at high risk for IAIs due to Candida spp. discontinuation of antimicrobial therapy has been associated with
also appears to be of benefit (Eggiman et al. 1999, Mazuski 2007). increased mortality in such patients (Visser et al. 1998).
Antifungal agents that have been evaluated for the treatment of
invasive candida infections include amphotericin B and its lipid
formulations, the azoles, fluconazole and voriconazole, among others,
■■CLINICAL OUTCOMES
and the echinocandins, caspofungin, micafungin, and anidulafungin For patients with complicated IAIs, the standard approach of
(Bassetti et al. 2006, Spanakis et al. 2006). Fluconazole is the agent most providing physiological resuscitation and support, source control,
frequently used for treatment of IAIs due to C. albicans. However, for and appropriate antimicrobial therapy has been associated with
critically ill patients, use of an echinocandin has been recommended a cure rate of around 80% and an overall mortality rate of 2–3%
as first-line therapy instead of fluconazole (Pappas et al. 2004, Reboli in clinical trials (Mazuski et al. 2002b). However, outcomes are
et al. 2007). There has been an increased incidence of yeast infections somewhat worse outside a clinical trial setting (Merlino et al. 2001).
due to non-C. albicans spp. in recent years (Maschmeyer 2006), which One statewide survey of patients with complicated IAIs demonstrated
may apply to patients with healthcare-associated IAIs as well. Some an overall mortality rate of 6%, a postoperative abscess rate of 10%,
of these non-C. albicans spp., particularly C. glabrata and C. krusei, and a reoperation rate of 13% (Mosdell et al. 1991). Outcomes are
are resistant to the usual dosages of fluconazole. Use of voriconazole strongly influenced by the characteristics of the patients and their
or an echinocandin is an option for treating patients from whom such infections. Mortality due to perforated appendicitis is substantially
microorganisms have been isolated. lower compared with rates observed in patients with other types of
complicated IAIs (Wilson and Faulkner 1998, Blomqvist et al. 2001,
Duration of antimicrobial therapy Anaya and Nathens 2003). In the statewide survey, the mortality rate
One way with which to avoid resistance and toxicity related to was 1% among patients with perforated appendicitis, but 13% among
antimicrobial therapy is to limit the duration of that therapy (Raymond patients with infections from another source (Mosdell et al. 1991).
et al. 2002, Gleisner et al. 2004, Davey et al. 2005, Dellit et al. 2007). The mortality rates of more severely ill patients have been reported
Much of the prolonged use of antimicrobial therapy that occurs in to be 17–32% (Mazuski et al. 2002b). Thus, complicated IAIs are still
IAIs is likely unnecessary, and may actually lead to a worse outcome responsible for considerable morbidity and mortality, particularly
(Gleisner et al. 2004, Hedrick et al. 2006). among patients with a non-appendiceal source of infection,
Patients who do not have a complicated IAIs should not receive those who have severe sepsis or septic shock, and those who have
prolonged antimicrobial therapy. The primary goal of therapy in such compromised organ function because of significant pre-existing
patients is prophylaxis against surgical site infection during the source comorbid conditions. Further research to identify optimal means of
control procedure. Patients undergoing laparotomy for traumatic or treating these patients is warranted.
86 INTRA-ABDOMINAL INFECTIONS

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 Chapter 7 Perirectal abscesses and
pilonidal disease
Susan Galandiuk

Compared with other surgical infections discussed in this book, many Perirectal and ischiorectal abscesses are the most frequent types,
of which are potentially fatal and complex in their management, the followed by the less common intersphincteric and supralevator ab-
etiology of primary and recurrent perirectal abscesses and pilonidal scesses (McElwain et al. 1975, Read and Abcarian 1979, Ramanujam et
disease is often overlooked and their treatment delegated to the most al. 1984). Factors involved in the cause of perirectal abscesses are diar-
junior personnel. Although these infections are infrequently fatal, rhea, trauma, hard stool, or foreign body), tissue injury (i.e., fissure),
considerable morbidity can attend those perineal infections that are Crohn disease, immunocompromised host, perforating carcinoma,
not managed in a prompt and appropriate fashion. hidradenitis suppurativa, tuberculosis (TB), and pelvic infections
such as diverticulitis or appendicitis (Gordon 2007).
■■PERIRECTAL ABSCESSES Figure 7.1a demonstrates the sites of these various types of peri-
rectal abscesses, and Figure 7.1b the location of fistulas. Perirectal
The cryptoglandular origin of abscess formation is generally accepted, abscesses tend to occur more frequently in males than in females
and infected anal glands have been demonstrated (Lockhart-Mum- (Goligher 1984, Ramanujam et al. 1984). Diagnosis of common peri-
mery 1929, Parks 1961). Anal glands extend from anal crypts through anal abscesses is usually straightforward and based on clinical findings
the lower half of the internal anal sphincter. An infection arising in and symptoms, including constant pain aggravated by defecation and
these crypts and glandular infections leads to an infection in the in- various types of Valsalva maneuvers such as coughing and sneezing,
tersphincteric plane where many glands terminate. Most anorectal and occasionally by fever. An erythematous, tender swelling in the
abscesses are due to infections within this intersphincteric space. perianal area most frequently occurs with perianal abscesses, and
Persistence of anal gland epithelium would result in the internal open- more diffuse swelling with ischiorectal abscesses. The most com-
ing remaining patent, with prevention of healing. One may consider mon symptoms of perirectal abscess are pain (98%), swelling (50%),
the pelvic floor as a cone within a cone; the inner cone consists of the and bleeding per rectum (16%), followed by other symptoms such as
rectum and internal sphincter and the outer cone (in caudal to cranial purulent anal discharge, diarrhea, and fever (Vasilevsky and Gordon
order) of the external anal sphincter, puborectalis muscle, and levator 1984). In patients for whom the diagnosis is unclear, needle aspiration
ani muscle. An infection within the intersphincteric plane between may confirm the presence of pus, or endorectal ultrasonography may
these two cones can extend: (1) distally between the internal and exter- confirm and map out the extent of perianal disease (Law et al. 1989).
nal anal sphincter muscles – perianal abscess, (2) through the external Differential diagnosis includes periurethral abscesses in the male, or
anal sphincter muscle as well – ischiorectal abscess, (3) proximally Bartholin gland abscesses in the female. Tubercular abscesses are
between the internal and external sphincter muscles – intersphincteric usually characterized by less viscous pus than conventional abscesses
abscess, or (4) above the levator ani muscle – supralevator abscess, or and may be associated with known pulmonary TB. Other differential
(5) perforate through the internal sphincter again, to lie beneath the diagnoses include hidradenitis suppurativa, sebaceous cysts, acti-
rectal mucosa – submucosal abscess. nomycosis, fissure in ano, pilonidal sinuses, and folliculitis of the

a b

Figure 7.1  (a) Types of perirectal abscesses: (A) Perianal, (B) ischiorectal, (C) intersphincteric, and (D) supralevator. (b) Types of fistulas: (A) Intersphincteric, (B)
transsphincteric, (C) extrasphincteric, and (D) suprasphincteric.
90 PERIRECTAL ABSCESSES AND PILONIDAL DISEASE

perianal skin. A pelvic abscess due to intra-abdominal disease may

present in the perineal area with fever and a palpable pelvic mass on
digital rectal or vaginal examination.

■■Treatment
Parenteral or oral antibiotics do not have a place in the treatment of
perirectal abscesses, except in the following circumstances:
⦁⦁ The presence of a prosthesis, such as a hip prosthesis, pacemaker,
or cardiac valve replacement
⦁⦁ Immunocompromised patients such as transplant recipients, those
with diabetes, human immunodeficiency virus (HIV) positivity, or
acquired immune deficiency syndrome (AIDS), and granulocy-
topenic patients such as those with leukemia or after aggressive
cancer chemotherapy
⦁⦁ As a temporizing measure if immediate surgical drainage is not
possible due to unavailability of a surgeon, or a patient is antico-
agulated or in extremely poor general medical condition.
⦁⦁ Significant cellulitis or an unusual degree of infection, such as a
massive pelvic/perianal infection with suspicion of the presence Figure 7.2  Perirectal abscess drainage: Cruciate incision with excision of
of gas-forming organisms “corners” allows for adequate drainage without the need for packing.
⦁⦁ When systemic antibiotics are used, large doses should be given
and terminated promptly to avoid meticillin-resistant Staphylococ-
cus aureus and Clostridium difficile superinfections. if a large abscess is present, and large Penrose drains can be placed
Digital rectal examination at the level of the dentate line for signs of through these counter-incisions to keep the skin edges open and
induration is usually the most accurate way of identifying an internal ensure adequate drainage. Perioperative antibiotics are unnecessary
fistula opening if one is present, and is superior to visual inspection before anorectal procedures, except in the circumstances outlined
with a rigid sigmoidoscope or anoscope. Rigid sigmoidoscopy does, above. The author performs drainage, whether in the office or in the
however, permit visual inspection of the lower rectum for signs of rectal operating room, with nearly all patients in a prone jack-knife position
Crohn disease, specific proctitis such as can occur in HIV-positive rather than in a lithotomy position. This gives the best exposure to the
and AIDS patients, as well as other pathology such as perforating area and permits the most careful examination. Pregnant women and
carcinomas. those unable to be positioned in this manner can be placed in a left
Perianal abscesses can usually be drained in the office under lo- or right lateral or lithotomy position.
cal anesthesia. This author prefers to use 1% lidocaine with 1:200 000
epinephrine. Ischiorectal abscesses are often too deep to drain without
general or regional anesthesia. This is also true of higher abscesses
■■RECURRENT ABSCESSES
or abscesses in the postanal space. In patients in whom the area is AND FISTULAS
too tender for an adequate examination, or in patients in whom no
physical abnormality can be detected despite significant symptoms Unless there is an unusual appearance to the abscess, or unusual ap-
or perirectal pain with or without pyrexia, an examination under pearance or consistency of the pus, the author often does not obtain
anesthesia is warranted. Two important considerations in treating cultures. The presence of enteric organisms when culturing perirectal
perirectal abscesses are to provide a large enough opening in the skin abscesses does not indicate the presence of a fistula. When initially
to prevent closure and re-accumulation of pus. Although one does treated for perirectal abscess, the patient should be informed that the
want to ensure adequate drainage, excessive manipulation to break abscess may recur. If it recurs, then a fistula is probably present, and
up loculations can result in trauma to the anal canal innervation. If will require definitive surgery. Fistulas represent a chronic anorectal
an internal fistula opening is identified, and the surgeon treating the disease, and recurring anorectal abscesses are an acute expression
abscess is knowledgeable, a primary fistulotomy can be performed. A of the presence of a fistula (Gordon 2007). Recurrent abscesses oc-
recent Cochrane review on this topic identified 6 trials involving 479 cur when persistent fistular tracts are overlooked, abscesses are
patients in which incision and drainage of a perianal abscess alone incompletely or only partially drained, or there is inflammation of
was compared with incision and drainage with treatment of the fis- extra-anal origin such as with hidradenitis suppurativa or pilonidal
tula (Malik et al. 2010). There was a significant reduction in abscess disease. Three-quarters of patients with recurrent perirectal abscesses
recurrence, persistent abscess or fistula, and repeat surgery in the have persistent fistula(s), with a third of these having had previous
latter group (relative risk = 0.13, 95% confidence interval 0.07–0.24). surgery (Chrabot et al. 1983). Of these patients with previous drainage,
Due to edema and the friable nature of tissue in the presence of two-thirds have an undiagnosed fistula, and a third a missed fistula
infection, a false passage can easily be made, and therefore fistulotomy component. The incidence of a persistent fistula after initial abscess
should be undertaken only if the internal opening and fistula are very drainage varies from 35 to 95% in various series (Killingback 1988).
obvious. The author prefers to drain abscesses by making a cruciate In looking for the internal fistula opening associated with a perirectal
incision over the abscess and excising the “corners” to provide for a abscess, the Goodsall rule applies (Figure 7.3). For abscesses or exter-
large cutaneous opening for drainage. This large opening prevents nal fistula openings on the posterior half of the anal circumference,
premature primary closure and eliminates the need for packing of the the internal opening is likely to be in the posterior midline, with a
wound (Figure 7.2). Radial counter incisions should be used liberally curved fistula tract, whereas, for those abscesses and external fistula
 Recurrent abscesses and fistulas 91

Fistulography may be useful in patients with suspected complex fis-

tulas and those with fistulas with high or supralevator extensions, and
also in patients with recurrent fistulas. However, routine fistulography
is generally not helpful (Kuijpers and Schulpen 1985).
Injection of hydrogen peroxide into external fistula openings may
be helpful in demonstrating internal fistula openings. Methylene blue
causes significant discoloration of adjacent tissue and is therefore
less useful.

■■Special considerations
Although drainage of perianal and ischiorectal abscesses is rela-
tively straightforward, other types of abscesses may require special
treatment.

Intersphincteric abscesses
Intersphincteric abscesses are an important cause of persistent
Figure 7.3  The Goodsall rule: Anterior fistula tracts are straight and located
undiagnosed anal pain, which is often aggravated by defecation.
radial to the external opening, and posterior fistula tracts are curved and with Swelling may not occur with this type of abscess, and there may be no
internal opening at the posterior midline. external sign of infection. Abscesses may drain spontaneously before
the patient is seen, and examination under anesthesia may be required
before a diagnosis can be made. All patients with an intersphincteric
openings on the anterior half of the anal circumference, the internal abscess have a fistula (Chrabot et al. 1983).
opening will be located on the external opening with a linear fistula
tract. One exception to this is the horseshoe abscess or fistula, which Submucosal abscess
is discussed later. Anterior abscesses may be extensions originating A high intermuscular or submucosal abscess is a variant of an inter-
from an internal fistula opening in the posterior midline. Although sphincteric abscess. It may rupture directly into the rectum. Transrectal
the definitive treatment of fistulas is beyond the scope of this chapter, unroofing of the abscess is usually sufficient.
several important points are pertinent to their management:
⦁⦁ One should err on the side of conservatism. Supralevator abscess
⦁⦁ As the puborectalis muscle is a sling extending from the symphysis Before definitive treatment of a supralevator abscess, one must first
and surrounding the rectum posteriorly and laterally, there is no determine the origin of the fistula, and whether it represents an upward
puborectalis anteriorly and therefore less muscle mass. More cau- extension of an intersphincteric abscess, an ischiorectal abscess, or an
tion and conservatism should therefore be exercised when treating extension of pelvic inflammation such as Crohn disease, diverticulitis,
anterior fistulas. or appendicitis.
⦁⦁ Primary fistulotomy should not be performed when the involved ⦁⦁ If the abscess is secondary to upward extension of an intersphinc-
part of the anal sphincter is more than 1 cm wide or thick. In these teric abscess, it should be drained into the rectum by dividing the
cases, a “delayed” fistulotomy is performed using a “seton.” This involved internal sphincter (Gordon 2007). Drainage through the
seton may be a no. 2 silk suture, or the author’s preference, a ves- ischiorectal space should be avoided because this will convert the
sel loop or a 3/8 inch Penrose drain. The seton is passed through process into a supralevator fistula.
the fistula tract and tied tightly, or tied using silk suture when the ⦁⦁ If the abscess has occurred as an extension of an ischiorectal ab-
Penrose drain is used. This results in local ischemia of the involved scess, it should be drained through the ischiorectal space, because
anal sphincter with subsequent necrosis. Two weeks later when drainage through the rectum would create an extrasphincteric
the patient is seen in the office, the seton, now loose, is again fistula (Gordon 2007).
tightened. This tightening does cause significant discomfort, and ⦁⦁ With abscesses originating from pelvic sources, drainage can be
oral pain medications are routinely prescribed. This same process achieved transrectally, through the ischiorectal space or through
is repeated until the sphincter muscle has been divided and the the abdominal wall (i.e., CT-guided drainage). If there is an open-
seton has fallen out. In slowly dividing the muscle in this manner, ing in the levator muscle through which pus is draining, it can
the seton causes a foreign body reaction and scarring, which in turn be widened to facilitate drainage, and a drain placed to ensure
results in the ends of the divided sphincter muscle being scarred adequate drainage. Treatment of the pelvic source of the abscess
or fixed in place with maintenance of good continence. This differs is required in nearly all patients.
from the “snapping apart” of the sphincter like an elastic band,
which occurs if the muscle is divided primarily, and could result Horseshoe abscess
in impaired continence. The tethering effect of the anococcygeal ligament may prevent poste-
Most primary fistula openings are posterior or anterior in the anal rior infections or abscesses (postanal space abscesses) from posterior
canal. There is a higher density of anal crypts in the posterior half of extension. These infections may extend anteriorly and laterally to
the anus (Marti 1990). Lateral location and increased number of fistula either or both sides of the perianal area to form a “horseshoe” ab-
openings are related to increasing fistula complexity. Sigmoidoscopy scess. This is explained by the fact that purulence generally spreads
can differentiate between anal canal and rectal fistula openings. In 355 along the path of least resistance. Knowledge of this type of extension
patients undergoing abscess drainage, an internal fistula opening was of posterior infections is essential for proper treatment. Horseshoe
identified in a third, whereas, in another study of 232 patients, fistulas abscesses can occur at three levels: Intersphincteric, ischiorec-
developed in two-thirds (Scoma et al. 1974, Ramanujam et al. 1984). tal, and supralevator, of which the second is the most common.
92 PERIRECTAL ABSCESSES AND PILONIDAL DISEASE

Posterior drainage should be performed, possibly with delayed may herald such massive infection include tachycardia, fever, hypo-
fistulotomy and counter-incisions for anterolateral extensions tension, and crepitus or necrosis of the overlying skin (Figure 7.5a).
(Hanley 1965) (Figure 7.4). Severe pain is typically the first symptom. In some patients, soft-
tissue gas can also be seen on conventional radiographs. Treatment
■■Postoperative care of choice in these patients is prompt drainage and debridement
(Figure 7.5b) and proper systemic antibiotics. Radical debridement
Wounds from drained abscesses heal by secondary intention, which and drainage must be performed as soon as possible, especially in
generally proceeds over 2–3 weeks. Sitz baths taken three to four the presence of gas-forming organisms. Appropriate systemic anti-
times daily for 10–15 min in very warm water will ease incisional biotic treatment is essential. In some reports, Escherichia coli is the
discomfort as well as maintain proper perianal hygiene. Patients most frequently cultured organism, whereas others report predomi-
are also instructed to take a laxative such as milk of magnesia twice nantly Clostridium spp. (Morpurgo et al. 2001). These infections may
daily until they have their first bowel movement after the drainage spread from the supralevator space to the pre-peritoneal space, or
procedure. This counteracts both the constipation secondary to alternatively extend to the perirectal soft tissue with necrosis of skin,
opiate pain medications and that due to apprehension about hav- subcutaneous tissue, or muscle. As the testicles receive their blood
ing a bowel movement after anorectal surgery. Patients are also supply from the spermatic vessels, they are not usually necrotic and
advised to take a psyllium or methylcellulose product to soften the can be banked in an abdominal wall or thigh “pocket” if surround-
consistency of their bowel movements to decrease both pain and ing tissue is debrided. The mortality rate for this type of infection
potential bleeding. Patients are seen 1 week after abscess drain- can be as high as 40%. Repeated examination and debridement as
age, and then biweekly until the wound has closed. If exuberant necessary are important.
granulation tissue is present, topical treatment with silver nitrate
sticks may speed healing.

■■Massive perineal infection

and soft-tissue necrosis
Crepitation or necrosis of the overlying skin with or without systemic
sepsis may be a sign of infection with a gas-forming organism. Many
fatal perianal infections have been reported (Abcarian et al. 1983,
Di Falco et al. 1986, Morpurgo et al. 2001). Delay in diagnosis, in-
adequate initial treatment, and the presence of associated diseases
contribute to the morbidity and mortality after massive soft-tissue
sepsis in the perianal area. Extensive infection of this type occurs
in <1% of patients with anorectal infections (Morpurgo et al. 2001).
Conditions frequently associated with extensive soft-tissue sepsis
and necrosis include diabetes mellitus, blood dyscrasias, organic
heart disease, chronic renal failure, hemorrhoids, previous abscesses
or fistulas, and anal trauma (Abcarian et al. 1983). Symptoms that
a

Figure 7.4  Technique of counter-incision for horseshoe abscess, with or Figure 7.5  Perirectal abscess with necrotizing infection in a patient with
without simultaneous treatment of posterior internal fistula opening type 1 diabetes. (a) Preoperatively and (b) after wide excision.
(arrow).
 Pilonidal abscess 93

■■Crohn disease also have diarrhea from colitis due to cytomegalovirus or other infec-
tious pathogens, which may further impair wound healing. Due to the
If unusual disease is encountered in terms of the number of abscesses high rate of non-healing of these wounds, conservatism is advised in
present, extent of the abscess(es), or unusual location, then skin dealing with these patients. A patient with a CD4 lymphocyte count
margins or granulation tissue or both should be sent for histological <200 or a clinical AIDS patient has higher morbidity rates than those
examination to see whether there is evidence of Crohn disease or any who are HIV positive but under control (Moenning et al. 1991). In the
other unusual pathology. Perirectal abscesses in patients with Crohn current era of highly active antiretroviral therapy (HAART), most HIV-
disease may be more difficult diagnoses than in other patients. Many positive individuals have low viral loads and normal wound healing
abscesses in these patients have already drained spontaneously at the (Horberg et al. 2006, Nadal et al. 2008). They can largely be treated
time of first presentation, and present as fistulas. Complex fistulas with without special considerations other than contact precautions.
atypical location of the external fistula opening are more common
in this group of patients. Although abscesses and fistulas in patients
with Crohn disease may have a cryptoglandular origin, they more
■■PILONIDAL ABSCESS
commonly originate from perforated fissures or ulcers that are visible Pilonidal disease is a relatively simple yet frequently frustrating prob-
by proctoscopy. Anal stricture secondary to Crohn disease may also lem that is characterized by its likelihood to recur. It most frequently
complicate diagnosis of this condition (Galandiuk et al. 2005). There is a occurs in young men who are hirsute, but can also occur in women.
tendency for the wounds of patients with Crohn disease to heal poorly. There are three different types of buttock contour: those individuals
Metronidazole may be especially helpful in these patients because who have a relatively deep buttock cleft and individuals with a rela-
of its immmunosuppressive effect. In some patients, diagnosis may tively sloping buttock cleft – more common among women; and the
be aided by the use of endorectal ultrasonography (Law et al. 1989). intermediate type (Nivatvongs et al. 1983). Pilonidal disease is more
Some of these patients may ultimately require proctectomy for their common among the first type, where there is more friction between
disease. Abscesses should be drained, but great caution exercised in the buttocks during walking and daily activities, and hair in this area
treating fistulas. can be driven back down the hair follicle and result in an abscess or
infected cyst within the hair follicle itself. Examination of individuals
■■Leukemic and with pilonidal disease will usually reveal the presence of “pilonidal
pits,” a frequent diagnostic sign (Figure 7.6).
granulocytopenic patients Traditionally, treatments for pilonidal disease have involved either
Perianal sepsis may be fatal in patients with leukemia and is treated local office procedures designed to temporize by draining infected
differently from that in “normal” patients. In severely granulocytopenic fluid collections, or more definitive treatments in the operating
patients, pus may not form and there may be diffuse infiltration, and room aimed at complete excision of the infection. The latter can be
induration without fluctuation. In such immunocompromised pa- divided into procedures in which the wound is left open for closure
tients, digital or sigmoidoscopic manipulation may lead to bacteremia by secondary intention, or closed primarily. Procedures in which the
and should be avoided. These patients should be treated aggressively wound is closed primarily are further divided into those with closure
with intravenous antibiotics. Sitz baths and analgesics should be used in the midline and those closed off midline. In all cases of operative
accordingly. Perianal infections in patients with leukemia are associ- excision, complete removal of the infected material with excision of
ated with a 45–78% mortality rate (Barnes et al. 1984). Although there infected collections, which often extend down to the presacral fascia,
is controversy over whether to aggressively perform drainage in these is of paramount importance. Excision and allowing these wounds to
patients, or to treat them only with intravenous antibiotics, one study
suggested that fewer postoperative complications occurred in these
patients if the granulocyte count was >1000/mm3 (Barnes et al. 1984, Figure 7.6
Shaked et al. 1986, Carlson et al. 1988). Candidates most suitable for Chronic
surgical treatment are leukemia patients in remission and those with pilonidal
abscess. Note
chronic forms of leukemia. Surgery should be reserved for those who
the multiple
do not respond to conservative therapy and in whom there is palpable draining
fluctuance (North et al. 1996). Attention should also be paid to the pilonidal pits in
platelet count, and transfusions given as needed should surgery be the natal cleft
necessary. and hirsute
nature of the
patient.
■■HIV-positive and AIDS patients
HIV-positive and AIDS patients may also present with perirectal ab-
scess or sepsis. In one study, the frequency of anorectal symptoms was
32% in HIV-positive patients, 43% in HIV-symptomatic patients, and
25% in AIDS patients (Miles et al. 1990). In that study, the incidence
of hospital admission due to anorectal disease was 14 times higher in
HIV-positive homosexual and bisexual men than in the general male
population. In one report, 80% of perianal wounds in HIV-symptom-
atic patients did not heal within 30 days postoperatively, with a 16%
rate of major complications (Wexner et al. 1986). In that series, peri-
rectal abscess was present in 16 of 51 HIV-positive patients requiring
anorectal surgery. Condylomata acuminata are often present and can
even spread to the healing abscess drainage site. These patients may
94 PERIRECTAL ABSCESSES AND PILONIDAL DISEASE

close secondarily or “marsupializing” them (i.e., suturing the edges

of the wound down to the fascia and allowing secondary closure) is
a very slow process. As a result of the same friction on the buttock
crease, as mentioned earlier, while walking or doing normal daily
activities, these wounds are notoriously hard to heal. In addition, the
posterior location of the wounds means that it is always difficult for
patients to care for it themselves, often leading patients to enlist the
aid of a family member or nursing help to help with weekly shaving
or depilation of hair and dressing changes. Simple sitz baths with an
antibacterial soap may be helpful. Negative pressure dressings have
also been used to help hasten wound healing albeit at significant cost.
Despite the longer time to heal and need to do dressing changes, a
recent Cochrane study did show that open healing reduces the risk of
recurrence by 35% when compared with any closed method (Al-Kha-
mis et al. 2010). Primary incision and closure of pilonidal abscesses
with midline incisions have been associated with a significant surgical
site infection rate and subsequent healing by secondary intention.
High surgical site infection rates with primary closure has led to the
development of alternative approaches using an “off-midline” incision.
a
One approach that has led to reports of the highest degree of healing
has been the concept of excision of the contributing hair follicles and
lateral placement of the incision, as advocated by Bascom (1983) (Figure
7.7). In that early report of 161 patients with a mean 3.5-year follow-up,
his mean time to healing was 3 weeks, with 17% of patients returning
with complaints of drainage of recurrent disease requiring intervention.
With this technique, an incision is made just lateral to the midline, and
the incision is angled downward toward the midline where the infected
abscess is excised, including excision of the pilonidal pits, which through
a modification can easily be excised using a skin-punch biopsy. The
pits can then be closed primarily, as is the lateral incision. If patients
come with a primarily infected pilonidal cyst, lateral drainage in the
office also permits a future lateral excision and facilitates the delayed
definitive procedure. There are numerous variations for treating chronic
pilonidal sinus that are beyond the scope of this chapter. Suffice it to
say that the aforementioned Cochrane review (Al-Khamis et al. 2010)
provides evidence that midline compared with “off-midline” procedures
are associated with higher rates of surgical site infection (relative risk
= 3.72, 95% confidence interval 1.86–7.42) as well as higher recurrence
rates (Peto odds ratio 4.54, 95% confidence interval 2.30–8.96).
Regardless of which way the pilonidal disease is approached,
frequent office follow-up is required to insure that the wound stays
hair free. As this often occurs in hirsute individuals, failure to keep the
vicinity of the wound free of hair can lead to a prompt persistence or re-
currence of the problem, as this is the source of the problem in the first
b
place. Hair growing into the wound also contributes to non-healing.
In cases in which patients have had multiple prior procedures or Figure 7.7  (a) The ellipse of skin to be removed is marked in red. The area
there are persistent wounds, flap procedures may be desirable. The to be mobilized as a full-thickness skin flap is outlined in blue. (With permission
goal of these procedures is to provide additional soft-tissue coverage from Bascom and Bascom (2002).) (b) Fit of the flap from the right is checked
to the wound while also “obliterating” or flattening the contour and before the flap from the left is cut away. Marking is designed for a cleft floor
“indentation” of the buttock cleft. Numerous flap procedures have that is shallower and less tense and for a suture line near the surface. (Redrawn
with permission from Bascom and Bascom 2002; © 2002, American Medical
been proposed, including a rhomboid flap (Limberg flap), Z-plasty,
Association. All rights reserved.)
and others (Mentes et al. 2008, Ates et al. 2011). The rhomboid flap is
a relatively simple procedure that provides for excision of the wound
with a minimal tissue rotation (Figure 7.8). Because of the vascularity
of these wounds, I favor placement of a suction drain for a short time
■■CONCLUSIONS
if such procedures are performed and especially in obese patients. Treatment of perirectal abscesses is based on prompt drainage and
After surgery for pilonidal disease, recurrence rates of 7% and recognition. An abscess is the acute form and a fistula is the chronic
higher are observed (Al-Khamis et al. 20101). Flap procedures are form of anorectal infection. Sound knowledge of pelvic floor anatomy
generally not performed for initial treatment of pilonidal disease and, should allow the clinician to identify and properly treat abscesses in
without proper follow-up, such procedures can be associated with this area. Although they can be confused by aberrant locations, piloni-
intrinsic wound healing complications. dal infections are quite different from perirectal abscesses and fistulas.
 References 95

Figure 7.8  (a) Chronic pilonidal abscess after

midline incision in 17-year-old girl. Chronic
drainage kept her from attending school for over
1 year. (b) Chronic abscess excised and treated by
Limberg (rhomboid flap) with delayed healing of left
suture line 4 months postoperatively. (c) Healed flap
a b
6 months postoperatively

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anorectal infection. Dis Colon Rectum 1983;26:516–21. Experience with primary fistulectomy for anorectal abscess, a report of 1000
Al-Khamis A, McCallum I, King PM, Bruce J. Healing by primary versus cases. Dis Colon Rectum 1975;18: 646–9.
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Database Syst Rev 2010;(1):CD006213. without treatment of anal fistula (Review). Cochrane Database Syst Rev
Ates M, Dirican A, Sarac M, Aslan A, Colak C. Short and long-term results of the 2010;(7):CD006827.
Karydakis flap versus the Limberg flap for treating pilonidal sinus disease: a Marti MC. Anorectal abscesses and fistulas. In: Marti MC, Givel JC (eds), Surgery
prospective randomized study. Am J Surg 2011;202:568–73. of Anorectal Diseases. Berlin: Springer, 1990: 84–98.
Barnes SG, Sattler FR, Ballard JO. Perirectal infections in acute leukemia: improved Mentes O, Bagci M, Bilgin T, Ozgul O, Ozdemir M. Limberg flap procedure
survival after incision and debridement. Ann Intern Med 1984;100: 515–18. for pilonidal sinus disease: results of 353 patients. Langenbeck’s Arch Surg
Bascom J. Pilonidal disease: long-term results of follicle removal. Dis Colon 2008;393:185–9.
Rectum 1983;26:800–7. Miles AJG, Mellor CH, Gazzard B, et al. Surgical management of anorectal
Bascom J, Bascom T. Failed pilonidal surgery: new paradigm and new operation disease in HIV-positive homosexuals. Br J Surg 1990;77: 869–71.
leading to cures. Arch Surg 2002;137:1146–50 Moenning S, Huber P, Simonton C, et al. Prediction of morbidity by T4
Carlson GW, Ferguson CM, Amerson JR. Perianal infections in acute leukemia: lymphocyte count in the HIV positive or AIDS anorectal outpatient. Dis Colon
second place winner. Conrad-Jobst Award. Am Surg 1988;54: 693–5. Rectum 1991;34:17.
Chrabot CM, Prasad MI, Abcarian H. Recurrent anorectal abscesses. Dis Colon Morpurgo E, Galandiuk S. Fournier’s gangrene. Surg Clin North Am
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Di Falco G, Guccione C, D’Annibale A, et al. Fournier’s gangrene following a Nadal SR, Manzione CR, Couto Horta SH. Comparison of perianal diseases in
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Galandiuk S, Kimberling J, Al-Mishlab TG, Stromberg AJ. Perianal Crohn disease: What changed in the 21st century? Dis Colon Rect 2008;51:1491–4.
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Goligher J, Duthie H, Nixon H. Anorectal abscess. In: Goligher JC (ed), Surgery of for selection of anesthesia and patient position in anorectal surgery. Dis
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(eds), Principles and Practice of Surgery of the Colon, Rectum and Anus, 3rd edn. management of infectious and noninfectious anorectal complications in
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 Chapter 8 Hospital-acquired and
ventilator-associated
pneumonia
Philip S. Barie

Hospital-acquired pneumonia (HAP) occurs by definition more US Centers for Disease Control and Prevention [CDC], which do not
than 48 h after hospitalization, and is commonplace among surgical require the identification of a pathogen) overestimate the incidence
patients. Most cases of HAP develop during mechanical ventilation, of VAP compared with either microbiological or histological data
and are thus termed “ventilator-associated pneumonia” (VAP), which (Meduri et al. 1994, Fagon et al. 2000). In a systematic review of 89 stud-
comprises nearly a third of all intensive care unit (ICU) infections ies in which the incidence of VAP was reported among mechanically
(Chastre and Fagon 2002, Rello et al. 2002) (Figure 8.1). The inci- ventilated patients, the authors reported a pooled incidence of VAP of
dence of VAP varies markedly in published reports, depending on 22.8% (95% confidence interval [CI] (18.8–26.9%) despite substantial
the diagnostic criteria used. Clinical criteria alone (e.g., those of the heterogeneity of diagnostic criteria (Safdar et al. 2005). However,
the incidence of VAP may be decreasing, although it remains higher
in surgical units compared with medical units, and especially so in
trauma, burn, and neurosurgical patients. The National Nosocomial
Infection Surveillance (NNIS) system reported for 1992–2000 that
VAP occurred at a rate of 7.5 cases/1000 ventilator days in medical
ICUs and 13.6/1000 ventilator days in surgical ICUs (NNIS 2000). By
contrast, NNIS data inclusive of 1992–2004 indicate the rates of VAP
to be 3.7 cases/1000 ventilator days in medical ICUs and 8.6/1000
ventilator days in surgical ICUs (Table 8.1) (NNIS 2004). Data from
2006–2008 from the National Healthcare Safety Network (NHSN),
the CDC’s successor program to NNIS, suggest a further decrease,
the rates of VAP being 2.2 cases/1000 ventilator days in medical ICUs
and 3.8/1000 ventilator days in surgical ICUs (Table 8.1) (Edwards et
al. 2009). However, the number of reporting hospitals is much larger
in NHSN compared with NNIS.

■■RISK FACTORS
Risk factors for VAP are summarized in Box 8.1. Perhaps most im-
Figure 8,1  A ventilator-associated pneumonia in the right lower lobe in an
portant is airway intubation itself, the use of which appears to have
87 year old trauma patient. Bronchoalveolar lavage documented methicillin- decreased only modestly in surgical units despite the availability of
sensitive Staphylococcus aureus which responded to appropriate antibiotic techniques for non-invasive positive pressure ventilation (NIPPV)
therapy. The patient had an incidental left upper lobe lung lesion identified. (see Table 8.1). The incidence of VAP varies with the duration of

Table 8.1 Rates of healthcare-associated pneumonia among various intensive care unit (ICU) types
ICU type TT use VAP rate Mean/Median
1992–2004 2006–2008 1992–2004 2006–2008
Medical 0.46 0.48 4.9/3.7 2.4/2.2
Pediatric 0.39 0.42 2.9/2.3 1.8/0.7
Surgical 0.44 0.39 9.3/8.3 4.9/3.8
Cardiovascular 0.43 0.39 7.2/6.3 3.9/2.6
Neurosurgical 0.39 0.36 11.2/6.2 5.3/4.0
Trauma 0.56 0.57 15.2/11.4 8.1/5.2
Based on data from National Nosocomial Infections Surveillance (NNIS) System Report (2004) and Edwards et al. (2009). Data available at www.cdc.gov.
TT use, number of days of indwelling endotracheal tube or tracheostomy/1000 patient days in ICU; VAP, ventilator-associated pneumonia
Infection rates are indexed per 1000 patient-days.
98 HOSPITAL-ACQUIRED AND VENTILATOR-ASSOCIATED PNEUMONIA

Box 8.1 Risk factors for ventilator-associated pneumonia.

⦁⦁ Age ≥60 years

⦁⦁ Acute respiratory distress syndrome
⦁⦁ Chronic obstructive pulmonary disease or other underlying
pulmonary disease
⦁⦁ Coma or impaired consciousness
⦁⦁ Serum albumin <2.2 g/dl
⦁⦁ Burns, trauma
⦁⦁ Blood transfusion
⦁⦁ Organ failure
⦁⦁ Supine position
⦁⦁ Large-volume gastric aspiration
⦁⦁ Sinusitis
⦁⦁ Immunosuppression

Figure 8.2  A left upper lobe Pseudomonas aeruginosa pneumonia

confirmed by bronchoalveolar lavage. The right subpulmonic effusion is
mechanical ventilation (MV), increasing at a rate of 3% per day over
identified and has been contributed to by this patients extensive abdominal
the first 5 days, 2% per day over days 5–10, and 1% per day after that malignancy.
(Cook et al. 1998a). The risk of HAP increases 6- to 20-fold in mechani-
cally ventilated patients (Celis et al. 1988, Torres et al. 1990, Chastre
and Fagon 2002); patients with respiratory failure managed with longitudinal prospective (1997–2008) French multicenter outcome
NIPPV have a lower incidence of pneumonia (Brochard et al. 1995, database, who acquired at least one episode of VAP. Patients were
Antonelli et al. 1998, Hilbert et al. 2001). VAP is especially common in included if they stayed in the ICU for at least 2 days and received MV
patients with the acute respiratory distress syndrome (ARDS), owing within 48 h of ICU admission. It was estimated that 4.4% (95% CI,
to prolonged MV and devastated local airway host defenses (Chastre 1.6–7.0%) of the deaths in the ICU by day 30 and 5.9% (95% CI 2.5–9.1%)
et al. 1998, Markowicz et al. 2000). by day 60 were attributable to VAP. With an observed ICU mortality
Whether VAP is an independent risk factor for mortality is contro- rate of 23.3% on day 30 and 25.6% on day 60, the ICU mortality rate
versial (Barie 2000). Most recent series have reported a crude mortality attributable to VAP was about 1% by day 30 and 1.5% by day 60.
rate in patients with VAP of 9–27% (CDC 2000, Rello et al. 2002, Kollef Noting that the attributable ICU mortality of VAP may be modest,
2006), although rates can exceed 75% in high-risk patients infected Tseng et al. (2012) examined risk factors associated independently
with multidrug-resistant (MDR) organisms (Craven et al. 1986, Chastre with mortality from VAP in a study of 163 patients. Variables examined
et al. 1998). Attribution of mortality in patients with VAP has been were the Sequential Organ Failure Assessment (SOFA) score, APACHE-
problematic because they are systemically more ill compared with II scores, oxygenation index, underlying comorbidities (Charlson
non-VAP patients. Several authors have addressed this issue with Comorbidity Index), septic shock status, tracheostomy status, and
a matched cohort study design. Heyland et al. (1999) matched 177 microbiology. Of 163 patients 92 survived. Multivariable logistic re-
patients who developed VAP to controls by age, admission diagnosis, gression analysis identified that a pre-existing Charlson Comorbidity
location before the ICU, and admission Acute Physiology and Chronic Index score (p = 0.011), initial oxygenation index (p = 0.025), SOFA
Health Evaluation (APACHE) II score. Patients with VAP had a longer score (p = 0.043), VAP caused by Acinetobacter baumannii (p = 0.030),
ICU length of stay (LOS), but no increase in mortality (23.7% vs 17.7%, and infection with MDR pathogens (p = 0.003) were independent risk
p = 0.19). Furthermore, attributable mortality was highest for patients factors for hospital mortality in patients with VAP. However, the small
infected with high-risk MDR organisms, defined as meticillin-resistant number of deaths decreases the statistical power, variables related to
Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Acineto- antibiotic choice, timing, and duration were not examined, and it is
bacter baumannii, and Stenotrophomonas maltophilia (Figure 8.2). unclear how many surgical patients comprised the study population.
However, appropriate initial empirical therapy may mitigate adverse
outcomes (Kollef et al. 2000). Hugonnet et al. (2004) matched patients
with and without VAP by age, severity of illness, and duration of MV
■■PATHOGENESIS
before the development of VAP. Compared with non-VAP patients, Both impaired host immunity and displacement of normal oropha-
patients with VAP had an increased ICU LOS, prolonged duration of ryngeal flora by pathogens predispose the critically ill, mechanically
MV, and higher ICU cost, but not mortality (32.0% vs 24.7%, p = 0.26). ventilated patient to VAP. Normal non-specific host defenses, such
However, when these and other matched-cohort studies were pooled as the epiglottis, vocal cords, cough reflex, and ciliated epithelium
by meta-analysis, patients with VAP were more than twice as likely to and mucus of the upper airways, are either bypassed or rendered
die compared with those without VAP (odds ratio [OR] 2.03, 95% CI ineffective by airway intubation. Bacteria gain access to the lower
1.16–3.56, p = 0.03), and incurred both a longer ICU LOS and a mean respiratory tract via aspiration through the endotracheal tube (where
increased ICU cost of $10 019 (Safdar et al. 2005). they may establish colonies impervious to the effects of antibiotics in
Using a competing risk survival analysis, treating ICU discharge as the glycocalyx biofilm that coats the lumen of artificial airway devices)
a competing risk for ICU mortality, in a marginal structural modeling (Wilson et al. 2012), migration around it (particularly if cuff inflation
approach to adjust for time-varying confounding by disease severity, pressure is not maintained) (Zolfaghari and Wyncoll 2011, Ramirez et
Bekaert et al. (2011) studied 685/4479 (15.3%) patients from the al. 2012), or, in rare instances, hematogenous spread from bloodstream
 Prevention 99

infections (usually when the host is neutropenic) (Fujitani et al. 2011). intubation is required, orotracheal intubation may decrease the risk
Displacement of normal flora by pathogens is also necessary for the of developing VAP compared with the nasotracheal route. Holzapfel
development of VAP (Johanson et al. 1969, 1972, Bonten et al. 1996). et al. (1993) found that the incidence of VAP in patients who were
Both the facial sinuses and stomach may serve as potential pathogen randomized to orotracheal intubation was only half that of patients
reservoirs, but measures to minimize passage of pathogens from these intubated nasotracheally (6% vs 11%). Considering this and the as-
sources into the lower airways have provided mixed results. sociation between nasotracheal intubation and the development of
Due to indiscriminant use of broad-spectrum antibiotics, MDR nosocomial sinusitis (Rouby et al. 1994), orotracheal intubation is
pathogens are implicated increasingly in VAP (Garnacho-Montero preferred.
2003, Neuhauser et al. 2003, Hidron et al. 2008, Kallen et al. 2010). Once intubation has occurred, most standard preventive measures
Recently (2006–7), the most common pathogens isolated from pa- against VAP aim to decrease the risk of aspiration (Pieracci and Barie
tients with VAP have been S. aureus (24%, most of which are MRSA), 2007, Ramirez et al. 2012). Evidence indicates that semirecumbent
Pseudomonas spp. (16%, of which about 40% are MDR), Enterobacter positioning (30–45° head-up) is protective, compared with supine
spp. (8%), Acinetobacter spp. (8%; half are MDR), Klebsiella spp. (7%, positioning, especially during enteral feeding (Torres et al. 1992,
of which about 15% are MDR), and Escherichia coli (5%) (Hidron et al. Orozco-Levy et al. 1995, Draculovic et al. 1999). Both maintenance
2008, Kallen et al. 2010). Infection with MRSA is particularly common of endotracheal cuff pressure >20 cmH2O (Cook et al. 1998b, Nseir et
in patients with diabetes mellitus and after traumatic brain injury al. 2011), and continuous aspiration of subglottic secretions achieved
(Lowy 1998, Fridkin 2001, Fry and Barie 2011). P. aeruginosa, the most through the use of an endotracheal tube equipped with an additional
common Gram-negative pathogen in VAP, is increasingly common lumen above the balloon, reduce the incidence of VAP. In a systematic
with an MDR phenotype, especially to fluoroquinolones (Neuheuser review of 13 randomized trials (2442 patients), 12 reported a reduction
et al. 2003, Scheld 2003) third-generation cephalosporins (NNIS 2003), in VAP rates associated with subglottic secretion drainage arm; by
and increasingly to carbapenems (Apisarnthanarak and Mundy 2010). meta-analysis, the hazard ratio for VAP was 0.55 (95% CI, 0.46–0.66;
Anaerobic bacteria are isolated infrequently from patients with p <0.00001). The use of subglottic secretion drainage was also associ-
VAP, although this finding may represent an inability to culture these ated with reduced ICU LOS, decreased duration of MV, and increased
organisms effectively from the oxygen-enriched environment of the time to first episode of VAP. There was no effect on mortality (Musce-
mechanically ventilated airway (Marik and Careau 1999). Although dere et al. 2011).
isolation of fungi such as Candida spp. and Aspergillus fumigatus from Compared with postpyloric feeding, intragastric feeding results in
endotracheal aspirates is common, it nearly always represents colo- more episodes of both gastroesophageal reflux and aspiration (Torres
nization of the immunocompetent host (Loo et al. 1996, El-Ebiary et et al. 1992). However, randomized controlled trials (RCTs) comparing
al. 1997), with Candida spp. estimated to cause VAP in only about 2% rates of VAP have produced variable results (Orozco-Levy et al. 1995,
of cases (Hidron et al. 2008). However, when fungi are isolated from Draculovic et al. 1999). Heyland et al. (2001) performed a meta-analysis
two or more normally sterile sites (e.g., urine and lower respiratory of 11 RCTs and reported a relative risk (RR) of 0.77 (95% CI 0.60–1.00,
tract) in an immunocompromised patient, systemic antifungal therapy p = 0.05) for VAP with postpyloric compared with gastric feedings.
should be considered (Pappas et al. 2009). Based on these data, most expert recommendations do not differ-
entiate between gastric and postpyloric feeding (Kearns et al. 2000,
■■PREVENTION Montejo et al. 2000, Heyland et al. 2001). Pro-motility agents such as
erythromycin may facilitate safe intragastric feeding should this route
It has been estimated that up to 55% of cases of VAP may be prevent- be used (Berne et al. 2002). The timing of onset of enteral feedings may
able using current evidence-based tactics (Umscheid et al. 2011). also influence the risk of developing VAP. Initiation of enteral feeding
Prevention of VAP requires a thorough understanding of modifiable on day 1 compared with day 5 resulted in significantly more episodes
risk factors. Strict infection control, including hand hygiene with of VAP (49.3% vs 30.7%, p = 0.02) and a longer ICU LOS in one prospec-
alcohol-based hand disinfectants, gowning, and gloving, minimizes tive trial of 150 patients (Ibrahim et al. 2002). More recently, Shorr et al.
person-to-person transmission of pathogens and is paramount to (2004) reported that enteral nutrition begun ≤48 h after the initiation of
deterring all ICU infections (Pittet et al. 2000, Girou et al. 2002). Pre- MV was independently associated with the development of VAP (odds
vention of VAP begins with minimization of endotracheal intubation ratio [OR] 2.65, 95% CI 1.93–3.63, p <0.0001).
and the duration of MV. Non-invasive PPV should always be consid- Pharmacological strategies intended to minimize the risk of aspi-
ered instead of intubation, because there is a lower incidence of VAP ration of pathogenic bacteria include selective decontamination of
(Brochard et al. 1995, Antonelli et al. 1998, Hilbert et al. 2001, Girou the digestive tract (SDD) with either topical or systemic antibiotics
et al. 2003). Evidence-based strategies to decrease the duration of MV or antiseptics, and minimization of prophylaxis against stress ulcer.
include daily interruption of sedation (Kress et al. 2000), standard- Myriad clinical trials have addressed SDD which, on balance, show
ized weaning protocols (Rice et al. 2012), and adequate ICU staffing a significant decrease in the incidence of VAP (Reed 2011). However,
(Marelich et al. 2000). enthusiasm for use of SDD has been limited by questionable study
Technological improvements in endotracheal tube design may methodology (van Nieuwenhoven et al. 2001), use of narrow patient
decrease the risk of VAP. Improved design of the balloon cuff, to subsets from ICUs in which MDR pathogens were rare (de Smet et
decrease longitudinal folding of standard high-volume, low-pressure al. 2012), and an increased number of infections caused by MDR
polyvinyl chloride cuffs, through which aspirated secretions may gain pathogens observed after SSD (Misset et al. 1994, Lingnau et al. 1998).
access to the lower airway, by improving the seal between cuff and For these reasons, SDD is currently not used widely for the routine
mucosa may decrease the risk of VAP from the microaspirations that prevention of VAP.
are ubiquitous in the ICU (Nseir et al. 2011, Zolfaghari and Wyncoll Alternatively, oropharyngeal decontamination can be accom-
2011). Coating the endotracheal tube with an antibacterial silver al- plished with a topical antiseptic, such as chlorhexidine. A systematic
loy was successful in decreasing the incidence of VAP and delaying review and meta-analysis of 14 studies (2481 patients), 12 of which
its onset in a randomized trial (Kollef et al. 2008). If endotracheal investigated the effect of chlorhexidine (2341 patients) and 2 that
100 HOSPITAL-ACQUIRED AND VENTILATOR-ASSOCIATED PNEUMONIA

evaluated povidone–iodine (140 patients), found that antiseptic use (Bordon et al. 2011), and the incidence of VAP is lower. Wang et al.
resulted in a significant reduction in the risk of VAP (RR 0.67; 95% CI (2011) conducted a meta-analysis, the objective of which was to re-
0.50–0.88; p = 0.004). Chlorhexidine application was effective (RR 0.72; view systematically and synthesize all randomized trials to compare
95% CI 0.55–0.94; p = 0.02), whereas the analysis of povidone–iodine important outcomes in mechanically ventilated, critically ill patients
was underpowered. Favorable effects were more pronounced in who received an “early” (e.g., ≤7 days of translaryngeal intubation) or
subgroup analyses for 2% chlorhexidine (RR 0.53, 95% CI 0.31–0.91), “late” tracheostomy (any time thereafter). Seven trials (1044 patients)
and in cardiothoracic surgical studies (RR 0.41, 95% CI 0.17–0.98) were analyzed. Early tracheostomy for critically ill patients did not
(Labeau et al. 2011). reduce short-term mortality (RR 0.86, 95% CI 0.65–1.13), long-term
Prophylaxis of stress-related gastric mucosal hemorrhage is a mortality (RR 0.84, 95% CI 0.68–1.04), or the incidence of VAP (RR
known risk factor for the development of VAP (Bonten et al. 1996, 0.94, 95% CI 0.77–1.15) The timing of tracheostomy was not associated
1997a); its use should be reserved for patients at high risk for hemor- with a reduced duration of MV (weighted mean difference [WMD]
rhage (e.g., prolonged MV, intracranial hemorrhage, coagulopathy, -3.90 days, 95% CI -9.71 to 1.91) or sedation (WMD -7.09 days, 95%
glucocorticoid therapy). RCTs comparing histamine H 2-receptor CI, -14.64 to 0.45), a shorter stay in the ICU (WMD -6.93 days, 95% CI
antagonists, sucralfate, and antacids have yielded conflicting results -16.50 to 2.63) or hospital (WMD 1.45 days, 95% CI -5.31 to 8.22), or
(Bonten et al. 1994, 1995, Cook et al. 1998c); no agent is preferred for more complications (RR 0.94, 95% CI 0.66–1.34).
prophylaxis based solely on efficacy for prevention of VAP.
Ample data document the relationship between blood transfusion
and infection risk in surgical (Ottino et al. 1987, Braga et al. 1992),
■■DIAGNOSIS
trauma (Claridge et al. 2002, Hill et al. 2003, Robinson et al. 2005), The goals in diagnosing VAP are to determine whether the patient has
and critically ill patients (Taylor et al. 2002). Shorr et al. (2004) found pneumonia, and the etiological pathogen. Poor specificity is particu-
red blood cell transfusion to be independently associated with the larly problematic in the diagnosis of VAP because it not only exposes
development of VAP (OR 1.89, 95% CI 1.33–2.68, p = 0.0004). Earley individual patients to unnecessary risk from overtreatment with antibi-
et al. (2006) documented a decreased incidence of VAP in a surgical otics, but also increases selection pressure and thus the emergence of
ICU after implementation of an anemia management protocol. After MDR bacteria within the ICU (Neuhauser et al. 2003, Niederman 2003,
implementation of the protocol, fewer blood transfusions were ad- Pieracci and Barie 2007). Conversely, inadequate initial therapy in pa-
ministered despite equivalent outcomes, and the incidence of VAP tients with VAP (poor sensitivity) has been associated consistently with
decreased from 8.1% to 0.8% (p = 0.002). increased mortality that cannot be reduced by subsequent changes
Several antibiotic administration strategies, including “de-esca- in antibiotics (Alvarez-Lerma 1996). The diagnosis of VAP should be
lation” and antibiotic rotation or “cycling,” have been suggested to considered in the presence of one or more of the following: Fever,
prevent VAP caused by MDR pathogens. De-escalation refers to the leukocytosis or leukopenia, purulent sputum, hypoxemia, or a new or
process of tailoring empirical broad-spectrum antimicrobial coverage evolving infiltrate viewed on chest radiograph. However, several non-
to specific pathogens once microbiologic data from lower respiratory infectious respiratory disease processes may mimic these signs, such
tract samples become available. Discontinuation of unnecessary as congestive heart failure, atelectasis, pulmonary thromboembolism,
antibiotics at this point curtails not only the emergence of MDR pulmonary hemorrhage, and ARDS (Rangel-Frausto 1995, Barie et al.
organisms, but also the risk of drug toxicity. Antibiotic cycling offers 2005), making clinical criteria alone nonspecific (Figure 8.3). Fabregas
the potential for antibiotic classes to be used on a scheduled basis et al. (1999) found the presence of a new infiltrate on chest radiograph,
to preserve overall activity against predominant pathogens (Fridkin along with two of the three aforementioned clinical criteria, to be 69%
and Gaynes 1999, Carlet et al. 2004). Several prospective trials have sensitive and 75% specific for the diagnosis of VAP when compared with
documented improved microbial ecology (Barie et al. 2005, Dortch et postmortem histology. Several subsequent reports have confirmed the
al. 2011), decreased incidence of VAP (Kollef et al. 1997, Gruson et al. low specificity of clinical acumen in the diagnosis of VAP (Baughman
2003), improved initial adequacy of therapy (Kollef et al. 2000), and 2003, Mabie and Wunderink 2003), and clinically diagnosed VAP is
decreased mortality (Raymond et al. 2001) after the implementation confirmed microbiologically in fewer than 50% of cases (Rodriguez
of scheduled antibiotic rotation. However, these studies have been de Castro et al. 1996, Fagon et al. 2000).
limited by the use of historical controls, and thus possible confound- Pugin et al. (1991) standardized clinical, radiographic, and micro-
ing by other changes in care. Other data have challenged the efficacy biological criteria into the Clinical Pulmonary Infection Score (CPIS).
of antibiotic cycling (van Loon et al. 2005). Pending further research, Temperature, leukocyte count, chest radiograph infiltrates, the ap-
cycling of antibiotics may be considered if multiple classes of antibi- pearance and volume of tracheal secretions, PaO2:FiO2 (ratio of partial
otics are cycled frequently together with other tactics to prevent the arterial O2 pressure to fraction of inspired O2), and culture and Gram
emergence of MDR pathogens (Kollef et al. 2006). stain of tracheal aspirate (0–2 points each) yield a maximum CPIS score
Education of staff concerning modifiable risk factors may be cost- of 12 points; a score of >6 points indicates a high probability of VAP.
effective in preventing VAP. Zazk et al. (2002) demonstrated that an Despite favorable test performance of the CPIS in its initial description,
education program administered to respiratory care practitioners and its subsequent modification to include radiological progression
and intensive care nurses which highlighted correct practices for the of pulmonary infiltrates (Singh et al. 2000), the specificity of CPIS is
prevention of VAP resulted in a significantly decreased incidence of no better than clinical acumen alone when compared with lower
VAP and increased cost savings. respiratory tract cultures obtained via bronchoscopic brochoalveolar
lavage (BAL) or protected specimen brush (PSB) (Fartoukh et al. 2003,
■■Tracheostomy Luyt et al. 2004, Veinstein et al. 2006). Croce et al. (2006) have argued
that the CPIS has no probative value for trauma patients. The NNIS
Timing of tracheostomy remains controversial. Proponents argue that diagnostic criteria for nosocomial pneumonia (CDC 2012), which
patient comfort and pulmonary toilet are improved, the risk of glot- include similar combinations of clinical and radiographic parameters,
tic injury and post-extubation swallowing dysfunction is decreased perform equivalently to the CPIS when compared with quantitative
 Diagnosis 101

However, this transient desaturation is of unclear importance, not hav-

ing been correlated with poorer outcomes (Torres and Mustafa 2000).
Irrespective of collection method, respiratory tract cultures may
be analyzed using either semiquantitative or quantitative microbiol-
ogy. The crucial issue is distinction of colonization from infection
(Niederman 1990). Whereas semiquantitative microbiology reports
growth in terms of ordinal categories (e.g., light, moderate, or heavy),
quantitative microbiology reports growth in number of colony-form-
ing units (CFU)/ml of aliquot. In the latter case, a threshold value
is selected to distinguish colonization from infection. Commonly
used thresholds are 103 CFU/ml for PSB, 104 CFU/ml for BAL, and
105 CFU/ml for EA, lowered by one order of magnitude if antibiotics
have been changed recently or started before sample acquisition
(American Thoracic Society 2005).
Endotracheal aspirates possess inferior specificity when compared
with both blinded PTC (Vidaur et al. 2005) and bronchoscopic BAL
a or PSB (Sanchez-Nieto et al. 1998, Wu et al. 2002, Elatrous et al. 2004,
Brun-Buisson et al. 2005). Two systematic reviews, one of broncho-
Figure 8.3  (a) scopic BAL (Torres and Mustafa 2000) and one of blinded invasive
An aggressive
techniques (Campbell 2000), reported similar test characteristics
Enterobacter spp
bilateral pneumonia. for the two techniques. However, methodological variability is wide-
(b) A chest CT scan spread. Of 23 studies 16 (70%) in the former review used histology
of the patient in as a reference standard, compared with only 4 of 15 studies (27%)
(a), identifying the analyzed in the latter review. Furthermore, the remainder of studies
severe compromise analyzed in the review of blinded invasive techniques used either
of ventilating units bronchoscopic BAL or PSB as the reference category. Both reviews
within the lung.
reported substantial interstudy variability in sampling technique as
well as threshold values. A recent study reported that, compared with
a reference standard of bronchoscopic BAL (threshold 104 CFU/ml),
blinded PTC was 77% sensitive and 94% specific (Sanchez-Nieto et
b al. 1998). Thus, despite the limitations, it is likely that bronchoscopic
techniques are more specific than blinded techniques, and that either
technique is superior to EA.
lower respiratory tract cultures (Miller et al. 2006). Incorporation of Evidence-based recommendations for the diagnosis of VAP have
Gram stain results into the CPIS improves specificity only marginally been difficult to formulate because trials have compared various
(Fartoukh et al. 2003). However, the negative predictive value of a permutations of collection and analytical methodology, threshold
negative Gram stain in a clinically stable patient approaches 100% values, and reference categories. The largest randomized trial of this
(Blot et al. 2000). type compared an invasive, quantitative approach with a non-invasive,
As a result of the low specificity of clinical signs, radiographic crite- semiquantitative approach (Fagon et al. 2000). A total of 413 patients
ria, and microscopic examination of lower respiratory tract samples, suspected of having VAP were randomized to evaluation with either
culture of lower respiratory tract samples before any manipulation of bronchoscopic BAL or PSB with quantitative cultures, or “clinical”
antibiotics is mandatory for workup of a suspected VAP to minimize management consisting of semiquantitative analysis of EAs. Antibiotic
false-negative results. Two questions are debated: The method of therapy was discontinued in clinically stable patients with negative
specimen collection (invasive vs non-invasive), and the method of culture results, regardless of the study arm. Compared with the clini-
specimen analysis (semi-quantitative vs quantitative). Non-invasive cal strategy, patients in the invasive group demonstrated decreased
techniques include sampling of the lower respiratory tract via endo- 14-day mortality rates (16% vs 25%, p = 0.02), less antibiotic use (11.9
tracheal aspirate (EA), blinded plugged telescoping catheter (PTC), vs 7.7 antibiotic-free days), decreased sepsis-related organ failure, and
blinded PSB, and mini-BAL. EAs are less specific due to both an decreased 28-day mortality after adjustment for severity of illness. The
increased likelihood of contamination by oropharyngeal flora (in- clinical strategy also resulted in more and broader-spectrum antibiotic
dicated by the presence of squamous epithelial cells on Gram stain) therapy compared with the invasive strategy, and increased emergence
and an increased likelihood that the presence of organisms indicates of fungi. It is unclear whether these improved outcomes resulted
colonization rather than infection. from the use of an invasive versus a non-invasive sputum collection
Invasive techniques (BAL or PSB) collect lower respiratory tract strategy, or a quantitative versus a semiquantitative analysis strategy.
samples usually by fiberoptic bronchoscopy, but non-bronchoscopic Two randomized trials have compared outcomes of patients with
“blind” techniques have been described. The main theoretical advan- suspected VAP managed with an invasive versus a non-invasive ap-
tage of bronchoscopy is direct visualization of the airways. However, proach when both samples were cultured quantitatively. Sanchez-Nieto
invasive techniques are more expensive and resource intensive than et al. (1998) randomized 51 patients with suspected VAP to EA versus
their non-invasive counterparts, and may not be readily available. bronchoscopic BAL or PSB. Initial antibiotic therapy was modified in
Although bronchoscopy is generally well tolerated, a reduction in a significantly higher percentage of patients with invasive compared
SaO2 (arterial O2 saturation) may be observed for up to 24 h afterward, with non-invasive approaches (42% vs 16%, p <0.05), but there was
possibly related to alveolar flooding caused by residual lavage fluid. no difference in severity-adjusted mortality, ICU LOS, or duration of
102 HOSPITAL-ACQUIRED AND VENTILATOR-ASSOCIATED PNEUMONIA

MV. Ruiz et al. (2002) randomized 76 patients with suspected VAP to observed in nine patients (32.1%) despite antibiotic therapy. There
EA versus bronchoscopic BAL or PSB, and found no difference in in- was no difference in hospital mortality rates between patients with
cidence of antibiotic modification, duration of MV, ICU LOS, or crude VAP and VAT (19.3% vs 21.4%, p = 0.789). The VAT entity always pro-
or adjusted mortality. In both studies, antibiotics were continued in longed the duration of MV. The pathogens associated with VAT were
all patients with negative cultures. often MDR, including MRSA, P. aeruginosa, and other non-fermenting
Shorr et al. (2005) performed a meta-analysis of the aforemen- Gram-negative bacteria, but the Enterobacteriaceae were significantly
tioned trials comparing EA (either quantitative or semiquantitative) less likely to cause VAT than VAP. Dallas et al. also documented that
with bronchoscopic quantitative cultures. There was no survival ad- the prevalence of VAT is much less frequent than that of VAP (3.2/1000
vantage to the invasive approach, but patients diagnosed invasively vs 9.4/1000 ventilator days).
were more likely to undergo changes in antimicrobial regimen. Despite VAT likely being a real entity, possibly being an intermedi-
Samples obtained via bronchoscopic BAL or PSB and then analyzed ate step between colonization and VAP, every aspect of its diagnosis is
quantitatively have the highest specificity in diagnosing VAP. Reported problematic. Diagnostic criteria are all of the standard criteria for VAP
outcomes in patients managed with an invasive versus a “clinical” except the criterion of radiographic infiltrate. The outcome for VAT may
strategy are conflicting. Several trials demonstrate that patients so be increased tracheal secretions; alternatively, worsening oxygenation
managed are also more likely to undergo antibiotic changes. Trials is less likely to occur with VAT, which may help distinguish it from VAP.
rebutting the use of the invasive/quantitative strategy are limited Systemic antibiotics have an unclear benefit in VAT. They do appear
because patients with negative cultures continued to receive antibi- to be a risk factor for the development of VAT. Lack of antibiotic treat-
otics, which negates the putative benefit (the ability to discontinue ment of VAT is associated with an increased risk of subsequent VAP
antimicrobial therapy). This last point is important because the value and prolonged MV, but systemic antibiotics do not appear to prevent
of invasive, quantitative specimens lies not with the decision to initi- progression consistently. Aerosolized antibiotics might be the ideal
ate therapy (these cultures will not become available for 48–72 h), treatment of VAT, but data are lacking.
but rather with either de-escalation or discontinuation of antibiotic
therapy when appropriate. ■■TREATMENT
■■Ventilator-associated Neither the decision to treat nor the choice of agent involves inter-
pretation of lower respiratory tract cultures, which do not become
tracheobronchitis available for 48–72 h. Rather, the treatment decision is based on
A controversial new entity, ventilator-associated tracheobronchitis clinical suspicion and Gram stain. Choice of agent is based on both
(VAT) has been described (Craven and Hjalmarson 2011). Progression individual patient risk factors for infection with MDR organisms and
of colonization to VAT and, in some patients, to VAP is related to the data from institutional (ideally unit specific) antibiograms (Barie
quantity, types, and virulence of invading bacteria versus containment 2012). Most data indicate that antimicrobial therapy may be withheld
by host defenses. Diagnostic criteria for VAT and VAP overlap in terms safely if (1) a Gram-stained lower respiratory tract sample reveals
of clinical signs and symptoms, and they share similar microbiologi- no organisms and (2) the patient does not have severe sepsis (Croce
cal criteria when endotracheal sputum aspirate samples are used. In et al. 1995, Ibrahim et al. 2001, Iregui et al. 2002, Kollef et al. 2005).
addition, the diagnosis of VAP requires a new, persistent radiographic Clinical signs of infection along with a negative Gram stain suggest
infiltrate, which may be difficult to assess in critically ill patients, as either an extrapulmonary source of infection or sterile inflammation
well as a positive bacterial culture of an EA or BAL specimen. The weak (e.g., intracranial hemorrhage) (Barie et al. 2005). It is crucial when
link in the diagnosis of VAT (and VAP) is arguably the requirement for treating VAP to administer “adequate therapy,” meaning at least one
no new or changing radiographic infiltrate for VAT. Multiple studies antimicrobial agent to which the pathogen is sensitive, in the correct
have documented the inaccuracy of routine radiographic interpreta- dose, via the correct route of administration, and in a timely manner.
tion (Wunderink 2000). At least 30% of infiltrates in the lower lobes A second crucial aspect of VAP therapy involves serial re-evaluation
found by chest computed tomography (CT) are missed by portable and interpretation of initial microbiology so that: (1) Therapy may
supine chest radiographs. Conversely, multiple other causes of new be discontinued if no organism is isolated and the patient has not
or changing radiographic infiltrates may cause the misdiagnosis of deteriorated clinically; (2) therapy is de-escalated to treat only the
VAT as VAP, or sterile inflammation as infection. specific etiological pathogen; and (3) an endpoint of therapy may be
Contention has arisen because of mandated public reporting of identified and adhered to in prospect.
hospital-acquired infections and the potential that VAP will be added There are ample data detailing the increased mortality associated
to the list of infections reported as a quality standard to measure with inadequate initial antimicrobial therapy in patients with VAP.
hospital safety (Wunderink 2011). Reports from multiple hospitals of Iregui et al. (2002) showed that delayed therapy (defined as initial
VAP rates of zero for prolonged periods may be achievable by greater antibiotic treatment administered ≥24  h after meeting diagnostic
attention to prevention tactics, but are inherently dubious. Aside from criteria for VAP) was independently associated with hospital mortality
the fact that VAP rates that are very low or zero or are not well docu- (OR 7.68, 95% CI 4.50–13.09, p <0.001). The mean difference in time to
mented, said low rates have not been associated with corresponding antibiotic administration between groups was 16 h. Similarly, Kollef et
decreases in antibiotic use or mortality. Is the reporting system being al. (2000) reported that inadequate initial antimicrobial therapy was
manipulated to avoid the diagnosis of VAP, while continuing to treat an independent risk factor for ICU mortality in patients with Gram-
patients using antibiotics suitable for VAP? negative infections (OR 4.22, 95% CI 3.57–4.98, p <0.001). Alvarez-
Dallas et al. (2011) examined the questions of the veracity and Lerma et al. (1996) demonstrated that attributable mortality from VAP
importance of VAT in a small epidemiological study of 28 patients was significantly lower among patients receiving initial appropriate
with VAT and 83 with VAP (incidence, 1.4% and 4.0%, respectively). antibiotic treatment compared with receipt of inappropriate treatment
Although VAP was more common in surgical than medical ICU pa- (16.2% vs 24.7%; p = 0.03). The essential nature of appropriate initial
tients (5.3% vs 2.3%, p <0.001), as expected, the occurrence of VAT therapy is underscored by the fact that Alvarez-Lerma et al. demon-
was similar (1.3% vs 1.5%, p = 0.845). Progression of VAT to VAP was strated that switching to appropriate therapy once culture results
 Treatment 103

became available did not ameliorate the excess mortality associated 750 mg/day, ciprofloxacin 400 mg every 8 h) makes their empirical
with inadequate initial therapy. use increasingly dubious (Neuhauser et al. 2003, Nseir et al. 2005).
Choice of initial antimicrobial therapy depends on patient risk Certain points regarding specific antibiotics warrant further discus-
factors for MDR pathogens (Box 8.2) and local microbiological data sion. Most notably, linezolid has emerged as an effective alternative
that may be obtained from the unit-specific antibiogram. Having a therapy for VAP caused by Gram-positive bacteria, and MRSA in par-
current and frequently updated antibiogram increases the likelihood ticular. Linezolid is theoretically appealing for the treatment of VAP
that appropriate initial antibiotic treatment will be prescribed (Rello because achievable concentrations in bronchial secretions exceed
et al. 1999, Gruson et al. 2000, Ibrahim et al. 2001). In general, therapy those in serum, dose adjustment is not needed for renal insufficiency,
for patients at risk for infection with an MDR organism should pro- and enteral administration has equivalent bioavailability. However,
vide coverage against MRSA, P. aeruginosa, and extended-spectrum a meta-analysis of linezolid versus glycopeptide (vancomycin or
b-lactamase-producing Klebsiella spp. and Escherichia coli. This will teicoplanin) for the treatment of nosocomial pneumonia suggests
likely require at least two drugs, one effective against MRSA (e.g., van- equivalent efficacy and, perhaps surprisingly, more adverse events
comycin or linezolid) and one effective against MDR Gram-negative with linezolid therapy (Kalil et al. 2010). Nine trials (vancomycin [n =
bacilli, particularly Pseudomonas spp. (e.g., meropenem). Empirical 7], teicoplanin [n = 2]) were included (2329 patients). The RR for clini-
therapy against A. baumannii may be indicated, depending on the cal cure was 1.01 (95% CI, 0.93–1.10; p = 0.83), and for microbiological
patient and the microbial ecology of the unit. Patients with early onset eradication, 1.10 (95% CI 0.98–1.22, p = 0.10). Subgroup analysis for
VAP (occurring <5 days after intubation) and none of the aforemen- MRSA yielded an RR for microbiological eradication of 1.10 (95% CI
tioned risk factors may be candidates for narrower-spectrum therapy. 0.87–1.38, p = 0.44). Comparing linezolid only with vancomycin, the
Trauma patients, who tend to develop VAP sooner than critically ill RR for clinical cure was 1.00 (95% CI 0.90–1.12), for microbiological
surgical patients, may also be candidates for narrower-spectrum eradication 1.07 (95% CI 0.90–1.26, p = 0.45), and for MRSA 1.05 (95%
therapy of earlier episodes of VAP (Becher et al. 2011). CI 0.82–1.33, p = 0.71). No differences were observed for all-cause
mortality (RR 0.95, 95% CI 0.76–1.18, p = 0.63) or acute kidney injury
(RR 0.89, 95% CI 0.56–1.43, p = 0.64), but risks of thrombocytopenia
Box 8.2 Risk factors for ventilator-associated pneumonia (VAP) (RR 1.93, 95% CI 1.30–2.87, p = 0.001) and gastrointestinal events (RR
with multidrug-resistant organisms. 2.02. 95% CI 1.10–3.70, p = 0.02) were higher with linezolid.
Abundant data document the association between prior fluoro-
⦁⦁ Late-onset VAP (occurring ≥5 days after intubation) quinolone use and the emergence of VAP caused by MDR pathogens,
⦁⦁ Antibiotics within previous 90 days particularly MRSA and Pseudomonas spp. (Trouillet et al. 2002, Nseir
⦁⦁ Hospitalization within previous 90 days et al. 2005) (Figure 8.4). Fluoroquinolone use in the treatment of VAP
⦁⦁ Current hospitalization >5 days should therefore be judicious, probably not for empirical use, but rather
⦁⦁ Admission from a long-term care/hemodialysis facility part of a program of de-escalation based on institutional antibiograms
⦁⦁ High frequency of antibiotic resistance in the community that are updated frequently. Whereas multidrug therapy against MRSA
⦁⦁ Immunosuppressive disease or therapy and P. aeruginosa is necessary to achieve adequate initial empirical
coverage in patients with suspected VAP until culture results become
available, combination therapy directed against a specific pathogen
Antimicrobial therapy for VAP should be administered initially via (e.g., “double-coverage” of Pseudomonas spp., meaning three anti-
the intravenous (IV) route. Enteral therapy may be considered if pa- biotics initially) is controversial. Proponents (usually of a b-lactam
tients demonstrate an adequate response to IV therapy, gastrointestinal agent plus an aminoglycoside) argue that the high risk of an MDR
function is normal, and the antibiotics used possess high bioavailability Gram-negative bacillus as the etiological agent requires two drugs to
when administered orally or enterally. Linezolid and fluoroquinolones maximize the possibility that at least one will provide coverage. Detrac-
have oral bioavailability adequate to the task (Paladino 1995). Aero- tors point to a lack of evidence of benefit, increased risk of toxicity,
solized antibiotics are theoretically attractive to optimize pulmonary and possibly increased mortality (Kett et al. 2011). Neither in vitro
antibiotic concentrations. Limited data suggest that addition of nor in vivo synergy of such Gram-negative combination therapy has
aerosolized aminoglycosides or colistin to intravenous therapy may been demonstrated consistently (Hilf et al. 1989, Fowler et al. 2003). A
improve response rates in patients with MDR organisms or refractory meta-analysis of all trials of b-lactam monotherapy versus b-lactam–
pneumonia. Adverse events can occur, especially with colistin. Aerosol- aminoglycoside combination therapy for immunocompetent patients
ized antibiotics administered by conventional nebulizer therapy may with sepsis, including 64 trials and 7586 patients, found no difference
not achieve standardized droplet size or complete dispersal within the in either mortality (RR 0.90, 95% CI 0.77–1.06) or the development of
lower airways, to ensure tolerability and good drug delivery, so further resistance (Paul et al. 2004). In fact, clinical failure was more common
research into the use and delivery of aerosolized antibiotics is needed with combination therapy, as was acute kidney injury.
(Wood 2011, Arnold et al. 2012, Florescu et al. 2012). After initiation of adequate antimicrobial therapy for suspected
Inadequate dosing of antibiotics leads to the emergence of MDR VAP, results of lower respiratory tract cultures may reveal: (1) No
bacteria and is associated with poorer outcomes in VAP (Guillermot growth or insignificant growth (below the predetermined threshold
et al. 1998). Appropriate initial dosing of vancomycin (15 mg/kg every value); (2) meaningful (above threshold) growth of a pathogen sensi-
12 h) and aminoglycosides (gentamicin or tobramycin 7 mg/kg once tive to a narrow-spectrum agent; or (3) growth of a pathogen sensitive
daily; amikacin 20 mg/kg once daily) is necessary to achieve high peak: only to a broad-spectrum agent. Regarding the first scenario, data
MIC (minimum inhibitory concentration) to optimize bacterial kill- indicate that antimicrobial therapy may be discontinued safely as
ing; although single daily dose aminoglycoside therapy has not been long as the patient has not deteriorated clinically (Croce et al. 1995,
associated with increased toxicity, the higher doses of vancomycin Bonten et al. 1997b, Kollef et al. 2005, Shorr et al. 2005). In the second
necessary to achieve recommended trough concentrations of 1–20 µg/ scenario, therapy is de-escalated to a narrow-spectrum agent with
ml have been associated with an increased risk of nephrotoxicity (Cano activity against the pathogen isolated (Eachempati et al. 2009,
et al. 2012). Increasing resistance to fluoroquinolones (levofloxacin Niederman et al. 2011). In the last scenario, the initial broad-spectrum
104 HOSPITAL-ACQUIRED AND VENTILATOR-ASSOCIATED PNEUMONIA

tion and analysis, and patients whose therapy ended at 8 days were
stable clinically at that time. Patients treated for 8 days had equivalent
mortality, ICU LOS, duration of MV, and recurrence of infection despite
significantly more antibiotic-free days. Recurrent infections were less
likely to be caused by MDR pathogens in patients treated for 8 days.
However, patients with VAP caused by non-fermenting Gram-negative
bacilli (NFGNB, e.g., P. aeruginosa, A. baumannii, S. maltophilia) were
more likely to develop recurrent pneumonia if treated for 8 days only.
Thus, an 8-day course of initially appropriate antimicrobial therapy ap-
pears safe and effective provided that the patient has not deteriorated,
especially if the pathogen is not an NFGNB. A recent meta-analysis
supports this conclusion (Pugh et al. 2011). Eight studies (1703 patients)
were included; few patients with a high probability of HAP were not
on MV. For patients with VAP, a short (7.8-day) course of antibiotics
compared with a prolonged (10- to 15-day) course increased 28-day
antibiotic-free days (OR 4.02, 95% CI 2.26–5.78) and reduced the re-
currence of VAP due to MDR organisms (OR 0.44, 95% CI 0.21–0.95),
without affecting other outcomes adversely. However, for cases of VAP
due to NFGNB, recurrence was greater after short-course therapy (OR
2.18, 95% CI 1.14–4.16). In three studies, discontinuation guided by
the serum procalcitonin concentration led to a reduction in duration
of therapy and increased 28-day antibiotic-free days (mean difference
a
[MD] 2.80, 95% CI 1.39–4.21) without affecting other outcomes.
In select patients, a shorter course of therapy may be effective for
Figure 8.4  (a) A
bilateral multidrug the treatment of VAP. Singh et al. (2000) randomized patients with
resistance suspected VAP and a CPIS score ≤6 points to receive either standard
Pseudomonas therapy (physician discretion) versus ciprofloxacin monotherapy,
aeruginosa with re-evaluation at day 3 and discontinuation of antibiotics if the
pneumonia CPIS remained ≤6. If the CPIS remained ≤6 at the 3-day evaluation
following subtotal point, antibiotics were continued in 96% (24/25) of patients in the
gastrectomy. (b) The
bilateral effusions in
standard therapy group, but in none of the patients in the experimen-
association with the tal therapy group (p = 0.0001). Mortality and ICU LOS did not differ
pneumonia. The left- despite a shorter duration (p = 0.0001); cost of antimicrobial therapy
sided effusion proved was decreased (p = 0.003) in the experimental arm.
to be an empyema Patients treated for VAP who do not improve clinically after ap-
treated with chest tube propriate antimicrobial therapy pose a dilemma. Inadequate therapy,
b drainage.
misdiagnosis, or a pneumonia-related complication (e.g., empyema or
lung abscess) must all be considered. A diagnostic evaluation should
be repeated, including quantitative cultures of the lower respira-
agent to which the pathogen is susceptible is continued. The goal of tory tract (using a lower diagnostic threshold given recent antibiotic
adequate empirical therapy is to initiate a combination of antibiotics exposure), and consideration of broadened coverage until new data
likely to cover all possible etiological pathogens, followed by tailored become available.
therapy if possible. The ideal treatment of suspected VAP thus involves The literature suggests a discrepancy between the principles of
an initial period of perfect sensitivity followed by a period of perfect care discussed herein and contemporary clinical practice. Rello et al.
specificity, once microbiology results are available. In this fashion, no (1997) reported that, in a cohort of 113 patients with VAP, nearly 25%
patient with VAP is untreated, and no patient without VAP is treated received inadequate initial therapy. In a second cohort study of 398
after microbiological data are available. ICU patients with suspected VAP from 20 ICUs throughout the USA,
Once pathogen-specific therapy has been initiated, its duration Kollef et al. (2006) documented more than 100 different antibiotic
must be determined such that prolonged and unnecessary periods regimens prescribed as initial therapy of VAP. Furthermore, the mean
of antibiotic administration are avoided. Resolution of clinical and duration of therapy was 11.8 ± 5.9 days, and in 61.6% of cases there
radiographic parameters typically lags behind the eradication of was neither escalation nor de-escalation. The use of standardized
infection (Luna et al. 2003). Vidaur et al. (2005) found that improved treatment protocols can improve substantially the likelihood that
oxygenation and normalization of temperature occurred within 3 adequate therapy is delivered for an appropriate duration. Ibrahim et
days in VAP patients without ARDS. Dennesen et al. (2001) observed al. (2001) compared outcomes before and after implementation of a
a clinical response to therapy of VAP, defined as normalization of VAP treatment protocol that involved standardized, broad-spectrum
temperature, white blood cell count, SaO2, and quality of tracheal initial coverage, with termination after 7 days of absent persistent
aspirates, within 6 days of therapy. signs of active infection. The proportions of patients who received
A randomized, multicenter trial of 401 patients with microbio- inadequate initial therapy and therapy of inappropriate duration were
logically confirmed VAP assigned participants to receive either 8 or significantly lower in the protocol arm. Several additional studies have
15 days of antibiotic therapy (Chastre et al. 2002). All patients received confirmed the effectiveness of protocol-driven therapy (Evans et al.
adequate initial therapy after invasive/quantitative specimen collec- 1998, Micek et al. 2004).
 References 105

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 Chapter 9 Postoperative urinary
tract infections
Jeffrey A. Claridge, Joseph F. Golob

■■DEFINITION AND DIAGNOSIS The definitions by the CDC use a variety of signs and symptoms. In
a symptomatic UTI, the patient may complain of urgency, frequency,
Urinary tract infections (UTIs) include those infections of the lower uri- dysuria, or abdominal pain. On physical exam, patients may demon-
nary tract (cystitis) and the upper urinary tract (pyelonephritis). Most strate suprapubic tenderness and/or costovertebral tenderness. Signs
UTIs are considered uncomplicated because they occur spontaneously of both symptomatic and asymptomatic UTIs include: Fever (>38°C),
without previous urinary tract instrumentation. However, within the positive urinalysis for leukocyte esterase and/or nitrite, pyuria (≥10
surgical population, virtually all UTIs are of the complicated (urinary white blood cells/mm3 of unspun urine or ≥3 white blood cells/high
catheter in place and/or functional/anatomical urinary tract abnormal- power field in spun urine), and a positive urine culture of ≥105 colony-
ity) and healthcare-associated variety due to urological instrumenta- forming units (CFU)/ml.
tion and/or indwelling urinary catheter placement (Klevens et al. 2007). Obtaining urinalysis and urine cultures are ideally done before
The Centers for Disease Control and Prevention (CDC) have very starting any antibiotics in patients for whom there is concern about
specific definitions of UTIs. The CDC divides UTIs into three catego- a UTI. If possible, the indwelling urinary catheter should be removed
ries: Symptomatic UTIs, asymptomatic UTIs, and other UTIs. The and a clean-catch midstream urine sample obtained because it is more
symptomatic and asymptomatic categories include definitions with difficult to distinguish true pathogens from colonizing organisms in
and without an indwelling urinary catheter. If a urinary catheter is catheterized patients. If the catheter must be maintained, the urine
present at the time of urine collection, or was collected within 48 h of sample should be removed from the port within the catheter tubing
catheter removal, the infection is called a catheter-associated urinary and not the urine bag. If there is no tubing port, the last resort is to re-
tract infection (CAUTI). The definitions, evaluation, and diagnosis of move the closed drainage system and obtain the sample directly from
CAUTI are detailed in Figure 9.1. the urinary catheter. However, there are some data that this technique

Figure 9.1  Identification of the catheter-

Patient has indwelling urinary catheter, or had associated urinary tract infection. (From Centers
catheter removed within prior 48 h, at the time for Disease Control and Prevention 2012.)
of specimen collection or onset of symptoms.

Signs and symptoms

At least one of the following without another cause:
• Fever (>38°C)
• Suprapubic tenderness
• Costovertebral pain/tenderness

Laboratory evidence
At least one of the following:
• Positive dipstick for esterase and /or nitrite
• Pyuria (>10 wbc/mm3 of unspum rine or>3
wbc/high power field of spun urine)
• Microorganisms seen on gram stain of unspun urine.

A positive urine culture of 105 CFU/ml A positive urine culture of 103and 105
with 2 species of microorganisms CFU/ml with 2 species of microorganisms

Symptomatic catheter-associated
urinary tract infection
110 POSTOPERATIVE URINARY TRACT INFECTIONS

may increase the risk of introducing pathogens into the urinary tract Table 9.1 NHSN urinary catheter usage and associated CAUTIs
(catheter-associated urinary tract infections).
(Gould et al. 2010).
Unfortunately, there are limited data to support when to obtain NHSN urinary catheter usage per patient-days
urinalysis and urine cultures in the surgical patient population. Even Surgical ICU 0.79
in the setting of fever and/or leukocytosis, it may not be prudent Trauma ICU 0.83
to obtain a urine specimen, especially from catheterized patients.
Pyuria and bacteriuria (≥102 CFU/ml) are frequent in the catheter- Neurosurgical ICU 0.77
ized patient and may or may not signify an infection that needs to Medical ICU (teaching hospital) 0.74
be treated (Tambyah and Maki 2000). Data from our institution Burn ICU 0.56
demonstrated that, in 510 critically ill trauma patients, fever, leu-
Urology – ward 0.21
kocytosis, or both did not predict a UTI (Golob et al. 2008). Some
continue to advocate evaluation of the urinary tract when patients Gynecology – ward 0.20
develop fever, or otherwise unexplained systemic manifestations Surgical – ward 0.23
compatible with infection, including malaise, altered mental sta- Orthopedics – ward 0.28
tus, hypotension, or metabolic acidosis (Fekete 2011). However,
NHSN CAUTIs per 1000 urinary catheter-days
data do not support obtaining routine surveillance urine cultures
in patients who are asymptomatic with long-term indwelling uri- Surgical ICU 2.6
nary catheters, such as spinal cord-injured patients (Nicolle 2005). Trauma ICU 3.4
Screening with routine urinalysis is appropriate only for pregnant Neurosurgical ICU 4.4
women and patients undergoing urological procedures in which
mucosal bleeding is anticipated, because these asymptomatic pa- Medical ICU (teaching hospital) 2.3
tients benefit from treatment to minimize risk of bacteriuria (Nicolle Burn ICU 4.4
2005, Lin et al. 2008). Urology – ward 1.2
Gynecology – ward 1.0
■■EPIDEMIOLOGY Surgical – ward 1.8
CAUTIs account for more than 40% of all nosocomial infections Orthopedics – ward 1.6
and are the leading cause of secondary nosocomial bacteremias ICU, intensive care unit; NHSN, National Healthcare Safety Network.
(Stamm 1991, Warren 2001). It has been shown that approximately
20% of hospital-acquired bacteremias arise from the urinary tract
(urosepsis). Of these bacteremias, approximately 10% result in sepsis,
multiorgan dysfunction, and eventual death (Gould et al. 2009). In
■■PATHOPHYSIOLOGY
1992, CAUTIs were responsible for approximately 900 000 additional The major risk factor for bacteriuria and UTIs in the surgical patient is
hospital-days per year and contribute to more than 7000 deaths an- an indwelling urinary catheter. The risk of UTI is directly proportional
nually. UTIs increase healthcare costs by up to $500 million per year to the duration the urinary catheter is in place. The daily incidence
(Hashmi et al. 2003). of UTI in the presence of an indwelling catheter is up to 5% per day.
According to the National Healthcare Safety Network (NHSN), After 1 week of catheterization, 25% of patients will have bacteriuria
general surgery and trauma patients, especially those treated in the or candiduria. However, only 10–25% of these patients will go on to
intensive care unit (ICU), have some of the highest rates of both meet the CDC definition of UTIs (Stark and Maki 1984, Tambyah and
indwelling urinary catheter usage and CAUTIs. The NHSN is a CDC Maki 2000, Maki and Tambyah 2001).
organization that collects data from a collaboration of hospitals regard- Other important UTI risk factors in a surgical population include
ing patient safety issues. Included in this data collection are urinary patients with other infectious sites, prolonged hospital stay, diabetes,
catheter usage and CAUTIs for both surgical and medical patient malnutrition, female sex, and ureteral stent placement (Kunin and
populations. The NHSN reports usage of indwelling urinary catheters McCormack 1966, Platt et al. 1986, Wald et al. 2008, Marchaim 2011).
as: Number of urinary catheter-days/number of patient-days. CAUTIs There is also less rigorous data to support older age, disconnection of
are reported by normalizing the data to 1000 urinary catheter-days the closed drainage system, renal impairment, insertion of the catheter
through the following calculation: outside the operating room, and a lower professional training of the
[Number of CAUTIs/Number of urinary catheter-days] × 1000. person inserting the catheter as risk factors for UTIs (Gould et al. 2010).
Table 9.1 contains data from the 2009 NHSN report regarding The microbiology of uncomplicated cystitis and pyelonephritis
urinary catheter usage and CAUTIs in specific patient populations. consists mainly of Escherichia coli (75–95%), Proteus mirabilis, Kleb-
ICU surgical and trauma patients have a urinary catheter usage siella pneumoniae, and Staphylococcus saprophyticus (Echols et al.
of 0.79 and 0.83, respectively. Not surprising, these patient popula- 1999, Czaja et al. 2007). Surgical patients with a CAUTI tend to grow
tions have some of the highest CAUTI rates. The CAUTI rate in ICU the same bacteria with the addition of Pseudomonas, Serratia, and
surgical patients is 2.6 CAUTIs per 1000 urinary catheter-days and Providencia spp., as well as various enterococci, staphylococci, and
in ICU trauma patients it is 3.4 CAUTIs/1000 urinary catheter-days. fungi (Hooton 2011). The broader bacterial flora seen in patients with
This is in comparison to a medical ICU rate of 2.3 CAUTIs/1000 complicated UTIs result from the presence of underlying chronic
urinary catheter-days. The highest rates of CAUTI are in burn and comorbid conditions, longer hospital courses, multiple different
neurosurgical ICU patients (4.4 CAUTIs/1000 urinary catheter-days) antibiotic drug therapies during hospital admission, and frequent
despite burn units having the lowest ICU rate of catheter usage (0.54) manipulations and contact with healthcare workers whose hands can
(Dudeck et al. 2009). become vehicles of bacterial transfer (Marchaim 2011).
 Prevention 111

These bacteria that cause UTIs are often chronic colonizers of the treatment with a penicillin derivative, trimethoprin sulfa, fluoroquino-
gut and perineum and subsequently invade the urinary system. The lone, or nitrofurantoin is adequate. If the host is compromised (chronic
presence of an indwelling urinary catheter creates an easy path for steroids, diabetes, lupus, cirrhosis, or multiple myeloma) then 5 days
the bacteria to follow. Bacterial adhesion onto the urinary catheter of antibiotics should be used (Cunha 2007). It has been suggested that
and subsequently the urothelial cells has been suggested to be the in patients with a urinary catheter, the catheter should be changed and
single most important bacterial virulence factor in causing CAUTIs treatment for 10–14 days is usually adequate (Trautner and Darouiche
(Richards et al. 1999, Meyrier 2011). 2004). Unfortunately, even with an extended duration of antibiotics,
The two most common UTI microbes, E. coli and P. mirabilis, have there is a high relapse rate if the indwelling urinary catheter is left in
flagella and fimbriae as virulence factors that facilitate migration into place (Stamm 1991).
the urinary bladder from the pericatheter space within the urethra. Asymptomatic candiduria rarely requires antifungal treatment
The flagella allow the organisms to be mobile, exit the fecal reservoir, unless it occurs in the setting of neutropenia or urinary tract surgery.
and migrate up the biofilm of the indwelling urinary catheter. Once Symptomatic candiduria should always be treated. Treatment should
in the bladder, the fimbriae adhesion systems have an overall positive be tailored to the Candida spp., and according to whether ascending
electrical charge and promote adhesion to the negatively charged or disseminated infection is present. Changing the urinary catheter
uroepithelial cell membrane via hydrophobicity. Once this adhesion and a 14-day course of an appropriate antifungal should be utilized. If
occurs, the bacteria can than cause cystitis and continue to spread amphotericin B is required, the non-lipid formulation should be used
into the upper urinary tract causing pyelonephritis (Mulvey 2002, because the lipid formulation does not penetrate into the kidney to
Oelschlaeger et al. 2002). achieve high concentrations in the bladder. Amphotericin B bladder
In addition to bacteria, fungi can also colonize and infect the uri- irrigations can be used to clear fungiuria, but should not be used as
nary tract. Although Aspergillus, Fusarium, Trichosporon, and Mucor sole treatment.
spp., and cryptococci have been implicated in UTIs, Candida albicans
and other Candida spp. are the most common pathogens. The National
Nosocomial Infections Surveillance System (now the NHSN) reported
■■PREVENTION
that candida UTIs increased from 22% for the period 1986–1989 to The single best UTI prevention strategy is to avoid inserting unneces-
nearly 40% in 1992–1997 (Richards et al. 1999). It is unclear from the sary urinary catheters and to remove any unneeded ones. There has
data if this candiduria was an actual infection or colonization. A large been substantial research on other methods to prevent CAUTIs such
prospective study identified several risk factors for fungiuria with the as utilization of external drainage systems in male patients, intermit-
top three being: Prior antibiotic therapy (90%), indwelling urinary tent catheterization versus indwelling catheters, drug-impregnated
catheter (83%), and diabetes (39%) (Kauffman et al. 2000). catheters, preconnected closed catheters versus standard catheters,
Differentiation between infection and colonization in fungiuria systemic antimicrobial prophylaxis, topical antimicrobials, and blad-
can be difficult. Most cases of candiduria are asymptomatic and most der irrigations.
likely represent colonization. Infected patients may or may not display In male patients without urinary tract obstruction and/or urinary
the typical UTI symptoms such as dysuria, frequency, and suprapubic retention, there is some evidence to suggest that use of an external
pain. Pyuria, presence of pseudohyphae, or the number of colonies condom catheter over an indwelling catheter will decrease the risk
growing in culture do not help distinguish colonization (Kauffman of a UTI, bacteriuria, and death (Gould et al. 2010). Likewise, inter-
et al. 2000). Evaluation of the entire clinical picture needs to occur in mittent catheterization is associated with lower rates of bacteriuria
order to diagnosis and treat a candida UTI. and symptomatic UTIs in patients requiring long-term indwelling
catheters such as spinal cord-injured patients (Weld and Dmochowski
■■TREATMENT 2000). However, there are no data to demonstrate that intermittent
catheterization is superior to indwelling urinary catheters in critically
The single best way to treat a CAUTI is to remove the indwelling ill surgical/trauma patients.
urinary catheter. This method alone has been shown in two-thirds There continues to be mixed results on the utilization of silver-
of patients with bacteriuria to assist in clearing the bacteria within 1 coated catheters and nitrofurazone-impregnated catheters. Both
week (Hartstein et al. 1981). If the patient is showing systemic signs the silver-coated and nitrofurazone catheters seem to be effective if
of a possible UTI, and the appropriate microbiological studies have duration of use was less than 7 days. After 1 week of use, there was no
been obtained (urinalysis and urine culture), empirical antibiotics difference in UTI rates between these special catheters and a standard
can be initiated pending the culture results. Choosing the empirical latex catheter, questioning the cost–benefit ratio for these special
antibiotic should be based on normal UTI flora, previous culture catheters (Gould et al. 2010).
results, and/or the hospital’s antibiogram. The typical UTI profile of Since 1966, the utilization of closed urinary drainage systems have
Gram-negative bacilli may be treated with a third-generation cepha- been the standard of care after a study published by Kunin showed a
losporin or a fluoroquinolone. If Pseudomonas spp. is suspected, dramatic decrease in UTIs (Kunin and McCormack 1966). More recent
treatment with fluoroquinolone alone or a penicillin in combination data demonstrated that disconnecting the drainage system increases
with an aminoglycoside can be utilized. When expanded-spectrum the risk of bacteriuria. Therefore, the CDC recommends the use of a
b-lactamase producing Gram-negative pathogens are encountered, closed urinary drainage system (category IB) with consideration of the
a carbapenem choice may be desirable. If Gram-positive cocci are presealed catheter tubing junctions (category II) (Gould et al. 2009).
seen on Gram stain, they may represent enterococci or staphylococci, To date, there is no evidence to suggest that systemic antibiotic
and vancomycin should be started. Once culture and susceptibility prophylaxis against UTIs is beneficial in patients with either short- or
results are available, the antibiotics should be tailored to treat the long-term indwelling urinary catheter usage (Neil-Weise 2005). Topi-
specific organism. cal antimicrobial agents such as methenamine do not prevent CAUTIs
The duration of treatment remains unclear, especially in patients and may actually increase the risk due to more frequent catheter
with a CAUTI. In normal hosts with an uncomplicated UTI, 3 days of manipulations (Warren 2001). Soaking catheters in an anti-infective
112 POSTOPERATIVE URINARY TRACT INFECTIONS

solution, placement of anti-infection solution into drainage bag, or and assessment. The sacred threshold of 105 organisms/ml of uri-
continuous bladder irrigations have not been shown to decease the risk nary sample is considered the standard for the diagnosis, but from
of CAUTIs (Warren et al. 1978, Maki and Tambyah 2001, Warren 2001). whence was that derived? The classic research that defined the 105
When placing a urinary catheter, sterile aseptic technique should microbes/ml threshold was by Kass (1957). This was done by studying
be employed by a health professional familiar with the technique of uncomplicated community-acquired, not catheter-associated, UTIs.
inserting the catheter appropriately. The person inserting the catheter This threshold of bacterial presence in the sampled urine has been
should wash his or her hands and use sterile gloves, sterile drapes, generally extrapolated to apply in CAUTIs. With the indwelling foreign
and an antiseptic solution to clean the urethral orifice. Once in place, body within the urethra as a direct conduit to the external perineal
a closed drainage system should be used and manipulations to the surface of critically ill patients, it is logical to assume that the catheter
catheter should be avoided. The collection tubing and bag should will have colonization. With binding and division of bacteria on the
always be located below the patient. Finally, prompt removal of un- surface of the foreign body, and the development of biofilms that
necessary catheters is key to avoiding CAUTIs. compromise efficient elimination of colonization, it may be that urine
specimens derived from the densely colonized catheter or from the
■■CONCLUSION urethra after removal of the catheter have colony counts that do not
accurately reflect invasive infection. False-positive urinary cultures
This chapter has presented the contemporary view of the diagnosis, leads to excessive rates of CAUTI being identified and certainly exces-
prevention, and management of CAUTIs in the surgical patient. The sive antibiotic administration.
standard practice methods for prevention and the antibiotic therapy If false-positive cases are identified and reported, this actually di-
for these infections are well understood. Concern about these com- lutes the impact of truly invasive CAUTIs. Laupland et al. (2005) and
plications is best reflected in the current policy of the US Medicare Clec’h et al. (2007) concluded that a CAUTI was not an independent
program, which refuses to pay supplemental costs to hospitals for variable in contributing to hospital deaths. Tambyah et al. (2002)
patient care when a CAUTI has occurred. CAUTIs and certain other found attributable costs of only $589 per patient for 235 patients with a
hospital-acquired infections (e.g., intravascular catheter infections) CAUTI based on positive cultures. In a multi-hospital study of hospital-
have been labeled “never events” by healthcare policy, the rationale acquired infections, Anderson et al. (2007) noted attributable costs of
being that these complications are totally preventable and should $25 000 for each ventilator-associated pneumonia and >$10 000 for
“never” occur. However, anyone who has cared for critically ill pa- each surgical site infection, but only $758 for each CAUTI. If coloniza-
tients with ongoing and necessary urinary bladder catheterization tion of the urinary tract is counted as a CAUTI, then the denomina-
knows that these infections will occur in the most capable practices. tor of population analyses is distorted and the cost-effectiveness of
Risk models can be formulated (Fry et al. 2010) to identify the clinical interventions will be equally distorted.
profile of the patient who is likely to develop a CAUTI. The true diagnosis of a CAUTI must be refined. Perhaps the mea-
An issue that obscures analytical methods for prevention and surement of leukocyte esterase, nitrites, or other objective biomarkers
treatment of CAUTIs is the criterion for establishment of this diag- of a UTI will supplement the quantitative microbial culture. There is no
nosis. Although Claridge and Golob (Golob et al. 2008) have used question that a CAUTI can be a severe event in the recovery of surgical
the conventional definitions that are employed in the diagnosis of patients. Effective preventive strategies and cost-effective treatment
a CAUTI, the diagnosis of a CAUTI requires additional investigation require that the diagnosis must be accurate.

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Maki DG, Tambyah PA. Engineering out the risk for infection with urinary level of bacteriuria is relevant? N Engl J Med 1984;311:560–4.
catheters. Emerging Infect Dis 2001;7:342–7. Tambyah PA, Knasinski V, Maki DG. The direct costs of nosocomial catheter-
Marchaim DKK. Infection in the intensive care unit, 2011. Available at: www. associated urinary tract infection in the era of managed care. Infect Control
uptodate.com (accessed May 15, 2012). Hosp Epidemiol 2002;23:27–31.
Meyrier A. Bacterial adherehnce and other virulence facture for urinary tract Tambyah PA, Maki DG. Catheter-associated urinary tract infection is rarely
infection, 2011. Available at: www.uptodate.com (accessed May 15, 2012). symptomatic: a prospective study of 1,497 catheterized patients. Arch Intern
Mulvey MA. Adhesion and entry of uropathogenic Escherichia coli. Cell Microbiol Med 2000;160:678–82.
2002;4:257–271. Trautner BW, Darouiche RO. Role of biofilm in catheter-associated urinary tract
Neil-Weise B. Antibiotic policies for short-term catheter bladder drainage in infection. Am J Infect Control 2004;32:177–83.
adults. Cochrane Database Syst Rev 2005. Wald HL, Ma A, Bratzler DW, et al. Indwelling urinary catheter use in the
Nicolle LE. Infectious Diseases Society of America guidelines for the diagnosis and postoperative period: analysis of the national surgical infection prevention
treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005;40:643. project data. Arch Surg 2008;143:551–7.
Oelschlaeger TA, Dobrindt U, Hacker J. Virulence factors of uropathogens. Curr Weld KJ, Dmochowski RR. Effect of bladder management on urological
Opin Urol 2002;12:33–8. complications in spinal cord injured patients. Journal of Urology 2000;163:768–72.
Paradisi F, Corti G, Mangani V. Urosepsis in the critical care unit. Crit Care Clinics Warren JW, Platt R, Thomas RJ, et al. Antibiotic irrigation and catheter-
1998;14:165–80. associated urinary-tract infections. N Engl J Med 1978;299:570–3.
Platt R, Polk BF, Murdock B, et al. Risk factors for nosocomial urinary tract Warren JW. Catheter-associated urinary tract infections. Int J Antimicrob Agents
infection. Am J Epidemiol 1986;124:977–85. 2001;17:299–303.
Chapter 10 Catheter-related
bloodstream infections
William P. Schecter

■■INTRODUCTION the catheter tip and bacteremia (Maki et al. 1977, Renaud and Brun-
Buisson 2001, Safdar and Maki 2004). Catheters placed through
In 1656, Christopher Wren, the genius who designed St Paul’s Cathe- moist contaminated areas such as the groin or burn eschar are
dral in London, injected opium drops intravenously into dogs using associated with an increased risk for bacteremia (Robinson et al.
a quill and bladder as the first intravascular device. However, major 1995, Goetz et al. 1998, Merrer et al. 2001). Repeated venopuncture
advances in intravenous therapy did not occur until the twentieth at one site increases the risk of local skin infection once successful
century. Before the Second World War, metal needles were the prime venous catheterization has been achieved, increasing the risk of
method of access to the vascular system. CRBSI.
Rudimentary flexible plastic catheters were first inserted by venous 2. Catheters constructed with materials having irregular surfaces have
cut-down in 1945. In 1950, the “Rochester” plastic intravenous cath- an increased risk of infection because of increased adherence by
eter was introduced into clinical practice (Rosenthal et al. 2006). In organisms such as Staphylococcus epidermidis and Candida albi-
the 1960s percutaneous plastic catheters were developed for central cans (Stillman et al. 1977, Hawser and Douglas 1994). The patient
venous access, which quickly became routine hemodynamic monitors forms a protein sheath around the catheter consisting of fibrin
and access ports for intravenous alimentation. In the 1970s both im- and fibronectin (Mehall et al. 2002). Certain organisms such as
plantable ports and the Broviac catheter for long-term vascular access Staphylococcus aureus can adhere to these proteins by producing
were introduced. The explosion of intravenous therapy in the latter clumping factors (ClfA and ClfB) (Herrmann et al. 1991, McDevitt
decades of the twentieth century was associated with a concomitant et al. 1995, Ni Eidhin et al. 1998, Mehall et al. 2002). Other organ-
epidemic of catheter-related bloodstream infections (CRBSIs). isms such as coagulase-negative staphylococci (von Eiff et al. 2002,
Mack et al. 2007), Pseudomonas aeruginosa (Murga et al. 2001), and
■■EPIDEMIOLOGY Candida spp. (Douglas 2003) produce an extracellular polymeric
substance (EPS) composed primarily of exopolysaccharide, which
US intensive care patients experience 15 million days of central ve- forms a biofilm layer that can bind antimicrobials before contact
nous catheter (CVC) exposure each year (Mermel et al. 2003); 80 000 with the cell wall and neutralize polymorphonucleocytes (Farber
CRBSIs occur in intensive care units (ICUs) each year (Mermel et al. et al. 1990, Donlan 2000, von Eiff et al. 2002). Repeated puncture
2003) giving an incidence rate of 0.0053 CRBSIs/day of CVC exposure of a vascular conduit created as vascular access for hemodialysis
in the ICU. The extent of hospital-acquired CRBSIs, however, is much increases the risk for mycotic pseudoaneurysm formation. The risk
greater. If we include CRBSIs associated with peripheral intravenous, and consequences are greater with a prosthetic conduit compared
arterial catheters, and vascular catheters connected to other medi- with an arteriovenous fistula or autogenous conduit (National
cal devices, an estimated 250 000 cases occur in the USA each year. Kidney Foundation 2001).
These infections are responsible for increased hospital length of stay 3. The catheter or intravenous extension tubing can be contaminated
and cost of care estimated to be $2.3 billion per year (Dimick et al. by the hands of healthcare workers (HCW), contaminated fluids,
2001, Renaud and Brun-Buisson 2001, Blot et al. 2005, Warren et al. or contaminated devices (e.g. pressure transducers) (Raad et al.
2006a). CRBSIs are associated with 28 000 deaths per year (O’Grady 1993, Dobbins et al. 2002). Contamination of infusion solutions is
et al. 2011). The risk of CRBSIs is even greater in the developing world a possible but infrequent cause of CRBSIs (Raad et al. 2001).
(Rosenthal et al. 2006). 4. Catheters can occasionally be infected by circulating organisms
It is important to differentiate local infection from catheter colo- from a remote site of infection (Annaissie et al. 1995). The risk of
nization and bloodstream infection when considering CRBSIs. Local infection by this mechanism increases if the indwelling catheter
infection refers to the presence of purulence at the catheter insertion directly injures the endothelium and causes local thrombosis or
site. Catheter colonization is defined as growth >15 colony-forming chemical phlebitis. Intravascular thrombus creates a scaffolding
units (CFU) using the semiquantitative roll-plate culture technique for seeding by circulating organisms.
(Pronovost 2008). A CRBSI is defined as a positive blood culture with
clinical and microbiological evidence pointing to the catheter as the
source of the infection. This evidence may include comparison of cul-
■■MICROBIOLOGY
tured blood drawn from a peripheral vein with blood drawn through The most common organisms associated with CRBSIs are coagulase-
the catheter (Pronovost et al. 2006). negative staphylococci, S. aureus, enterococci and Candida spp.
(Wisplinghoff et al. 2004). Gram-negative bacilli account for 19–21% of
■■PATHOPHYSIOLOGY all CRBSIs (Table 10.1) (Wisplinghoff et al. 2004, Gaynes and Edwards
2005). Many organisms causing hospital-acquired infections, includ-
There are four recognized causes of CRBSI: ing Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa,
1. A direct route is created alongside the barrel of the catheter, which and Candida spp., are now resistant to previously effective antibiotics
permits skin bacteria to proliferate distally and results in infection of (Gaynes and Edwards 2005, Lipitz-Snydermanet et al. 2011).
116 CATHETER-RELATED BLOODSTREAM INFECTIONS

Table 10.1 Categories of recommendations. cohort study of 103 Michigan ICUs reporting 375 757 catheter-days
Category IA Strongly recommended for implementation and over an 18-month period between March 2004 and September
strongly supported by well-designed experimental, 2005 demonstrated a reduction in the median rate of CRBSI per
clinical, or epidemiological studies 1000 catheter-days from 2.7 at baseline to zero at 3 months after
Category IB Strongly recommended for implementation and implementation of the 5 evidence-based interventions (p <0.002)
supported by some experimental, clinical, or (Pronovost et al. 2006).
epidemiological studies and a strong theoretical A follow-up study demonstrated that the reduced rates of CRBSIs
rationale; or an accepted practice (e.g., aseptic
achieved in the initial 18-month study were sustained for an ad-
technique) supported by limited evidence
ditional 18 months by continuing to orient staff and report CRBSIs
Category IC Required by state or federal regulations, rules, or and catheter days to the appropriate stake holders (Pronovost et al.
standards
2010). The state-wide implementation of these five interventions to
Category II Suggested for implementation and supported by reduce CRBSIs, together with measures to reduce ventilator-associated
suggestive clinical or epidemiological studies or a pneumonia (recumbent positioning, daily interruption of sedatives,
theoretical rationale
and prophylaxis for both peptic ulcer disease and deep venous throm-
Unresolved issue Represents an unresolved issue for which evidence is bosis), were associated with a significant reduction in the mortality
insufficient or no consensus regarding efficacy exists rate in the study group compared with the surrounding area (Lipitz-
Snyderman et al. 2011). The Keystone Project studies provide evidence
that CRBSIs can be significantly reduced and that the reduction can
However, meticillin-resistant S. aureus (MRSA) is a particularly im- be sustained by measuring the rate of CRBSIs and providing ongoing
portant pathogen that plays a major role in central line-associated feedback to practitioners.
bloodstream infection (CLABSIs) (Gaynes and Edwards 2005, Lipitz-
Snyderman et al. 2011). ■■PREVENTION OF CRBSIs –
■■The special problem of MRSA CRBSIs EVIDENCE-BASED GUIDELINES
S. aureus CRBSI (SACRBSI) is a special problem because of its tendency The Centers for Disease Control (CDC) published guidelines for
to cause deep infections at multiple metastatic sites remote from the prevention of CRBSIs in 2011. (O’Grady et al. 2011) Recommenda-
initial source of the infection. Locating the occult source of infection tions were made in the areas of (1) education, training, and staffing,
is particularly challenging; it is often never identified even after an (2) selection of catheters and sites, and (3) hand hygiene and aseptic
extensive evaluation. The mortality rate for MRSA bacteremia is higher technique. The recommendations were categorized based on the level
than for meticillin-susceptible S. aureus (MSSA) (Cosgrove et al. 2003). of supporting evidence (see Table 10.1). This chapter reviews only the
Endocarditis may be a complicating event from SACRBSIs. This risk of recommendations based on category 1 evidence. A complete review
endocarditis is increased by a permanent intracardiac device, hemo- of all recommendations is in the published guidelines (O’Grady et
dialysis dependency, spinal infection, and non-vertebral osteomyelitis al. 2011).
(Kaasch et al. 2011). All patients with a SACRBSI should be evaluated
by echocardiography. Transesophageal echo (TEE) is the diagnostic
tool of choice because of increased sensitivity compared with trans-
■■Education, training, and staffing
thoracic echo (TTE). All patients with a positive blood culture should Appropriate education and knowledge assessment of healthcare
receive a follow-up blood culture within 48 h of the initiation of drug personnel regarding the indications, techniques of vascular catheter
therapy regardless of their clinical response to exclude prolonged insertion, and infection control precautions are associated with a
bacteremia. The decision to use empirical antibiotic therapy for a reduced rate of CRBSIs. Clinical privileges should be restricted to
presumed MRSA CRBSI before blood culture data should be based trained healthcare workers (category 1A) (Nehme 1980, Eggimann et
on clinical suspicion and knowledge of the prevalence of MRSA in al. 2000, Sherertz et al. 2000, Yoo et al. 2001, Coopersmith et al. 2002,
one’s particular hospital microbial flora. 2004, Warren et al. 2003, 2004, 2006b, Higuera et al. 2005).

■■Reduction of CRBSIs in the ICU: ■■Selection of catheters and sites

The Keystone Project There are a wide variety of intravascular catheters used in clinical
A prospective cohort study of surgical ICU patients demonstrated near practice (Table 10.2). For practical purposes, the catheters can be
elimination of CRBSIs by adherence to evidence-based guidelines separated into three broad categories: Peripheral catheters, central
(Berenholtz et al. 2004). Five interventions, with the strongest evidence venous catheters, and umbilical catheters (for use in neonates).
and the lowest barriers to implementation, were chosen: Handwash-
ing, use of full barrier precautions during insertion of central venous Peripheral catheters
catheters, skin preparation with chlorhexidine, avoidance of femoral The operator should be familiar with the selected peripheral catheter
venous catheterization when possible, and removal of unnecessary (category 1B) (Band and Maki 1980, Tully 1981, Ryder 1995). Peripheral
catheters (Pronovost 2008). catheters should be removed immediately if the patient develops signs
The quality and safety research group from the Johns Hopkins of phlebitis (pain, erythema, edema, warmth. or a palpable venous cord)
University partnered with the Michigan Health and Hospital Associa- (category IB) (Maki et al. 1991). Metal needles (“scalp veins”) should
tion Keystone Center for Safety and Quality to determine whether not be used for the administration of fluids and medications that can
or not similar results could be achieved in a large number of ICUs cause tissue necrosis in the event of extravasation (category 1A) (Band
from diverse hospitals by use of these guidelines. A collaborative and Maki 1980, Tully 1981). Although not a CDC recommendation,
 Prevention of CRBSIs – evidence-based guidelines 117

Table 10.2 Catheters used for venous and arterial access.

Catheter type Entry site Length Comments
Peripheral venous catheters Usually inserted in veins of forearm or hand <3 inches (7.6 cm) Phlebitis with prolonged use; rarely associated with
bloodstream infection
Peripheral arterial catheters Usually inserted in radial artery; can be <3 inches (7.6 cm) Low infection risk; rarely associated with
placed in femoral, axillary, brachial, posterior bloodstream infection
tibial arteries
Midline catheters Inserted via the antecubital fossa into the 3–8 inches (7.6–20.3 cm) Anaphylactoid reactions have been reported with
proximal basilica or cephalic veins; does not catheters made of elastomeric hydrogel; lower rates
enter central veins, peripheral catheters of phlebitis than short peripheral catheters
Non-tunneled central venous Percutaneously inserted into central veins >8 cm depending on Account for most CRBSIs
catheters (CVCs) (subclavian, internal jugular, or femoral) patient size
Pulmonary artery catheters Inserted through a Teflon introducer in a ≥30 cm depending on Usually heparin bonded; similar rates of
central vein (subclavian, internal jugular, or patient size bloodstream infection as CVCs; subclavian site
femoral) preferred to reduce infection risk
Peripherally inserted central Inserted into basilic, cephalic, or brachial ≥20 cm depending on Lower rate of infection than non-tunneled CVCs
venous catheters (PICCs) veins and enter the superior vena cava patient size
Tunneled central venous Implanted into subclavian, internal jugular, ≥8 cm depending on Cuff inhibits migration of organisms into catheter
catheters or femoral veins patient size tract; lower rate of infection than non-tunneled
CVCs
Totally implantable Tunneled beneath skin and have ≥8 cm depending on Lowest risk for CRBSI; improved patient self-image;
subcutaneous port accessed with a needle; patient size no need for local catheter site care; surgery required
implanted in subclavian or internal jugular for catheter removal
vein
Umbilical catheters Inserted into either umbilical vein or ≥6 cm depending on Risk for CRBSIs similar with catheters placed in
umbilical artery patient size umbilical vein versus artery
CRBSIs, catheter-related bloodstream infections.

the author’s own practice is to restrict infusion of medications that are 1995, Goetz et al. 1998, Merrer et al. 2001). However, the risk of infec-
thrombogenic or noxious to soft tissues (e.g., potassium chloride or tion must be weighed against the experience and skill of the operator.
calcium salts) to central venous catheters. This practice minimizes the Bleeding from the injured subclavian artery is difficult or impossible to
risk of pain and phlebitis, and avoids extravasation, which can cause tamponade. A subclavian artery injury combined with a pneumotho-
soft-tissue necrosis. rax can lead to massive hemothorax and exsanguination. As a general
Care must be taken with the use of infusion pumps. Very rarely, a principle, the clinician should choose a catheterization technique for
subfascial infusion of fluid under pressure can cause a compartment which she or he has the appropriate training and experience.
syndrome. If unrecognized and untreated, irreversible nerve injury Ultrasound guidance for placement of central venous catheters
and myonecrosis can result in addition to the risks of soft-tissue infec- has been shown to significantly reduce the number of cannulation
tion at the site of extravasation. attempts and the mechanical complications of central venous cath-
eterizations (category 1B) (Randolph et al. 1996, Hind et al. 2003,
Central venous catheters Lamperti et al. 2008, Froehlich et al. 2009, Schweickert et al. 2009,
Central venous access can be achieved via a peripheral vein or the Fragou et al. 2011). Reductions in cannulation attempts and mechani-
femoral, subclavian, or internal jugular veins. A peripherally inserted cal complications reduce infections at the catheter site.
central catheter (PICC) placed under ultrasound guidance is the pre- Occasionally central venous access must be performed in an
ferred site of access for long-term intravenous therapy, administration emergency under less than ideal circumstances. If the sterility of
of phlebitogenic or noxious medications, or intravenous nutritional the catheter insertion is in question, the catheter should be removed
support because of the low risk of mechanical complications (e.g., within 48 h when the patient’s hemodynamic status has stabilized
pneumothorax, hemothorax, and air embolism). A femoral venous (category 1B) (Mermel et al. 1991, Mermel and Maki 1994, Raad et
catheter should be avoided when possible because of the increased al. 1994, Capdevila et al. 1998, Abi-Said et al. 1999, National Kidney
risk of CRBSIs (category Level 1A) (Goetz et al. 1998, Merrer et al. 2001, Foundation 2001). ICU patients frequently have fever associated
Lorente et al. 2005, Parienti et al. 2008) and deep venous thrombosis with leukocytosis of uncertain cause, raising the question of CRBSIs.
(Merrer et al. 2001). Prompt removal of the catheter, a previously recommended practice,
Subclavian and internal jugular catheters may be tunneled subcu- is no longer essential (category 1A) (Lederle et al. 1992, Parenti et
taneously or non-tunneled. Non-tunneled central venous catheters al. 1994, Raad et al. 1994, Berenholtz et al. 2004, Pronovost 2008).
account for most CRBSIs (O’Grady et al. 2011) and should be avoided Hemodynamically stable patients can be evaluated for the cause of
if possible. infection before removal of a catheter. In general, the catheter should
Subclavian venous catheters are associated with a lower risk of be removed only for a definitively diagnosed infection. On occasions,
CRBSIs and are preferable to internal jugular venous catheters for a catheter can be removed after failure to identify an alternative cause
non-tunneled central venous access (category 1B) (Robinson et al. of infection.
118 CATHETER-RELATED BLOODSTREAM INFECTIONS

■■Hand hygiene and risk for CRBSIs, particularly if the catheters have been in place for an
extended period of time.
aseptic technique
Insertion of an intravascular catheter is a surgical procedure and Making a definitive diagnosis of CRBSIs
should be treated as such. Prior hand washing with conventional soap With certain exceptions, patients without positive blood cultures do
and water or alcohol-based hand rubs (Pittet et al. 1999, Bischoff et not have a CRBSI. A careful search for alternative sources of infection
al. 2000, Boyce et al. 2002, Coopersmith et al. 2002), with strict aseptic using microbial cultures, physical examination and appropriate imag-
technique for insertion and care of the catheters, is essential (category ing techniques (CT scans of the abdomen and chest), depending on
1B) (Mermel et al. 1991, Raad et al. 1994, Capdevila et al. 1998, Abi-Said the clinical problem, is essential. Neither the fever nor the white blood
et al. 1999). Clean, rather than sterile, gloves may be worn for insertion cell (WBC) counts are particularly helpful. Patients with leukopenia
of peripheral venous catheters as long as the skin is not touched after (WBCs <2000) or leukocytosis (WBCs >18 000) merit special attention.
sterile preparation (category 1C). Maximal sterile barrier precautions In most cases, a positive blood culture, especially with Gram-positive
including cap, mask, sterile gown, gloves, and full body drape should organisms, suggests the diagnosis. If the fever resolves after the cath-
be used for all insertion and guidewire exchanges of central venous eter is removed, a CRBSI is highly probable. Culture of the catheter
catheters (category 1B) (Mermel et al. 1994, Raad et al. 1994, Sherertz tip is usually unnecessary. Placing the catheter tip in broth media is
et al. 2000, Carrer et al. 2005). a waste of time. The culture will be ‘positive’ even if only one colony
A solution of 70% isopropyl alcohol, tincture of iodine, or a >0.5% grows. In the unusual case where a culture is desirable, the roll-plate
chlorhexidine preparation with isopropyl alcohol may be used to method should be used. The catheter tip is rolled on a blood agar plate
prepare the skin (category 1A) (Maki and Ringer 1991, Mimoz et al. and the number of colonies counted. By convention, >15 colonies are
1996). There are no data comparing the efficacy of the various skin considered an infection.
preparations. Basic surgical principles should be employed in the From an operational point of view, if the catheter is removed, the
management of the catheter insertion site. Topical antibiotics should blood cultures become negative and the fever resolves, a retrospective
not be used on insertion sites, except for dialysis sites, because of the diagnosis of CRBSI is made. In a few highly suspicious unusual cases,
risk of fungal infections and antimicrobial resistance (category 1B) a quantitative culture of the catheter tip is reasonable.
(Flowers et al. 1989, Zakrzewska-Bode 1995). There is no indication
for systemic antimicrobial prophylaxis before or during intravascular Indications for catheter removal
catheter insertion (category 1B) (van de Wetering and van Woensel (Figure 10.1)
2007).
The same principles are applied to the insertion of peripheral The catheter should be removed immediately if there are positive blood
arterial catheters except that sterile gloves are mandated for all arte- cultures and no other source of infection is identified. In general, cath-
rial line insertions (category 1B) (Rijnders et al. 2003, Traore et al. eters should be removed immediately if S. aureus or Candida spp are
2005, Koh et al. 2008). There are various recommendations for the identified on blood cultures. Occasionally, a difficult-to-place essential
management of the pressure monitoring system attached to the line can be changed over a guidewire and observed while the patient
arterial catheter (O’Grady et al. 2011). The basic principles are use of is treated with antibiotics. However, in almost all cases, patients with a
disposable transducers when possible, use of a closed system, use of S. aureus or Candida spp. blood-borne infection will require catheter
topical antiseptics before accessing the system, and replacement of removal. Patients with SACRBSIs should receive an echocardiogram
tubing and connectors contaminated with blood. to exclude the infrequently associated case of endocarditis. Patients
with a Candida spp. CRBSI should receive an ophthalmic examination
■■APPROACH TO THE FEBRILE to exclude candida endophthalmitis.
In selected clinical situations, including infection with S. epider-
PATIENT WITH A LONG-TERM midis, the catheter can be temporarily preserved during antibiotic
INDWELLING VASCULAR treatment. Eventually, most infections require catheter removal.

CATHETER Duration of antibiotic therapy

Patients with S. aureus and Candida spp. infections require 14 days
An ICU patient with a long-term indwelling central venous catheter of antibiotic therapy after catheter removal. The optimal duration of
who develops fever and leukocytosis usually has multiple potential treatment for CRBSIs secondary to coagulase-negative staphylococci
sites of infection, including the central venous catheter. The clinician remains unknown. Most clinicians give a minimum of 7 days of anti-
must determine the cause of the infection and whether the catheter biotic therapy for a CRBSI in this circumstance.
should be removed. The catheter is always a consideration for infec-
tion but the risk is directly proportional to the duration of catheter-
ization. The longer the catheter has been in place, the greater the risk
■■CONCLUSION
of a CRBSI. Other variables to be considered include the anatomic Advances in clinical care have led to the proliferation of intravascular
site of catheterization, whether or not the catheter is tunneled, the catheterizations. This has resulted in an epidemic of CRBSIs account-
condition of the skin at the insertion site, and the function of the cath- ing for significant morbidity, mortality, and increased cost of care.
eter. The femoral and internal jugular venous catheters are at much Advances in bacteriology and pathophysiology have led to effective
greater risk for CRBSIs compared with subclavian venous catheters. strategies that have demonstrated significant reductions in the risk of
Tunneled catheters are less likely to be associated with CRBSI than CRBSIs in both single and multi-institutional studies. Adherence to
non-tunneled ones. Catheter insertion sites draining fluid or pus or the 2011 CDC guidelines for the prevention of intravascular catheter-
surrounded by erythematous skin are of great concern. Percutaneous related infections (O’Grady et al. 2011) is essential to control the
central venous catheters for hemodialysis access also have a significant epidemic and achieve safe intravascular therapy.
 Vasc catheter
+
fever

SIRS No SIRS

Known source No source of Postitive blood Negative blood

of infection infection cultures cultures

Fever wordk-up
Rx infection imaging Other Infection source Infection source
MRSA Candida Spp
empiric antibx organisms not identified identified

No Easy to replace Hard to replace Antibx Antifungals Rx infection

Improvement Infection source No
improvement catheter catheter remove catheter remove catheter Improvement follow-up blood
identified improvement
TEE ophthalmic exam cultures

Remove Follow-up Remove Poor response Good response Follow-up

Start antibx Observe
catheter blood cultures catheter to antibx to antibx blood cultures

Remove Follow-up
catheter blood cultures Response to No response
antibx to antibx

Remove
Observe
catheter

Figure 10.1  Management of patients with an indwelling vascular catheter and a fever. (Reprinted from O’Grady et al. (2011). Copyright 2011, with permission from Elsevier.)
Conclusion
119
120 CATHETER-RELATED BLOODSTREAM INFECTIONS

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Chapter 11 Clostridium difficile infection
Donald E. Fry

Clostridium difficile is an anaerobic, Gram-positive rod that was

not identified until 1935 (Figure 11.1). It is a difficult bacterium to
■■PATHOGENESIS
culture, hence the name “difficile.” It was not associated with clinical As it is an obligate anaerobe, C. difficile exists as a spore when outside
disease until the late 1970s when experimental studies in guinea-pigs a host. When confronted with an unfriendly environment, the spore
identified it as the pathogen of the antibiotic-associated enterocolitis permits survival of the bacterium until it finds a suitable milieu to
syndrome. Since its identification, Clostridium difficile infections transform into the vegetative phase that leads to clinical infection.
(CDIs) have progressively increased in frequency as a complica- The cell target for C. difficile in causing human disease is the colo-
tion of hospitalized patients. In the USA, it occurs in nearly 400 000 nocyte. The spore gains access to humans by being ingested from the
hospitalized cases per year and exceeds 1% of all hospitalized adult external environment. The thick coat of the spore permits survival in
patients (Agency for Healthcare Research and Quality 2011) (Figure passing through the acid environment of the stomach. The passage
11.2). Total cases have been estimated to approach 3 million per year into the small intestine does not favor the transition to the vegetative
including ambulatory, post-discharge, and relapsing cases from prior phase because of the oxygen tension in this area. Only in the distal
infection. The number of deaths associated with CDIs has steadily ileum and then in the colon are environmental anaerobic conditions
increased as the number of cases has increased (Zilberberg et al. within the lumen favorable for the vegetative phase of the organism.
2008). CDI has become an international epidemic among all cohorts As an abundance of non-specific host defense mechanisms exist
of patients (Gerding 2010), but is especially problematic for patients within the colon, a critical inoculum of ingested spores is necessary
undergoing major surgical procedures. Infections can be quite un- to yield a clinical infection.
predictable, and occur in episodic clusters within given hospitals. Colonization resistance best describes the normal colonic mucosa’s
CDI has followed a clinical trajectory that can be compared with ability to withstand CDI because of the normal microbial constitu-
meticillin-resistant Staphylococcus aureus (MRSA) infection. The ents. The normal microflora have 10 000 anaerobes for each aerobic
organism has assumed a more virulent profile in addition to being a organism in the rectosigmoid colon, so competition for substrates to
more common cause of infections. Similar to MRSA, it is now being support the vegetative state for C. difficile is problematic. Metabolic
identified with increased frequency as a community-acquired patho- end-products of competing microflora may be sufficiently toxic to C.
gen. Preventive strategies have been inconsistently successful. Little difficile to repress the vegetative state transition. Even if the vegetative
progress has been made over the last two decades in the development transition occurs, the competitive inhibition of the normal anaerobic
of new treatments. It has rapidly become one of the most severe com- population of bacteria for receptor sites on the target colonocytes may
plications among surgical patients. preclude binding and the resultant CDI.
In addition to colonization resistance, other non-specific host de-
fense mechanisms protect the colon mucosa from infection mediated
by C. difficile or other pathogenic bacteria. Surface mucins form an
initial protective barrier. IgA antibody may bind to C. difficile surface
targets to impede the binding to colonocytes. Effective gut motility
can propel spores through the colon and minimize the opportunity for
vegetative forms to bind to the colonocyte. Thus, in surgical patients it
is easy to identify that disruption of normal feeding, anesthetics and
analgesics, and non-specific ileus, which attends bowel manipulation
during laparotomy, can lead to a diminished colonic transit time that
favors the emergence of CDI.
Binding to the colonocyte is a critical determinant for CDIs to
occur. Fimbriae and flagellae play a role in motility and binding of
the vegetative form. Specific surface receptors of the bacterial cell
bind to the colonocyte and have been a therapeutic focus because
receptor blockade will modulate microbial virulence. The positive
electrical charge of the C. difficile surface and the negative charge of
the colonocyte surface are also considered to play a role in adhesion
of the pathogen.
Once binding occurs, the C. difficile microorganism elaborates two
unique toxins that synergistically damage the mucosa of the colon.
Figure 11.1  Micrograph of Clostridium difficile. (From the Public Health Toxin A is an enterotoxin and toxin B a non-specific cytotoxin. The
Image Library, Centers for Disease Control, courtesy of Dr Gilda Jones: http:// toxins bind to the plasma membrane of colonocytes, are internalized,
phil.cdc.gov/phil/details.asp.) and damage the cytoskeleton of the host cell, leading to necrosis.
124 CLOSTRIDIUM DIFFICILE INFECTION

Figure 11.2  The progressive increase in

Clostridium difficile infections among discharged
patients from US hospitals over the last 10
years. (Data from the National Inpatient Sample,
Healthcare Cost and Utilization Project, http://
hcupnet.ahrq.gov.)

The loss of cytoskeleton leads to the observed “cell rounding” in the that is strongly associated with the rapid evolution of full-thickness
affected colonocyte before frank membrane disruption and necro- necrosis of the colon. These variants result in such a rapidly evolv-
sis. The presence of these toxins is essential for microbial virulence ing enterocolitis that the diarrhea phase of the disease may be very
because C. difficile strains are identified that do not produce toxins transient or not present at all. Surgical intervention has become much
and do not have virulence. more common and mortality rates for these patients are dramatically
Other virulence factors facilitate CDIs once the process has been greater than identified with conventional CDIs. In addition, these hy-
initiated by toxins A and B. Hyaluronidase and collagenase disrupt pervirulent strains have been associated with a binary toxin known at
the extracellular matrix between colonocytes and in the subsequently C. difficile transferase (Papatheodorou et al. 2011). This binary toxin is
exposed submucosal tissues. A polysaccharide capsule retards phago- distinct from toxins A and B, but it may be synergistic with them. Some
cytosis of the pathogen by host leukocytes. The necrosis of colonocytes evidence indicates that the binary toxin may enhance the adherence
and the effects of other bacteria in the heavily populated colon lead of C. difficile to the colonocyte and promote enhanced virulence by
to progressive injury of the transmural population of colonic cells. this mechanism.
With inflammatory changes of smooth muscle, poor peristalsis, in-
creased intestinal pressure, and tissue ischemia occur as the disease
progresses.
■■RISK FACTORS
CDI has distinct pathological stages. In advanced cases it is pos- A number of patient variables and healthcare interventions are associ-
sible to identify all four stages affecting different areas of colonic ated with the development of CDIs (Ananthadrishnan 2011). Among
mucosa. The erythematous mucosa reflects early consequences of patient factors, increasing age is the most commonly recognized
the toxins. At this stage, diarrhea and crampy abdominal pain begin. association. Despite stool detection of the toxins of C. difficile in 50%
Patchy necrosis represents areas where toxic effects have caused cell of neonates in intensive care settings, CDIs are very uncommon in
necrosis and lysis with a robust mucosal inflammatory response. neonates and infants. It is thought that the neonatal and infant popula-
Pseudomembranes are identified at diagnostic endoscopy as inflam- tions have lower rates of infection because of the reduced expression
matory exudates form over areas of necrotic mucosa. The clinical of the target receptor for C. difficile on the immature colonocyte. The
symptoms of diarrhea and crampy abdominal pain are exacerbated. incidence of the infection increases with increasing age (Figure 11.3).
Abdominal distension reflects inflammatory effects on colonic smooth Most CDIs occur in patients aged >60 years. Although the frequency of
muscle. Transmural inflammation and toxic megacolon emerge as infection is linked to the number and duration of hospitalizations, age-
the disease progresses because of impaired and poorly coordinated adjusted profiles of hospital days by decade of life still demonstrates
colonic peristalsis. Severe abdominal pain and distension are present. that CDIs increase with age as an independent variable. This associa-
The patients are systemically toxic. Diarrhea commonly ceases at this tion with increased age appears to be related to a progressive reduction
point. Transmural necrosis occurs with smooth muscle death from in colonization resistance in elderly people, the increase in the use of
severe inflammation and ischemic changes of colonic distension. antibiotics with each passing decade, increased hospitalization and
The microcirculation may thrombose from the intense inflamma- nursing home days, and the immunosuppression of chronic diseases.
tion. The adventitial layer of the colon may maintain viability, giving Many specific patient disease variables are being associated
a deceptive external appearance to the extent of the colonic mucosal with an increased odds ratio for the development of CDIs (Loo et
necrosis underneath. With necrosis of the overlying serosa, bacterial al. 2011). Patients with ulcerative colitis and regional enteritis have
peritonitis and potentially even perforation of the necrotic segment increased frequency and severity of CDIs. Colon cancer patients
may occur in very advanced cases. have similarly been noted to have increased rates due to either a
Over the last decade, new hypervirulent strains (BI/NAP1/027) of more vulnerable colonic barrier or weight loss from the illness. Re-
C. difficile have emerged and are associated with unusually severe nal failure patients receiving dialysis have the immunosuppression
and rapidly evolving CDIs (McDonald et al. 2005). These hyperviru- of chronic disease, frequent antibiotics, and frequent transfusion
lent strains represent mutants with loss of the regulatory gene that as potential causative factors. Most patients with several chronic
controls the production of toxins A and B. Mutant strains produce disease conditions have been associated with CDIs, and even
15–20 times the quantity of these toxins and yields a fulminate disease pregnancy has been recognized (Rouphael et al. 2008). Vitamin
 Diagnosis 125

Figure 11.3  The age distribution of Clostridium

60.0% difficile infection from a 20% national sample
of patients in the USA from 2000 to 2009. (Data
50.0% from the National Inpatient Sample, Healthcare Cost
and Utilization Project, http://hcupnet.ahrq.gov.)
Percentage of cases

40.0%

30.0%

20.0%

10.0%

0.0%
<1 >1-17 18-44 45-64 65-84 85+
Age ranges

D deficiency is another recently identified variable. Probably the

strongest patient characteristic is the history of prior CDIs. There
■■DIAGNOSIS
is no sexual predilection for this infection. The diagnosis of a CDI has become so common among adult hospi-
Although selected host factors do contribute to the frequency of talized patients that virtually all patients aged >60 years and those
CDIs, it is most strongly linked to being a healthcare-associated dis- with any duration of time in the ICU must be considered at risk. All
ease. Over 90% of cases are linked to the use of systemic antibiotics. physicians and surgeons should have a high index of suspicion for
Ampicillin, amoxicillin, and clindamycin were the antibiotics as- CDIs. Any of a number of different clinical signs or symptoms must
sociated with CDIs in the early descriptions of this infection, but the trigger an evaluation.
quinolone group of drugs has recently been very strongly correlated Diarrhea has been the most frequent clinical event that heralds a
with this complication. The cephalosporin group has had a consistent CDI. A formal definition has included three unformed stools over 24 h
association over the three decades of tracking this disease. Virtually for 2 consecutive days, or 8 unformed stools over 48 h, or 2 individual
every antibiotic has been associated with CDIs, including vancomycin watery stools within a 24-h period. In elderly patients, in particular,
and metronidazole as the drugs used to actually treat the infection. the duration of the diarrhea phase of the disease may be very transient
This latter paradox speaks to the complexity of the numerous variables and no consolation should be taken from diarrhea that spontaneously
that result in this clinical infection. resolves. The hypervirulent strains of C. difficile may not have a diar-
The hospital length of stay has a strong correlation with CDI infec- rhea phase at all. Bloody diarrhea is not a feature of CDIs and if present
tion because the hospital is the source of spores for most patients. requires an evaluation for alternative diagnoses.
Duration of stay in the intensive care unit (ICU) appears to have a Although abdominal pain and abdominal distension are common
stronger relationship than conventional ward hospitalization. The features of patients after major surgical procedures, the new onset
endotracheal tube of ventilator patients provides an entrance route of crampy abdominal pain and distension is a consistent feature of
for spore entry via the oropharynx. Enteral feeding likely provides an patients with CDIs. This crampy abdominal pain in association with
access route for the spore from the external environment and also new-onset diarrhea usually differentiates the pain of CDI from that
neutralizes gastric acid as a primary barrier to colonization. However, associated with diarrhea secondary to enteral feeding or other causes.
enteral feeding can be viewed as a method to foster a normalization Fever and leukocytosis are not consistent features of CDIs. Dehydra-
of gut colonization. tion, electrolyte abnormalities, and hypoalbuminemia will be seen
Many specific treatments are associated with CDIs. Both antifungal with advanced CDIs but can occur from a number of different causes
and antiviral chemotherapy are linked but the underlying patient in postoperative patients.
disease is a likely contributor as well. Antineoplastic chemotherapy However, CDIs may be the diagnosis in only as few as 30% of diar-
may have specific gastrointestinal toxicities that would appear to injure rhea syndromes in hospitalized patients. The dramatic increase in
the colonic mucosa and increase the vulnerability for CDIs. Corti- the used of enteral feeding regimens over the last 20 years provides
costeroids and other immunosuppressive drugs that are commonly both an access route for the C. difficile spore, but provides a high-
employed in transplant recipients certainly contribute to increased probability alternative source of diarrhea due to poor patient tolerance
rates of CDIs in this population of patients. The use of histamine of feeding formulations. A host of different medications can provoke
antagonists and proton pump inhibitors has had the greatest associa- diarrhea (Ringel et al. 1995). Impaction continues to be a clinical as-
tion in recent years because of the loss of protective effects of gastric sociation with diarrhea and a rectal examination is required in all of
acidity (McCarthy 2010). these patients.
The postoperative surgical patient, particularly those undergoing Conventional abdominal radiographic studies are commonly used
major abdominal procedures, is at high risk for CDIs. Nasogastric in the patient with clinical symptoms consistent with CDI. Often these
tubes provide the avenue for spore introduction, the generous use of are done because of concern for postoperative intestinal obstruction.
antibiotics disrupts the normal colonic environment, and impaired Non-specific colonic distension is usually found in the CDI patient
gut motility due to ileus and opiate analgesics all become synergistic and the identification of air–fluid levels means that other diagnoses
effects to make CDIs a major problem. Although mechanical bowel are applicable. The abdominal computed tomography (CT) scan has
preparation has been associated with CDIs, recent evidence has not been useful with thickened colonic wall being a feature of transmural
demonstrated any correlation (Krapohl et al. 2011). edema in the patient with CDI infection.
126 CLOSTRIDIUM DIFFICILE INFECTION

Proctosigmoidoscopy has been a traditional method for the diagno-

sis of CDIs. It can be a logistical problem in patients with severe diar-
■■PREVENTION
rhea or poor cooperation. Pseudomembranes are generally considered The prevention of CDIs requires particular attention to those clinical
diagnostic when present but their presence depends on the duration variables that have been clearly associated with the infection. En-
of illness. Finally, even with the longer, flexible proctosigmoidoscopy, hanced infection control practices are essential. If the patient is not
the diseased segment of the colon may not be accessible with the exposed to the C. difficile spore, the CDI will not occur. It is essential
bedside examination. to have enhanced hand hygiene for prevention of CDIs as well as
As large numbers of patients with diarrhea do not have CDIs, a the other pathogens (e.g., MRSA) in the hospital setting. Mechanical
specific diagnosis must be established before treatment is under- cleansing of the hands after patient contact is necessary. Alcohol-
taken. Direct recovery of C. difficile by bacterial cultures can be per- based hand gets and rubs do not eliminate C. difficile spores and
formed but is a pain-staking process that is generally not performed give the artificial sense that infection control is being practiced when
except in research centers. Culture methods commonly employ egg it is not. Chlorhexidine hand washes and scrubs do appear to have
yolk agar that is supplemented with cycloserine, cefoxitin, and fruc- benefit, but it may be the mechanical scrubbing of the hands that is
tose. As C. difficile has a consistent pattern of cefoxitin resistance, most important. Patients with established infection should be placed
it is added to the media to suppress the growth of other anaerobic into single hospital rooms, or should be put together. Some hospitals
species. The plated culture medium is incubated under anaerobic have advocated segregating infected patients to a dedicated ward or
conditions. Precise anaerobic culture technique is required, and wing of the hospital, and have dedicated nursing personnel provide
recovery of C. difficile does not define the issue of the organism the care for those patients to prevent dissemination of the spores. Pa-
being a toxin producer. As specific sensitivities of clinical isolates tients with infection should remain isolated until diarrhea symptoms
have not been of value in the selection of specific antimicrobial have resolved for 48 h. The use of gloves for handling and placement of
therapy, cultures are usually not performed. Other studies such as indwelling oropharyngeal tubes and devices is important. Gloves and
Gram stains, fecal leukocyte detection, and occult blood detection gowns are likewise necessary for all contacts with active CDI patients
are not of value. to avoid transmission to others.
The most common diagnosis method for CDIs is detection of the Environmental decontamination is necessary for patient rooms,
toxins in the diarrhea specimen using an enzyme immunoassay. ICUs, and even the operating room after occupancy by CDI patients.
Current immunoassays detect both toxin A and toxin B. As sensitivity Similarly, all reusable hospital equipment (e.g., endoscopes) requires
and specificity are <95%, the study of a single diarrheal specimen may the same vigilance for decontamination after each patient contact.
not be positive in the CDI patient. The rapidity of performance of the When outbreaks occur, a greater dependence on disposable supplies
immunoassay is such that sequential specimens may be studied if is often indicated. Chlorine bleaches have the greatest effectiveness
the initial results are negative in patients in whom compelling clinical in the elimination of environmental spore contamination. Sodium
signs and symptoms are consistent with a CDI. This diagnostic method hypochlorite solution at 1000 parts/million has been recommended
should be used only on diarrheal stools, because the accuracy of the as- to be effective in the reduction of CDI rates (Cohen et al. 2010).
say is diminished in formed stool. This latter observation underscores Monitoring and surveillance of CDI cases over time within the
that the immunoassay for toxins cannot be used as a screening tool in hospital can provide useful information about targeting overall pre-
patients who are at risk for the infection but have not yet demonstrated ventive strategies. Even though CDI rates are similar to those seen
symptoms of the disease. with MRSA, the degree of surveillance of these infections has not
The expanded use of the polymerase chain reaction (PCR) for been given the same level of attention that MRSA infections receive.
diagnosis is available in most clinical laboratories and this method Accurate monitoring of events, establishing the hospital ward or unit
has been employed for detection of specific genes for toxins A and responsible for the infection, and establishing control charts to quickly
B. PCR has greater sensitivity and specificity than other diagnostic identify clusters of infection are very important in the evolution of an
methods. The PCR method can be done quite rapidly. This advan- effective hospital-based preventive strategy.
tage of quick diagnosis followed by prompt isolation of CDI patients More effective use of antibiotics in the surgical patient is as impor-
has the advantage of rapid initiation of therapy and enhancement tant as infection control practices. Despite the abundance of evidence
of infection control practices in the hospital (Bartlett 2010). PCR that has demonstrated no value to extending preventive antibiotics
may supplant direct toxin measurement as the diagnostic method into the postoperative time frame, the practice of multiple days of
of choice. systemic antibiotics continues. Preventive antibiotics only have a
Other diagnostic methods are uncommonly employed. The direct role in the prevention of infection at the surgical site (see Chapter
detection of glutamate dehydrogenase has been used as an antigen 4). Preventive systemic antibiotics do not provide patient benefit
marker for the presence of C. difficile. This method has better sensi- in covering open wounds or individual indwelling devices or tubes.
tivity than the toxin detection method, but has lower specificity. This Systemic antibiotics do not penetrate only those areas for which
study is positive when patients have non-toxigenic colonization with the clinician is using them, but they penetrate virtually all tissues of
C. difficile. For the latter reason, positive studies for the antigen require the body. Prolonged antibiotics eliminate sensitive organisms from
confirmation by the toxin assay. the patient’s colonization and have disruptive effects on the normal
The cytotoxicity assay employs the filtrate of the stool to directly colonic microflora. Antibiotics with anaerobic activity are especially
determine toxic effects. The filtrate is incubated overnight with refer- troublesome in this regard.
ence cell cultures to identify the typical “rounding” effects of toxins A Therapeutic use of antibiotics has been a major influence in
and B. It is a direct bioassay of toxicity and may be the most accurate promoting CDIs, as have preventive drugs. When patients have
of studies when correctly performed. It is a technically demanding established infection, the putative organism is commonly not im-
and expensive method that is not practical for routine use in the mediately available and accordingly the initial choice of antibiotics
clinical setting. tends to be very broad in the expectation of covering all possibilities
 Treatment of CDIs 127

until the culture and sensitivity data are available. This has resulted in
the initiation of antibiotic combinations of three or more drugs that
■■TREATMENT OF CDIs
comprehensively cover Gram-positive, Gram-negative, and anaerobic The treatment of CDIs has multiple components in addition to the use
species. Although the broad initial coverage is understandable in the of antimicrobial chemotherapy. As these patients are commonly el-
setting of uncertainty about the pathogen or pathogens involved in derly and the volume of diarrhea can be large, extracellular fluid deple-
the infection, especially in the ICU, the philosophy of de-escalation of tion and electrolyte imbalance can be major issues. The inflammatory
antibiotic therapy is not uniformly obeyed and patients are continued response within the colonic wall can lead to dislocation of plasma
on multiple drugs for an excessive period of time. proteins and extracellular water, in additional to the consequences
Furthermore, once patients are started on appropriate antibiotics of the diarrhea. Monitoring and managing fluid and electrolytes are
there is clinical uncertainty as to when they should be discontinued. important to maintain adequate perfusion of the inflamed colon.
Recent studies have demonstrated benefit to earlier discontinua- A major component of management is to re-evaluate the antibiotics
tion of systemic antibiotics for patients with ventilator-associated that are likely to provoke CDIs. Unnecessary postoperative preventive
pneumonia (VAP) (Pugh et al. 2011) and those with intra-abdominal antibiotics and prolonged therapeutic antibiotic administration that
infection (Solomkin et al. 2010). The duration of administration for do not have legitimate value should be discontinued. Ampicillin,
VAP patients may be sufficient for 7–10 days instead of the traditional amoxicillin, clindamycin, cephalosporins, and quinolone antibiot-
14 days or more. Intra-abdominal infection patients may benefit from ics have the strongest association with CDIs and alternative drug
only 5–7 days, and patients with perforative appendicitis may require choices should be considered when continuation of antibiotic therapy
fewer days than that. The duration of antibiotic therapy for catheter- is necessary. A minority of CDIs may resolve by simple cessation of
associated urinary tract infection remains poorly defined and is systemic antibiotics without specific treatment addressed to C. difficile.
probably excessive (see Chapter 9). Similarly, antibiotic use for soft- Obviously specific antibiotic therapy will be warranted in most CDI
tissue infections is commonly excessive when effective debridement patients but it is reasonable to expect a more difficult resolution of the
has been achieved. Confusion continues to exist with open wounds infection and a higher rate of recidivism if other systemic antibiotics
about what constitutes infection and what is colonization that will not are being continued during the effort to treat CDIs.
benefit from systemic antibiotics. In most clinical circumstances of A common reaction among surgeons when patients develop
treating established infection in the surgical patient, the tendency is postoperative diarrhea is to symptomatically treat the patient with
to over-treat patients. The result is that the normal colonic microflora antiperistaltic agents. Diarrhea is the response of the colon to expel
is obliterated with C. difficile and other highly resistant bacteria being noxious agents, and the elimination of C. difficile toxins that are not
the residual intraluminal colonists. bound to colonocytes is an appropriate response of the host. Anti-
Selective gut decontamination (SGD) remains a controversial meth- peristaltic agents lead to impaired colonic contractility, with retention
od to prevent infections including CDIs among hospitalized patients of toxins, and increased intraluminal pressure. Furthermore, effective
(Stoutenbeck et al. 2007). SGD is an attempt to suppress pathogenic anti-peristaltic therapy can obscure the early clinical recognition of
bacteria from colonizing the gastrointestinal tract in severely ill patients. CDI, and after treatment has been started may give the false impression
Some evidence suggests that it may be effective in reducing certain that therapy is effective. The risk of toxic megacolon can be expected
nosocomial infections where the gastrointestinal tract is thought to be to be enhanced from the use of diphenoxylate and atropine (Lomotil)
a reservoir of pathogenic organisms. Others still question the utility of or loperamide (Imodium).
this method, fearing that a longer-term evolution of resistant pathogens Specific antimicrobial therapy is the most important component of
will be the consequence. It is a concern that continued spore exposure treatment to eradicate the pathogen. As systemically administered an-
from the external environment for patients with deliberate eradication tibiotics poorly penetrate the lumen of the colon, orally administered
of gut bacteria would set the stage for increased rates of CDI. Most SGD drugs that give therapeutic intraluminal concentrations are desirable
regimens attempt to preserve the anaerobic colonic microflora by using for therapy. Metronidazole and vancomycin are the antimicrobial
only antimicrobials against Gram-negative aerobic bacteria. SGD has choices that have been most commonly chosen for CDI treatment
not been associated with increased rates of CDI. (Table 11.1).
It is inevitable that some discussion would evolve around the use Metronidazole has been used most commonly over the last few
of either vancomycin or metronidazole to prevent CDIs. No current decades, but has features that currently limit its use to mild and
evidence has demonstrated the benefits of such a strategy. Metro- moderately severe CDIs. It is efficiently absorbed in the proximal
nidazole is absorbed from the gastrointestinal tract and may have gastrointestinal tract, but is eliminated in active form within the bile
long-term resistance implications for this antimicrobial agent. The to yield an adequate concentration within the bowel lumen. Metroni-
implications of using vancomycin in such a fashion would further dazole has a comprehensive spectrum of activity against all intestinal
destabilize the precarious emergence of vancomycin-resistant Gram- anaerobic bacteria and is viewed as a disruptive intervention upon the
positive pathogens. colonic microflora. It is very inexpensive and has a long track record

Table 11.1 The current recommended antimicrobial treatment options for the initial episode of CDI.
Antimicrobial treatment Dosage Commentary
Metronidazole: mild-to-moderate infection 500 mg orally three times/day, 10–14 days Food and Drug Administration (FDA) approved
Vancomycin: severe infection 125 mg orally every 6 h, 10–14 days FDA approved
Vancomycin: severe and complicated 500 mg orally every 6 h + metronidazole 500 mg FDA approved drugs for an unapproved dosing
intravenously every 8 h until clinical resolution regimen
Fidaxomicin 200 mg orally every 12 h, 10–14 days FDA approved
128 CLOSTRIDIUM DIFFICILE INFECTION

of effectiveness in the management of CDI. Metronidazole is dosed within the gastrointestinal tract to the level of the colon in relevant
at 250–500 mg every 6 h for 10–14 days as the usual course of treat- concentrations. Penetration of the colonic lumen by the intravenous
ment. Higher doses used for the full 14 days of treatment are thought route in distended colon with either metronidazole or vancomycin is
to reduce rates of recurrent or relapsing infection after cessation of suspect. A limited number of patients have been successfully treated
therapy. As it is efficiently absorbed, it does have nausea, headache, with intravenous tigecycline at 50 mg every 12 h in the management
alteration of taste, and peripheral neuropathy as associated adverse of unresponsive cases with prior conventional therapy (Larsen et al.
events. Although metronidazole should have the advantage of less 2011). There is speculation that tigecycline may penetrate the colon
induction of resistant Gram-positive overgrowth in the colon, one better than alternative agents. Additional studies are needed to vali-
study identified that vancomycin-resistant enterococci (VREs) are as date tigecycline therapy for the difficult CDI case that is refractory to
common with metronidazole as with vancomycin in the treatment of conventional management.
CDIs (Al-Nassir et al. 2008).
Based on recent studies, oral vancomycin is the recommended
treatment for severe cases of CDIs (Zar et al. 2007). Vancomycin is
■■Recurrent infection
not absorbed from the gastrointestinal tract and yields very high Recurrent CDI within 60 days of treatment occurs in up to 30% of
concentrations in the colon after oral administration. It has a focused cases. Recurrent infection may not even be with the same C. difficile
activity against Gram-positive pathogens, and has the theoretical strain of the original infection, which obviously implicates host issues
advantage of not influencing Gram-negative rods or Gram-negative as being of significance in this population of patients. Recurrence is
colonic anaerobes. It will promote VREs in the colon and increase generally not associated with C. difficile strains that were resistant to
rates of VRE nosocomial infection. It does not have systemic toxicity the primary antibiotic choice, because sensitivities of these bacteria
because it is not absorbed, but it is significantly more expensive than to metronidazole and vancomycin have remained stable and recur-
metronidazole. The oral preparation has periodically been in short rent pathogens are sensitive to the antimicrobials initially used for
supply because it has no clinical use other than the treatment of CDIs. treatment. Recurrent infection with the hypervirulent BI/NAP1/027
Vancomycin is dosed at 125 mg every 6 h for 10–14 days. strains and chronic recurrent infection among a selected subset of
Dissatisfaction with metronidazole and vancomycin has led to patients have been the major impetus for the development of more
the search for alternative agents that would give a better clinical effective treatments.
response to initial treatment, but also reduce the frequency of re- It has been difficult to define patient comorbidities that are unique
current/relapsing infection once the treatment regimen has been to the population of patients with recurrent or relapsing infection.
completed. This dissatisfaction with metronidazole and vancomycin Treatment variables associated with recurrent CDI include prior
has not been because of emerging resistance but rather because of relapse of infection, inadequate dosing or duration of treatment for
recurrent infection. Fidaxomicin is a new oral treatment that has the initial episode, poor patient compliance with the initial treatment
been approved for use by the Food and Drug Administration (FDA) regimen, continued or interval reintroduction of systemic antibiotic
in the USA, and has the promise of better results in the treatment therapy, and with certain strains of C. difficile. An explanation for
of CDIs. recurrent CDIs remains very elusive for many patients.
Fidaxomicin is a macrocyclic antibiotic with antimicrobial activity The management of recurrent infection generally follows the guide-
against C. difficile that exceeds that of vancomycin. This in vitro supe- lines of initial care with larger doses and a full 14 days of treatment.
riority is also seen against the hypervirulent strains. It has a greater Some have advocated a longer course of treatment for recurrent cases,
post-antibiotic effect than vancomycin, and has fostered the hope that although success with this strategy has not been clearly documented.
recurrence of infection will be less with this treatment. Fidaxomicin is A host of different treatments has been employed for recurrent cases.
minimally absorbed and does not appear to have any systemic toxic- For extraordinarily difficult cases, donor fecal enemas have been
ity. Colonic concentrations of the drug are quite high. Fidaxomicin is used as a desperate but not particularly popular treatment to restore
active against Gram-positive bacteria, which include most strains of normal colonic microbiota (Bakken 2009). Table 11.2 illustrates many
staphylococci. It does not have activity against Gram-negative rods of the unique regimens that have been used in the management of
or anaerobes of the colon. recurrent CDIs.
A multicenter randomized clinical trial of 596 patients with CDIs An important observation has been that patients with recurrence
were treated with doses of either 200 mg fidaxomicin or 125 mg van- of CDIs after apparently successful initial treatment commonly do not
comycin (Louie et al. 2011). Each drug was given every 6 h and the have an anti-toxin A antibody response compared with those patients
total duration of treatment was for 10 days. Clinical resolution of CDIs without recurrence (Kyne et al. 2001). Indeed, the odds ratio of having
at the completion of treatment was statistically the same, at 88% for recurrent disease without the appropriate IgG antibody response to
fidaxomicin and 86% for vancomycin. Recurrent or relapsing infections toxin A was 48.0. This has led to the conclusion that the adaptive im-
within 36–40 days after randomization were less frequently observed mune response may play an important role in the resolution of CDIs.
with fidaxomicin in the modified intention-to-treat patients (15% vs It has raised the speculation that active or passive immunization of the
25%, p = 0.005). However, there was no difference in recurrence rate host may facilitate the resolution of the clinical disease and reduce the
among those patients with CDI secondary to the BI/NAP1//027 strain incidence of recurrence. Experimental treatment with antibodies to
type. These observations have been confirmed in a second large ran- toxins A and B have further fueled speculation of a therapeutic benefit
domized trial where outcomes of initial treatment were the same, but for infected patients (Babcock et al. 2006).
recurrent infections were higher in the vancomycin-treated patients A prospective randomized clinical trial with fully human monoclo-
(Cornely et al. 2012). nal antibodies to toxins A and B has demonstrated potential benefits
A real clinical problem is the patient with severe fulminate CDI (Lowy et al. 2010). Antibodies were administered as a single dose
and the patient with severe ileus or toxic megacolon. Orally admin- at the start of treatment. Antibody treatment and placebo patients
istered antibiotics will have little or no chance of advancing distally received either metronidazole or vancomycin as primary treatment
 Treatment implications for surgeons 129

Table 11.2 A survey of alternative therapies that have been used in the treatment of recurrent and relapsing Clostridium difficile infection.
Antimicrobial options Reference Commentary
Tapered vancomycin dosing Cohen et al. (2010) Vancomycin continued after conventional dosing with additional 125 mg twice
daily for 7 days; then 125 mg four times daily for 7 days; then 125 mg four times
daily for 2–8 weeks. Do not use metronidazole
Vancomycin + rifaximin Johnson et al. (2007) Anecdotal data; rifaximin is a poorly absorbed rifampin derivative; it may
promote resistance
Vancomycin + cholestyramine Lagrotteria et al. (2006) No evidence to support cholestyramine; used to bind C. difficile toxins.
Cholestyramine binds vancomycin
Gut recolonization strategies
Vancomycin + Saccharomyces boulardii Tung et al. (2009) Competitive inhibition of C. difficile; some evidence that it may be useful; risk of
fungemia in host with damaged colonic mucosa?
Lactobacilli + other gut anaerobes Venuto et al. (2010) Probiotic strategy to restore anaerobic colonization of the colon; evidence is
mixed.
Yogurt Pochapin (2000) Probiotic concept, inexpensive, and little evidence to support its clinical use for
C. difficile
Brewer’s yeast Schellenberg et al. (1994) Limited evidence; Saccharomyces cerevisiae has been seen as pathogen in
humans
Non-toxigenic C. difficile Gerding (2012) Blocks colonocyte receptor and prevents binding of the pathogen. Currently
being investigated
Enterococcus faecium SF 68 Marteau et al. (2001) Competitive inhibition of C. difficile at the colonocyte receptor
Fecal bacteriotherapy Bakken (2009) Restores normal colonic colonization quickly; many centers are evaluating this
treatment; no controlled trials
Immunomodulation
Anti-toxin monoclonal antibodies Lowy et al. (2010) Binds the toxins, but does not affect C. difficile colonization
Intravenous immunoglobulin Abougergi and Kwon (2011) Passive immunization against C. difficile enterotoxins, but limited clinical data

of the CDI. The results demonstrated a statistically significant reduc-

tion in recurrent infection in those patients receiving the antibodies
■■TREATMENT IMPLICATIONS
at 84 days after initiation of antimicrobial therapy. Patients with FOR SURGEONS
BI/NAP1/027 strain infection had a similar reduction in recurrent
infections. The severity of diarrhea was interpreted to be less in the The changing frequency and the changing epidemiology of CDI have
antibody-treated patients than the placebo group. The monoclonal implications in both preventing and managing this complication after
antibody treatment did not improve the results of treatment for the operations, and in the previously infrequent circumstance of necessary
primary CDI. Duration of hospitalization, time to resolution of the surgical intervention. With more patients having an initial infection
initial diarrhea, and severity of diarrhea were similar for the initial with C. difficile, it is likely that more patients will have the carrier state
infection event. and will have had a prior episode of CDI. A clinical history of CDI
The role of using monoclonal antibodies that address the toxins becomes a necessary part of the evaluation of patients for major op-
of C. difficile will require continued study and evaluation. Of interest, erations. Patients with a prior CDI history must understand that it is a
some treated patients still developed recurrent disease even with clinical risk for any surgical procedure. Rigid restrictions in the use and
documented antibody titers. Whether the duration of disease and the selection of antibiotics become very important for the patient with a
severity of inflammation before antibody administration affected the prior episode of CDIs, but also for the elderly patient who is at increased
treatment outcome is unclear. Does successful avoidance of clinically risk for this complication of care. Systemic preventive antibiotics need
recurrent disease mean that the patient has a chronic carrier state to be stopped in the immediate postoperative period. The changing
where the toxins are neutralized but the C. difficile pathogen remains character of CDIs means additional important issues for surgeons.
as a viable colonist of the colon in a non-symptomatic state? Some
clinical evidence indicates this as a real possibility (Kyne et al. 2000).
As this treatment is passive immunity and colonization of the host may
■■Community-acquired CDIs
be a consequence of treatment, longer follow-up may be necessary to The epidemic of CDIs among hospitalized patients has led to an
identify the evolution of recurrent events. increased number of patients with the asymptomatic carrier state.
The record of monoclonal antibody treatment in other areas has With 40 million hospitalizations per year in the USA and equally large
resulted in a dramatic increase in the expense of treatment. A discus- numbers of hospitalizations in other countries, vast numbers of the
sion of whether this treatment will be used should be offered to all resilient C. difficile spores are being transported out of the healthcare
patients with CDIs if continued evaluation validates effectiveness environment and into the community. It should not be surprising that
of the antibody treatment. Offering it to all patients will be treat- the ubiquitous dissemination of spores and the equally widespread
ing 70–80% of patients for no benefit. A preferable strategy may be use of outpatient antibiotics for indicated and poorly indicated reasons
to reserve this treatment for patients known to develop recurrent would be a combination for community-acquired CDIs (CA-CDIs)
infections. to emerge as a clinical issue. As the ecological issue of the colonic
130 CLOSTRIDIUM DIFFICILE INFECTION

environment that favors the emergence of CDI remains poorly defined, and the hypervirulent strain. Necrosis of the mucosa extends into
and knowing that CDIs can occur in the absence of antibiotic exposure, the submucosa and muscularis of the colon. The severe inflamma-
the evolution of CA-CDIs is a totally predictable event. tory response results in complete loss of colon motility. Increased
Numerous studies have reported large numbers of patients with intraluminal pressure compromises perfusion. The clinical picture of
CA-CDIs (Dial et al. 2005, Khanna et al. 2012). None has had infection progression of disease in the face of aggressive medical therapy and
previously as an inpatient. Small percentages have had ambulatory the evolution of systemic inflammation and multiple organ dysfunc-
exposure to antibiotics. An association with proton pump inhibitors tion means that the surgical option is required. At this point in the
and histamine blockers would imply that a loss of gastric acidity may evolution of CDI, failure to exercise surgical intervention results in
be a contributing variable. A different perspective indicates that 94% a fatal outcome.
of CDIs have had an exposure to the healthcare environment, but that At abdominal exploration, the surgeon is confronted with a com-
75% of current new cases have their onset outside the hospital (Centers plex circumstance that requires appropriate judgment. Findings
for Disease Control 2012). may vary from the identification of massive distended colon without
CA-CDIs and the simultaneous evolution of the BI/NAP1/127 strain evidence of transmural necrosis to long segment necrosis of the colon
give the surgeon a new source of concern when evaluating an elderly with or without perforation. Patchy necrosis may be encountered.
patient arriving from home with complaints of crampy abdominal pain Commonly necrotic mucosa is encountered at the ends of segmental
and distension. The differential diagnosis of this clinical scenario must resections indicating that the seromuscular coat of the colon is viable
add CA-CDIs to the list of intestinal obstruction, colonic impaction, but the mucosal lining is not.
non-specific ileus, and the many other sources of abdominal pain As the pattern of severe CDIs will have non-contiguous “skip”
and distension seen in patients aged ≥70 years. Diarrhea may or may areas, segmental resection of the colon, even when one has resected
not be a part of the symptom complex and the hypervirulent strain to a point where retained colonic mucosa appears to be viable, is a
makes prompt diagnosis difficult but necessary in a short time frame gamble that other areas of significant necrosis remain. Best results
if a major catastrophe is to be avoided. are achieved with subtotal colectomy (Butala and Divino 2010)
(Figure 11.4).
■■Fulminant CDIs An innovative solution for the surgical management of the patient
requiring laparotomy for advanced CDI has recently been introduced.
CDIs cover a vast continuum of severity. At the mild end of the dis- Neal et al. (2011) have introduced the concept of performing a loop
ease, patients may recover by simple cessation of the antibiotics that ileostomy at laparotomy for the patient with surgical indications but
provoked the infection and do not require any specific treatment for without transmural necrosis of the colon. The ileostomy becomes the
C. difficile. At the other end of the spectrum are those patients with a conduit for the introduction of vancomycin irrigation directly into the
fulminate disease that rapidly progresses to toxic megacolon and the colon on a continuous basis, and avoids the poor pharmacokinetics
risk of necrosis, toxemia, and death. of systemic administration in the patient with toxic megacolon. Early
Fulminate CDIs occur in about 5% of total cases but appear to be in- results are favorable but additional experience with this treatment
creasing in frequency. The fulminate infection occurs in two scenarios: strategy is necessary.
First, in the immunosuppressed and debilitated patient or, second, in
the patient with the hypervirulent BI/NAP1/127 strain of infection.
The patients characteristically have a rapidly evolving disease, with a
■■CONCLUSION
diarrhea phase that may be quite transient or non-existent in about In summary, CDIs are increasing in frequency and severity. The clinical
20% of cases. Crampy abdominal pain and distension are associated onset of disease may be in the community or as a hospital-acquired
with hypotension, oliguria, hypoalbuminemia, and leukocytosis or infection. First-line oral antibiotic therapy has been effective for many
even leukopenia. Abdominal radiographs demonstrate distension of cases, but surgical intervention is still necessary for selected cases.
the colon with marked thickening of the colonic wall. As the diarrhea New management strategies are necessary for both prevention and
phase of the disease is fleeting to non-existent, stool sampling for the management of this very important bacterial infection. CDIs have
diagnostic toxin assay may be compromised. Bedside flexible sigmoid- become an infection of considerable clinical significance for the
oscopy may be necessary to identify pseudomembranes so that treat- practicing surgeon.
ment can be initiated. Volume administration and pharmacological
support of blood pressure is usually required for the fulminate CDI.
Antimicrobial therapy for the patient with fulminate disease is
compromised. The loss of colonic motility yields poor delivery of the
antibiotic to the lumen of the infected colon. Systemic metronidazole Figure 11.4  A
or vancomycin is generally chosen, but the penetration of antibiotic colectomy specimen
into the inflamed and distended colon is poor, with a similarly poor from a patient
clinical response to treatment. As noted above, tigecycline may be with far-advanced
Clostridium difficile
useful in this setting. With a failure of clinical response to systemic
infection. (Figure
antibiotic therapy, the clinician is confronted with the decision for courtesy of Dale N.
the surgical option and colectomy. Gerding, MD)

■■Surgical management
The surgical management of CDIs has increased in frequency over the
last decade because of both the increase in frequency of the infection
 References 131

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diarrhea. Clin Infect Dis 2006;43:547–52.
Chapter 12 Burn wound infections
David N. Herndon, Noe A. Rodriguez, Katrina Blackburn Mitchell, James J. Gallagher

Infection is a common and problematic outcome of burn injury. Burn

injury predisposes individuals to infection in three main ways. The Box 12.1 American Burn Association sepsis criteria (from Green-
most obvious is through the loss of skin, which serves as the primary halgh et al. 2007).
barrier to infection. Second, larger burns can induce immunosup-
pression and weaken cellular and humoral defenses. Finally, damaged 1. Temperature: >39˚C or <36.5˚C
tissue can provide a fertile substrate for pathogen growth. This chapter 2. Progressive tachycardia:
discusses definitions of infection, potential pathogens, and treatment ⦁⦁ Adults: >110 beats/min
options for successful management of the burn patient. ⦁⦁ Children: >2 standard deviations (SD) above age-specific
norms
■■PATHOBIOLOGY OF 3. Progressive tachypnea:
⦁⦁ Adults: >25 breaths/min if not ventilated, or minute ventila-
THE BURN WOUND tion >1 l /min on the ventilator
⦁⦁ Children: >2 SD above age-specific norms
Thermal injury kills both the bacteria and tissue cells on the skin 4. Thrombocytopenia (3 days post initial resuscitation)
surface. Accordingly, initial cultures are usually sterile. However, ⦁⦁ Adults: <100 000/µl
subsequent cultures will be positive because of the survival of bacteria ⦁⦁ Children: >2 SD below age-specific norms
present in the hair follicles and sebaceous glands. Indeed, the number 5. Hyperglycemia (applies only to non-diabetic patients)
of bacteria (103/g) may be equal to pre-injury levels (Teplitz et al. ⦁⦁ Untreated plasma glucose >200 mg/dl, or
1964, Robson and Krizek 1973a, Pruitt et al. 1998). Given that bacterial ⦁⦁ Insulin resistance (>7 U insulin/h IV drip or >25% increase
doubling time is only about 20 min, a single bacterial cell can generate in insulin requirements over 24 h
10 billion cells within a 24-h period (Robson 1979). Viable resident 6. Inability to continue enteral feedings >24 h because of:
bacteria and secondary contamination from the environment become ⦁⦁ Abdominal distension, or
the early potential pathogens of the burn wound. In the absence of ⦁⦁ Residual twice the feeding rate for adults or >150/h in chil-
burn treatment, bacterial proliferation may lead to vessel thrombosis dren, or
and necrosis of any remaining dermal elements. This may transform ⦁⦁ Uncontrolled diarrhea
partial-thickness burns to full-thickness burn injuries. Continued
proliferation will result in a greater risk of viable tissue invasion and
septicemia (Burke et al. 1977, Artz and Moncrief 1979). Invasive in- This conference also developed useful definitions to differentiate
fections are histologically characterized by the presence of bacteria infectious and non-infectious clinical issues in the burn wound
and hemorrhage in unburned tissue, small-vessel thrombosis with (Table 12.1).
ischemic necrosis of unburned tissue, and dense bacterial growth in
the subeschar space. Advancement of the infection is usually associ-
ated with the progression of colonization from early Gram-positive
■■RECOGNITION AND DIAGNOSIS
to later Gram-negative bacteria. In fact, almost two-thirds of burn OF INFECTION IN THE BURN
wounds that are still open at 21 days will contain extended-spectrum
β-lactamase-producing Pseudomonas spp. Fortunately, effective
WOUND
topical wound management usually blocks this natural progression
of bacteria multiplication and tissue invasion. However, even con-
temporary burn care practice may still ineffectively control virulent
■■Use of burn wound cultures
pathogens that have arisen early after injury, leading to invasive burn Colonization or infection of major burn wounds usually occurs within
wound infections and necrotizing soft-tissue infection. 3–5 days of admission. Infection often arises from the patient’s own
Severe burn injury triggers a profound response to injury. This bacterial flora. Burn wounds should be inspected daily by the burn
includes a hypermetabolic response, which can mimic multiple surgeon, and any area of the wound that has changed in appearance
aspects of the systemic inflammatory response syndrome (SIRS) should undergo biopsy with pathological assessment. Histological
and make detection of the infection more difficult. Challenges such evidence of burn wound infection correlates with quantitative cultures
as this have prompted international forums to create definitions of showing high bacterial counts in approximately 80% of cases (Pruitt et
infection so that the diagnosis and management of patients can be al. 1998, Mayhall 2003). Bacterial counts exceeding 103 organisms/g
standardized. In 2007, a consensus conference was formed within the tissue require a change in topical therapy, whereas those exceeding 105
American Burn Association (ABA) to define sepsis and infections in organisms/g tissue require localized burn wound infection to be con-
burn injury (Greenhalgh et al. 2007). This consensus conference relied sidered and a histological examination to be performed. Histological
on methodology use by other societies (Bone et al. 1992, Levy et al. evidence of invasion requires wound excision and systemic antibiotics.
2003) to develop general definitions of SIRS and sepsis (Box 12.1). The burn wound must be closely assessed for these manifestations
134 BURN WOUND INFECTION

Table 12.1 Definitions for differentiating between non-infectious and infectious complications of the burn wound (from Greenhalgh et al. 2007).
Syndrome Clinical and pathological criteria
Wound erythema Redness surrounding the burn injury that is not a first-degree burn; redness appears 2–3 days after burn and dissipates by 5 or 6
days after burn; not infectious
Wound colonization Isolation of low levels of bacteria (<105 bacteria/g tissue) from the wound surface; no invasive infection
Wound impetigo Small multifocal superficial abscesses that can cause extensive loss of epithelium from previously healed split-thickness skin
grafts and that manifest as graft “melting or ghosting” or scalp folliculitis; Staphylococcus aureus associated
Wound infection Isolation of high levels of bacteria (>105 bacteria/g tissue) in the excised burns, donor site, or wound eschar; no invasive infection
Invasive infection Pathogens present in the burn wound at a sufficient concentration (frequently >105 pathogens/g tissue), depth, and surface
area to cause suppurative separation of the eschar or graft loss, invasion of unburned tissue, or sepsis syndrome
Cellulitis High levels of bacteria (>105 bacteria/g tissue) present in the wound and/or wound eschar, with surrounding tissue revealing
erythema, induration, warmth, and/or tenderness
Necrotizing infection, fasciitis Aggressive, invasive infection with underlying (beneath the skin) tissue necrosis

of bacterial sepsis and fungal invasion. Changes in the color, odor, or

exudate will frequently precede bacterial sepsis. A rapidly emerging Box 12.2 Burn wound cultures in burn care.
and spreading dark discoloration signals fungal invasion.
The routine use of wound cultures varies considerably. Robson and ⦁⦁ Early cultures should be negative or have low counts, with sen-
Krizek (1973b) demonstrated that burn wound colony counts >105/g sitive Gram-positive organisms. Therefore, positive cultures or
tissue led to only a 19% graft survival rate. On the other hand, colony high counts suggest early contamination of the burn
counts <105/g tissue had a 94% chance of graft survival. This led to ⦁⦁ If invasive burn wound infection is suspected, then wound
widespread use of burn wound biopsies and cultures. Steer et al. (1996) culture and histological analysis can aid in confirmation of the
demonstrated that a wide variation exists in the bacterial densities clinical diagnosis
within a wound at any given time. This finding challenged the value of ⦁⦁ Routine culturing and identification of colonization may aid in
clinical management based on routine burn wound culturing. Barret empirical antimicrobial coverage if the patient subsequently
and Herndon (2003) investigated the effect of burn wound excision on becomes ill
bacterial colonization and invasion. They discovered that preoperative ⦁⦁ Increasing colony counts may indicate a need to change topical
colony counts >105 were reduced to counts <104 when wounds were antimicrobial agents
treated aggressively through surgery. This type of treatment led to ⦁⦁ Not all organisms are created equal. Wound colonization with
excellent skin graft take. This difference may be attributable to changes particularly virulent or resistant organisms may be a predictor
in the surgical paradigm and technique. Barret and Herndon (2003) of coming invasive burn wound infection
identified a subgroup with preoperative colony counts exceeding ⦁⦁ Operative wound colony counts >106 suggest a high risk of
106 organisms/g tissue. Although this group had post-excision, pre- infectious complication and graft failure
grafting cultures that averaged 104 organisms/g tissue, they suffered a ⦁⦁ Burn wound culture results may aid in the evaluation of nosoco-
75% infection rate and graft loss. Although burn wound colony counts mial spread of organisms and guide infection control practice
have significant value in guiding patient care, they may also be unreli-
able and inaccurate due to sample site variation. The reasons and uses
for burn wound cultures are described in Box 12.2. of prophylactic antimicrobials (both topical and systemic) should
Several major benchmarks must be achieved to ensure reliable also be noted so that appropriate inhibitors and sufficient dilutions
clinical microbiology (Heggers and Robson 1991). Effective micro- can be prepared or reagents added to void any effects of drug interac-
biological diagnosis depends on appropriate specimen selection, tions. The specimen should be collected and placed in a sterile con-
specimen collection, and transport of specimens to the laboratory. tainer containing appropriate transport media. All specimens must be
Appropriate specimen management affects patient care in several promptly transported to the laboratory. Direct communication with
significant ways: the microbiologist can often be very helpful.
⦁⦁ It is key for accurate laboratory diagnosis.
⦁⦁ It influences therapeutic decisions.
⦁⦁ It affects hospital infection control, the length of the patient’s stay,
■■Definitions for the burn patient
and overall hospital costs. Small burns (<10%) are common and typically clean when examined
⦁⦁ It plays a major role in laboratory costs and efficiency. for early treatment. Fever alone does not indicate infection, because
Before analysis, the specimen collection site must be selected. This burn injury increases the body temperature set point. Fever can ac-
site must represent a location of active disease. The area of the wound company burns of any size. Moreover, the frequency or severity of
with the worst clinical appearance is an optimal location from which fever is not proportional to the burn size or depth. Evaluating burns
to culture pathogens. In addition, an appropriate device must be used for possible infection requires an awareness of burn wound erythema
for sample collection. (Figure 12.1). This redness usually appears 2–3 days after injury and
With burn wounds, obtaining a culture that is not contaminated dissipates by 5–6 days. Burn wound erythema is not a first-degree burn
with the normal surface flora of the injured skin is particularly impor- and is not infectious. It results in local inflammatory cytokines and
tant. In addition, the size or amount of the specimen plays an essential mediators. Burn wound erythema is normally non-tender to palpation,
role in the appropriate identification of the etiological agent. The use as opposed to infectious cellulitis.
 Recognition and diagnosis of infection in the burn wound 135

Figure 12.1  Burn

wound erythema on
post-burn day 2 (a)
and its spontaneous
resolution on day
12 (b).

Figure 12.2  (a) Successful skin grafting pictured 2 months post burn. (b) At
3 months, a new open wound has formed from burn wound impetigo.

Burn wound impetigo

Burn wound impetigo (Figure 12.2) refers to small multifocal super-
ficial abscesses. These may present as folliculitis on the scalp. These
abscesses can extensively damage previously healed split-thickness
skin grafts and donor sites (Pruitt et al. 1998). This phenomenon has
been termed “graft melting” or “ghosting.” Staphylococcus aureus,
particularly meticillin-resistant S. aureus (MRSA), is commonly seen
in these conditions. Successful treatment requires frequent cleans-
ing with disinfectants, unroofing of any abscesses, and twice-daily
application of a topical antimicrobial such as silver nitrate, Dakin
solution, or mupirocin.

Burn wound colonization

Burn wound colonization (Figure 12.3) is defined as the presence of
low concentrations of bacteria on the wound surface, the absence of Figure 12.3  The appearance of burn wound colonization.
136 BURN WOUND INFECTION

any invasive infection, and <105 bacteria/g tissue (Greenhalgh et al. and often a rash, although the burn appears clean. If the infection is
2007). Burn wound colonization is treated through continued burn left untreated, shock ensues, usually around 2–4 days after the burn
care with cleaning, topical antimicrobials, and surgery. If serial colony injury. During this time, the mortality rate can reach 50%. Knowledge
counts increase, the topical agent may need to be changed. of TSS and aggressive treatment are the best defenses against prevent-
ing this condition (Tompkins and Rossi 2004). TSST infections are
Burn wound infection commonly caused by MRSA, so administration of empirical anti-MRSA
This is characterized by >105 bacteria/g tissue. The presence of cel- antimicrobials is advised in all cases of suspected TSS (White et al.
lulitis forms the basis for this diagnosis. In early burns, painless and 2005, Napolitano 2009).
surrounding blanching erythema is seen. It is an not infection, and
antibiotics are not needed. Cellulitis is characterized by pain, advanc-
ing erythema, warmth, and tenderness. In addition, pathological
■■BACTERIA AND THEIR TREATMENT
colors and odors often signal the presence of an infection. Infected
burn wounds are usually treated with thorough cleansing, topical
■■Gram-positive organisms
antimicrobials, and systemic antibiotics. Antibiotic therapy is guided Staphylococcus aureus is the most important cause of bacterial burn
by culture and sensitivity results. Gram-positive organisms (e.g., S. wound infections (Murray 2003). Septicemia, cellulitis, impetigo,
aureus) are suspected early and then Gram negatives later in the scalded skin syndrome, surgical site infections, and many other condi-
patient’s management. Neglected wounds may have fluctuant pus tions are associated with S. aureus. Staphylococci, including S. aureus,
beneath the eschar and progress to a full-thickness injury. Similar to produce a large variety of toxic metabolites including proteases, col-
any abscess, these areas should be opened and drained. Evaluation lagenases, and hyaluronidase. These factors digest the extracellular
of burn wounds in elderly and diabetic individuals requires special matrix, which is essential for wound healing. Pathogenic strains of
care, as the inflammatory response can be blunted and wound severely staphylococci also produce pyrogenic exotoxins, leukocidins, and
underestimated. TSST-1. TSST-1, along with the other staphylococcal by-products,
causes TSS in susceptible patients (Edwards-Jones and Greenwood
Invasive burn wound infection 2003). Patients with TSS experience a sudden onset of fever, vomiting,
This is defined as “the presence of pathogens in a burn wound at diarrhea, and shock. They also have a diffuse macular erythematous
sufficient concentrations in conjunction with depth, surface area rash. Hyperemia of various mucous membranes and desquamation
involved and age of patient to cause suppurative separation of es- on the hands and feet then occur. However, the role of TSS has not
char or graft loss, invasion of adjacent unburned tissue, or cause been completely elucidated in the burn patient. We have observed
the systemic response of sepsis syndrome” (Greenhalgh et al. 2007). that, although burn patients may be infected with TSST-producing
Burn wounds with invasive infections have many different colors S. aureus, they do not always develop TSS.
and distinct odors. However, because time and some topical agents All staphylococci produce penicillinases. These enzymes hydrolyze
also produce color changes, the most reliable sign of invasive burn the penicillin β-lactam ring. Accordingly, these types of infections are
wound infection is conversion of an area of partial-thickness burn to treated with penicillinase-resistant penicillins. Parenteral antibiotics
full-thickness necrosis or the necrosis of previously viable tissue in in this category include nafcillin, meticillin, and oxacillin. Cephalo-
an excised wound bed. As indicated by the definition above, a burn sporins are also used. MRSA infections are resistant to all β-lactam
wound infection does not need to be accompanied by sepsis to be drugs and are commonly treated with vancomycin. Vancomycin
considered invasive. Nevertheless, many invasive burn wound infec- acts on bacteria at a different site from the penicillins. Vancomycin
tions are life threatening and require immediate surgical treatment. is eliminated at a greater rate in hypermetabolic burn patients, who
Invasive infections can progress very rapidly and affect normal skin, exhibit an increased glomerular filtration rate. Furthermore, a wide
causing erythema and pain followed by hemorrhagic bulla and pos- variability in vancomycin elimination exists among burn patients.
sibly necrotic satellite lesions. Thus, dosages must be adjusted for each patient to optimize time-
Invasive infection of burn wounds, particularly large burns, can be dependent serum concentrations. The peak and trough levels are
prevented through removal of dead tissue. Once an invasive infection determined using the minimum inhibitory concentration (MIC) for a
has been established, it must be aggressively treated. To this end, sur- particular bacterial organism. A trough level of 10–15 µg/ml is normally
geons must eliminate all dead tissue, including dead muscle, to control used for vancomycin monitoring, with care being taken to ensure that
the infection and ensure that wound sites will support grafting. Such this serum level is maintained between dosing intervals. Maintaining
aggressive surgical intervention can include conversion of a tangential appropriate trough levels is important for effective treatment of the
excision to the fascial level or even amputation of a limb. For treatment infected patient, but also to avoid the emergence of resistant bacte-
of the wound surface, dead tissue is completely removed, and the wound rial strains. For burn-associated MRSA pneumonia, a vancomycin
is treated with topical antimicrobial soaks such as silver nitrate, sulfa- trough concentration of 15–20  µg/ml should be the target (Rybak
mylon, and Dakin solution. If fungus is a concern, these soaks can be 2006). Treatment of microorganisms in burn wound infections may
used in combination topical nystatin. More frequent soaking dressing also require higher vancomycin trough serum concentrations due to
changes (four times a day) may also be necessary. Effective antibiotics “vancomycin MIC creep.”
are administered based on culture and sensitivity information. Streptococci are virulent pathogens in the burn patient and are as-
sociated with invasive cellulitis of the burn wound and skin graft losses.
Toxic shock syndrome Streptococcus pyogenes (group A streptococci) and S. agalactiae (group
Toxic shock syndrome (TSS) in the burn wound is a form of severe B streptococci) are the major species of burn infection interest. These
soft-tissue infection from TSS toxin (TSST)-1-producing S. aureus. TSS bacteria can be treated with penicillins (i.e., phenoxymethylpenicillin)
commonly occurs in young children (mean age 2 years) with small or the first-generation cephalosporins (cefazolin).
burns (<10%) and has an incidence of 2.6%. The prodromal period lasts Enterococci are resistant to the cephalosporin class of antibiotics,
1–2 days and is associated with pyrexia, diarrhea, vomiting, malaise, and have become important causes of burn wound infection for that
 Bacteria and their treatment 137

reason. Enterococci as a group are significant pathogens during the Gram-negative infections are typically treated based on culture
hospitalization of the burn patient (Law et al. 1994). Vancomycin is and sensitivity data, but empirical choices while awaiting culture
effective against most enterococcal bacteria. However, a combina- information may be selected from the antibiogram specific for the
tion of agents such as ampicillin and aminoglycosides may be used. unit or hospital. Antibiotic synergism may result in multiple drugs for
Vancomycin-resistant enterococci (VREs) have emerged in burn treatment of these organisms. Historically, the antibiotics of choice
units, causing major concern. VREs are best treated with linezolid for treating Gram-negative infections were the aminoglycosides,
or daptomycin (see Chapter 2). Specific sensitivities are needed to particularly gentamicin. Quinolones, carbapenems, aztreonam,
validate therapy for VREs. and others become choices when the sensitivity data is available
(see Chapter 2).
■■Gram-negative organisms Serious systemic infections caused by multidrug-resistant Gram-
negative bacteria are treated with polymyxins. From 2000 to 2004, the
A distinctive group of Gram-negative rods contributes to burn wound pediatric burn hospital, Shriners Hospitals for Children in Galveston,
infections. These include Pseudomonas spp., Acinetobacter spp., and TX, reviewed the use of colistimethate sodium in 109 patients (72
the Enterobacteriaceae. The Pseudomonas spp. are the most frequently boys and 37 girls, median and mean age of 9 years) with a total body
encountered burn wound pathogens. Wound infections due to P. ae- surface area (TBSA) burn ranging from 21% to 99% (median 60% and
ruginosa are particularly troublesome. Pseudomonas spp. can produce mean 62%). The overall survival rate was 80% in these patients, who
disease ranging from superficial skin infections to fulminate sepsis. In- had incompletely treated and life-threatening Gram-negative infec-
vasive Pseudomonas spp. produce ecthyma gangrenosum (Figure 12.4), tions. Polymyxin B binds, via its free amino acid groups, to negatively
which appears as a purple–blue–blackish area in previously healthy charged phospholipids. Binding is greatest in the kidney and brain,
tissue. These organisms survive in aqueous environments and prefer followed by the liver, muscle, and lung. Repeated administration
moist environments. For this reason, they have become problematic in of this drug causes it to accumulate in tissues, with concentrations
the hospital environment. Indeed, P. aeruginosa is the leading cause of reaching four to five times peak serum concentrations and persisting
nosocomial respiratory tract infection. for at least 5–7 days. The extensive tissue binding of this drug makes
Acinetobacter sp. is another significant Gram-negative pathogen removal by dialysis difficult. For these reasons, nephrotoxicity and
commonly associated with burn infection. These microorganisms are central nervous system toxicity should be monitored during sys-
normal colonists of human skin and the respiratory, gastrointestinal, temic use of this drug. The adverse effects of colistimethate sodium
and genitourinary tracts. These pathogens are problematic for burn occur in proportion to the length of its use and include Clostridium
patients, not only for burn wound infection, but also for pulmonary, difficile-associated colitis, renal dysfunction, and neuropathies (un-
intravenous catheter, and urinary tract infections. These organisms published data).
have a low intrinsic virulence and occur in the most immunosup- Sensitive organisms are commonly treated using aminoglycoside
pressed of the burn population. They also tend to acquire a high de- antimicrobials. These agents may be more effective and less toxic at
gree of resistance, most likely associated with previous antimicrobial single daily doses than multiple daily doses. Randomized, controlled
therapy (Albrecht et al. 2006). studies have revealed that, in adults, efficacy (e.g., bacteriological
Enterobacteriaceae such as Escherichia coli, Klebsiella spp., En- and/or clinical cure), nephrotoxicity, and ototoxicity are similar or
terobacter spp., Serratia marcescens, and Proteus spp. are additional improved after a single daily dosing of aminoglycosides compared
Gram-negative organisms infecting burns and other sites in the burn with multiple daily dosing. Decreasing the frequency of dosing may
patient. These organisms often cause nosocomial pneumonia in pa- counter aminoglycoside-induced adaptive resistance (i.e., reversible
tients with inhalational injury. They are also responsible for urinary refractoriness to the antimicrobial effects of subsequent aminogly-
tract infections associated with indwelling urinary catheters (Patel coside doses because of decreased uptake of the drug after the initial
and Williams-Bouyer 2009). dose). It may also help prevent selection of aminoglycoside-resistant
subpopulations of Gram-negative bacteria by providing a recovery
period in which serum aminoglycoside concentrations are negligible.
Despite these findings, once-daily dosing of aminoglycosides may not
be advisable in burn patients with serious infections and impaired host
defenses (e.g., patients with P. aeruginosa infections and neutropenia)
or in patients exhibiting rapid clearance or unpredictable aminoglyco-
side pharmacokinetics (e.g., extensive burns, cystic fibrosis, massive
ascites). If aminoglycosides are used in burn patients with any dosing
strategy, pharmacokinetic dosing is essential.
Extended-spectrum penicillins are less toxic alternatives in burn
patients with Gram-negative bacterial infections. The most frequent
adverse reactions of extended-spectrum penicillin are hypersensitivity
reactions, gastrointestinal effects, and local reactions. Gram-negative
infections may be treated with fourth-generation cephalosporins
such as cefepime, extended-spectrum β-lactamase inhibitor peni-
cillins (piperacillin/tazobactam and ticarcillin/clavulanate), and
the carbapenems (imipenem/cilastatin, meropenem, ertapenem).
These antibiotics are most effective when the serum concentrations
between dosing intervals are maintained at once or twice the MIC.
Thus, more frequent dosing or longer infusions may be necessary to
Figure 12.4  Ecthyma gangrenosum. maintain this MIC.
138 BURN WOUND INFECTION

■■Anaerobes molds confirm the diagnosis. Infection with mold is often invasive and
requires very aggressive treatment, with topical medication, surgery,
Of the anaerobes, Bacteroides and Fusobacterium spp. are the most and intravenous (IV) medication. It is common to work with a patholo-
commonly seen and may play a role in burn wound infections. These gist to ensure that margins are free of hyphae at the conclusion of a
anaerobes are normally present in the body. In burned patients, an- debridement. Amphotericin B has been the standard choice for IV
aerobic infections are usually associated with avascular muscle seen in treatment of invasive mold infection. Currently, there are five classes
electrical injuries, frostbite, or cutaneous flame burns with concomi- of systemic antifungal medications: the polyenes, azoles, nucleoside
tant crush-type injuries. The incidence of anaerobic infections has analogs, echinocandins, and allylamines. These new drugs offer im-
been considerably decreased by early excision and grafting. In cases proved side-effect profiles over amphotericin B.
of suspected anaerobic infection, appropriate collection methods Although amphotericin B dexolate (AmBd) has been the standard
to maintain anaerobic conditions for transport to the laboratory are choice for IV treatment of life-threatening invasive mold, this drug is
necessary. Metronidazole has continued to be the drug of choice for associated with significant toxicity, including infusion-related events
the treatment of anaerobic soft tissue infections. and dose-limiting renal dysfunction. Three new lipid formulations of
amphotericin B (AmB lipid complex [ABLC], AmB colloidal dispersion,
■■Fungi: Yeasts and molds and liposomal AmB [AmB-L]) offer several advantages over AmBd.
These advantages include increased daily doses of the parent drug
Fungal infections were not common in burned patients until the (up to 1- to 15-fold), high tissue concentrations in reticuloendothe-
advent of topical antimicrobial agents. The incidence of mycotic inva- lial organs, decreased infusion-related events (especially ABLC and
sion has doubled since the implementation of topical antimicrobial AmB-L), and a marked decrease in nephrotoxicity. These lipid drugs
agents. Fungal infections most commonly affect the burn wound, with are more expensive than AmBd, but cost is best assessed pharmaco-
an increasing number of local or disseminated fungal infections being economically (cost of drug acquisition as well as cost of hospital stay,
seen in the urinary tract, respiratory tract, vagina, and gastrointestinal monitoring, complications, etc.).
tract (Sheridan 2005). Special media are required for fungal isolation, For most patients with systemic candidiasis, cryptococcosis, and
and special biochemical tests are necessary for identification of the the endemic mycoses (e.g., blastomycosis, histoplasmosis, and coc-
several possibilities for fungal infection. Of fungi, Candida spp. most cidioidomycosis), AmBd or azole drugs (voriconazole, fluconazole,
commonly colonizes burn wounds. Positive blood cultures or positive itraconazole, or posaconazole) should be used as initial therapy.
cultures from three organs (wound, urine, bronchial washings, retina) Initial treatment with a lipid drug for these patients cannot be justi-
are usually required for the diagnosis of candidal sepsis. The addition fied, unless the patients require AmB therapy and have pre-existing
of nystatin to topical silver sulfadiazine has considerably decreased renal dysfunction. Invasive aspergillosis is treated with voriconazole
candida sepsis (Desai et al. 1992). Early diagnosis may be aided by due to its efficacy and lower toxicity profile. AmBd may still be used as
antibody detection. (Desai et al. 1987). Unfortunately, less than 40% an alternative treatment agent. Posaconzole is an effective treatment
of infected patients received a timely diagnosis (Kobayashi et al. 1990). for aspergillosis. The azoles (fluconazole, itraconazole, voriconazole,
Other fungi such as Aspergillus, Penicillium, Rhizopus, Mucor, and posaconazole) demonstrate similar activity against most Candida
Rhizomucor, Fusarium, and Curvularia spp. may also be present and spp. But each of the azoles has less activity against C. glabrata and C.
cause burn wound infection. In severely immunosuppressed patients, krusei. The echinocandins (caspofungin, anidulafungin, micafungin)
these lesser-known fungi may have a greater invasive potential than have very good efficacy against most Candida spp., but may have
yeasts (Horvath et al. 2007). less activity against C. parapsilosis. Flucytosine has limited clinical
Early diagnosis of fungal infection can be difficult, because symp- indications and may be used with AmBD in selected life-threatening
toms frequently mimic bacterial infections. Routine culture techniques candida syndromes.
may require from 7 days to 14 days to identify fungal contaminants,
delaying the initiation of treatment. Correlation between histopatho-
logical and culture identification has been shown to be inconsistent.
■■Viral infection of the burn wound
Therefore, histopathology alone can be inadequate for determining the The diagnosis and treatment of viral infections in burned patients have
best antifungal agent (Schofield et al. 2007). Arterial blood cultures and received increasing attention. Subclinical viral infection is extremely
retinal examination for characteristic candidal lesions can be useful. common, as seen by prospective and retrospective assays of sera.
Unlike candidal infections, true fungal infections occur early in the Linnemann and MacMillan (1981) conducted a large retrospective
hospital course of patients with specific predisposing characteristics. study of stored sera from burned children. They found that 22% of
Most frequently, burned patients infected with fungi are exposed to patients exhibited a fourfold increase in antibodies to cytomegalo-
spores from either rolling on the ground or jumping into contaminated virus (CMV). They also found that 8% had increased herpes simplex
surface water at the time of injury. Other environmental sources have titers and 5% had increased varicella-zoster titers. Follow-up revealed
been cited for nosocomial fungal infection, including bandaging sup- that CMV infection developed in 33%, herpetic infection in 25%, and
plies, heating and air-conditioning ducts, and floor drains (Becker adenovirus infection in 17%.
et al. 1991). Once colonized, fungi invade subcutaneous tissue with CMV infection rarely alters the clinical course of the patient. This
non-branching hyphae, stimulating an inflammatory response. This type of infection frequently accompanies bacterial and fungal infec-
phenomenon is diagnostic of fungal wound infection. Vascular inva- tions. Primary CMV infection or reactivation of CMV occurs at an
sion is common and often accompanied by thrombosis and avascular overall frequency of 33%. CMV inclusions have been detected in mul-
necrosis, clinically observed as rapidly advancing dark discolorations tiple organs, although they have not been reported to be found in the
of the wound margins with well-demarcated lesions. Systemic dissemi- burn wound itself (Deepe et al. 1982). Prospective analyses conducted
nation of the infection occurs with invasion of the vasculature. Yeast by Linnemann and MacMillan (1981) revealed that CMV infection
isolation from the wound may not represent infection and should be is directly correlated with more severe burns, more skin grafts, and
validated by clinical observations. Clinically observed lesions from subsequently higher numbers of blood transfusions. Patients with
 Topical antimicrobial compounds and agents 139

burns covering <50% of the TBSA rarely manifest clinical signs of CMV
infection. Infection with CMV occurs about 1 month after burn injury
and appears as an unexplained fever and lymphocytosis, which is as-
sociated with a concomitant rise in specific antibodies.
CMV infection frequently occurs in immunocompromised patients
and produces an array of adverse conditions. These conditions range
from febrile illness to systemic infections with organ involvement
(e.g., lungs, brain, liver, colon, and pancreas) (Ljungman et al. 2002).
Up to 23% of severely burned patients who are seronegative serocon-
vert, whereas more than half of seropositive patients undergo CMV
reactivation based on a fourfold or greater rise in antibody titer (Ke-
aley et al. 1987, Bale et al. 1990). Systemic CMV infection in severely
burned patients has been described in only two reports (Nash and
Foley 1970, Hamprecht et al. 2005). This suggests that severely burned
patients rarely contract systemic infections. However, severely burned
patients frequently have increased CMV antibodies, which suggests
that these infections are subtle and have been overlooked. CMV-
associated pathological changes have been detected in endothelial
and periendothelial cells present in generalized, non-healing burn Figure 12.5  Herpetic burn wound infection.
wounds (Swanson and Feldman 1987). In one reported case of CMV
infection, a cadaver allograft from a CMV-positive donor was trans- necrotizing hepatic and adrenal lesions. Patients with a disseminated
planted onto a severely burned adult. Immunohistochemical staining herpes infection have a morality rate that is twice as high as that in
of the allograft revealed the presence of inclusion bodies consistent patients with a similar age and burn size. Previously infected herpetic
with CMV infection as well as CMV antigens; however, there was no wounds can be adequately covered by split-thickness grafts, although
clear relationship between CMV infection and the necrosis, inflam- secondary graft loss often occurs and reoperation with patch grafting
mation, and increased vascularity present in the infected skin (Bale is needed.
et al. 1992). In experimental animals, severe burn injury increases the Chickenpox (varicella-zoster) can be life-threatening to immuno-
risk of CMV infection, and CMV infection is associated with a greater compromised hosts, such as burn patients. These infections are rapidly
susceptibility to sepsis (Hamilton and Overall 1978, Bale et al. 1982). spread through inhalation of the virus. Indeed, small chickenpox
Cadaver skin may transmit CMV infection, as do blood transfusions. epidemics have occurred in pediatric burn units. This type of infection
Often, burn patients who contract CMV infection have received mul- manifests itself as fluid-filled lesions. In some cases, they may present
tiple blood transfusions. Tennenhaus et al. (2006) conducted surveys as hemorrhagic, oozing pockmarks, which are prone to secondary
in US and German burn centers to investigate awareness, perceptions, infection and scarring. Vesicles can be present in uninjured epithe-
diagnosis, and treatment of CMV in burn patients. They found that the lium, mucus membranes, and healed or healing partial-thickness
incidence of CMV infection was 1:870 in US burn centers and 1:280 burns. These vesicles are much more destructive to injured skin than
in German burn centers. An analysis of testing methods revealed that uninjured skin, because newly healed or healing skin is particularly
19% of US and 70% of German burn centers used serology, 25% of US fragile. Damage can be inflicted on neovascularized skin grafts with
and 52% of German centers used body fluid viral isolation, and 6% of resultant graft loss.
US and 43% of German centers relied on leukocyte CMV DNA analy-
sis. Half the US centers distinguished infection from clinical disease,
whereas only two-thirds of the German centers did. Moreover, 19%
■■Tetanus
of the US and 43% of the German centers surveyed would treat the Routine prophylaxis for tetanus (Clostridium tetani) is part of the
established infection. admission protocol for the burn center. Patients receive 0.5 ml tetanus
Herpes simplex virus is another problematic viral pathogen toxoid if it has not been received in the previous 3 years. If the patient’s
encountered in burn patients (Haik et al. 2011). In healing partial- last booster was more than 10 years ago, 250 U tetanus antitoxin is
thickness burns or split-thickness donor sites, herpes simplex infec- also administered.
tions usually appear as vesicles (Figure 12.5). However, in immuno-
compromised burn patients, they are barely noticeable and appear
as red macules. After the appearance of these macules, the infection
■■TOPICAL ANTIMICROBIAL
rapidly progresses, spreading over entire donor sites and previously COMPOUNDS AND AGENTS
healed areas. This can lead to a near-total loss of epidermal cover-
age. In addition, this infection can sometimes affect other epithelial The proper use of prophylactic topical agents has been achieved in
surfaces such as the oral or intestinal mucosa, potentially causing burn wound management. Maintaining low concentrations of bac-
erosion and perforation. Patients usually experience an unexplained terial colonization diminishes the frequency and duration of septic
fever unresponsive to routine antibiotic coverage before the appear- episodes. Topical antimicrobial agents have significantly reduced burn
ance of herpes simplex lesions. Burn patients with herpetic infections mortality. However, no single agent is completely effective against all
have been found to experience greater mortality, extensive visceral organisms, and each possesses its own advantages and disadvantages.
involvement, and necrotizing tracheobronchitis. Herpes infection Although most topical agents retard wound healing, the application of
of partial-thickness burns and donor sites may eventually produce some antimicrobial agents may increase metabolic rate. Their effec-
full-thickness injuries that require skin grafting for closure. Herpes tiveness is measured by their ability to inhibit bacterial growth in vitro
infections may also lead to multisystem organ failure by producing and reduce wound colony counts in vivo. Studies have demonstrated
140 BURN WOUND INFECTION

that some agents used in the past are ineffective in inhibiting bacte- DNA of the microbe, releasing the sulfonamide. This agent is most
rial growth in vitro (Kucan and Smoot 1993). If quantitative cultures effective against P. aeruginosa and the Enterobacteriaceae. It is also
demonstrate bacterial concentrations >102 organisms/g, then a change equally effective as any antifungal drug against C. albicans. However,
in the topical agent is strongly recommended. some strains of Klebsiella spp. have been less effectively controlled.
Recently, P. aeruginosa resistance to silver sulfadiazine has been
■■Sodium hypochlorite (NaOCl) reported. Silver sulfadiazine is equally effective when applied using
either the closed or the open method. Antimicrobial effectiveness
The most effective topical antibacterial for cleansing a wound is has been observed to last for up to 24 h, and it still is considered by
NaOCl. This agent has superior topical antimicrobial effects and lower most to be the first line prophylaxis against Gram-negative organisms.
tissue toxicity than such products as povidone–iodine, acetic acid, More frequent changes are required if a creamy exudate forms on the
and hydrogen peroxide. Although povidone–iodine is bactericidal at wound. Some of the benefits of this topical agent are its ease of use
concentrations of 1% and 0.5%, it is toxic to fibroblasts. Acetic acid is and that it is pain free. Tissue penetration is limited to the surface
toxic to fibroblasts, but not bactericidal, when used at a concentration epidermal layer (Heggers et al. 1991). Nevertheless, it is not associ-
of 0.25%. Hydrogen peroxide is toxic to fibroblasts at 3% and 0.3% con- ated with acid–base disturbances or pulmonary fluid overload. Silver
centrations, but is bactericidal at only the 3% concentration. Heggers sulfadiazine can be used in combination with other antibacterials
et al. (1991) have reported the efficacy of NaOCl at a concentration and enzymatic escharotomy compounds. It can be combined with
of 0.025%. A 0.025% NaOCl solution is a tenth of the concentration of nystatin to enhance antifungal activity. Silver sulfadiazine has been
“half-strength Dakin,” the formulation that is used by many hospitals shown to retard wound healing. An adverse reaction to this drug may
as a topical antimicrobial agent. It is an excellent cleansing agent that be a reversible granulocyte reduction.
is bactericidal, non-toxic to fibroblasts, and does not inhibit wound
healing. However, the 0.025% NaOCl solution is only effective over a
24-hour time frame after the buffer (0.3 mol/l NaH2HPO4) is added
■■Mafenide acetate (Sulfamylon)
to the NaOCl (Holder et al. 1979). Mafenide acetate is available as an 8.5% water-soluble cream or a 5%
Soaks in buffered 0.025% NaOCl solution are beneficial in reduc- aqueous solution. This agent has more bacteriological data supporting
ing the bacterial numbers in a wound. The 0.025% NaOCl solution is efficacy than other topical agents. Mafenide acetate has been shown
a broad-spectrum antiseptic and is bactericidal against P. aeruginosa to be effective against a broad range of microorganisms, especially
and S. aureus, as well as other Gram-negative and Gram-positive all strains of P. aeruginosa. After wound debridement, 8.5% mafenide
organisms (Nash et al. 1971, Strock et al. 1990). It is effective against acetate cream is applied to the wound like “butter” (Lindberg butter)
meticillin-resistant staphylococci and enterococci. A 0.025% NaOCl (Lindberg et al. 1968). The treated burn surface is left exposed for
solution may be used separately or together with other antibacterial maximal antimicrobial potency. The cream is applied a minimum
agents to control colonization or infection. This solution also enhances of twice a day and reapplied between applications if rubbed off the
wound healing compared with mafenide acetate (Strock et al. 1990). wound. Advantages of the cream are its ability to control P. aerugi-
nosa wound infections, ease of application, and the absence of the
■■Silver nitrate (AgNO3) need for dressings. It effectively penetrates burn eschar and prevents
colonization of the burn.
AgNO3 is now used as a 0.5% solution that is non-toxic, does not The 5% solution is used to saturate an eight-ply gauze dressing and is
injure regenerating epithelium in the wound, and is bacteriostatic applied to the burn wound area. The dressing should be kept saturated
against S. aureus, Escherichia coli, and P. aeruginosa. AgNO3 is most with the 5% mafenide acetate solution to produce maximal antimicro-
effective when the wound is debrided of all dead tissue and carefully bial effects. The dressings may be changed every 8 h. Shortcomings
cleansed of emollients and debris. Multilayered coarse-mesh dress- of mafenide acetate include overgrowth with C. albicans, it being a
ings should be placed over the wound and saturated with the AgNO3 carbonic anhydrase inhibitor that causes a metabolic acidosis, and
solution. Similar to silver sulfadiazine, AgNO3 has limited eschar pain from application on partial-thickness wounds. However, it is
penetration (Moncrief 1968, Fuller et al. 1971, Heggers et al. 1991). quite effective in burn wounds with poor perfusion such as on the
As it is hypotonic it can result in hyponatremia and hypochloremia. ear. The 5% aqueous solution of mafenide acetate can be used in a
Serum electrolytes must be monitored very carefully. A 0.5% AgNO3 wet dressing covered by a splint. The 5% mafenide acetate solution in
solution is light sensitive and turns black on contact with tissues major burn patients reduces fatalities by 33% (Pruitt and Foley 1973,
and other chloride-containing compounds when it is allowed to dry. Desai et al. 1987). Mafenide acetate can be used together with other
Hyperpyrexia may also occur if AgNO3 becomes dry and is covered antimicrobials. It does retard wound healing.
with an impervious dressing. Some institutions have combined
AgNO3 with miconazole powder. The resulting 0.5% AgNO3 and 2%
miconazole aqueous solution is effective in preventing fungal over-
■■Povidone–iodine (Betadine)
growth in burn wounds. Klebsiella spp., Providencia spp., and other A 10% ointment of povidone–iodine has been in use for over half
Enterobacteriaceae have lesser susceptibility to 0.5% AgNO3 solution. a century after the active agent demonstrated a broad spectrum of
A 0.5% AgNO3 solution with Enterobacter cloacae and other nitrate- antimicrobial activities in liquid form. Povidone–iodine has a broad
positive organisms may cause methemoglobinemia by converting spectrum of antibacterial and antifungal activities. Povidone–iodine
nitrate to nitrite in the body. ointment can be used effectively in both the closed and the open
techniques. Quantitative bacteriological data show that it is most
■■Silver sulfadiazine efficacious when applied every 6 h. Adverse effects associated with
topical povidone–iodine include pain with application; absorption
Silver sulfadiazine (Silvadene, Thermazine, Flamazine, and SSD) causing iodine toxicity, renal failure, and acidosis; and cytotoxicity
is available as a 1% water-soluble cream. The silver ion binds with to fibroblasts. It remains a highly effective when used on intact skin.
 Infection control best practice 141

■■Gentamicin sulfate (Garamycin) inhibitory and fungicidal concentrations for a particular organism.
Nystatin is not active against bacteria, protozoa, or viruses.
Gentamicin sulfate is available as a 0.1% water-soluble cream. It Nystatin is not absorbed systemically and is used orally for the
has a broad spectrum of antimicrobial activity. Its popular use in treatment of intestinal candidiasis. In our burn population, nystatin
wounds is based on its antimicrobicidal efficacy against P. aerugi- ‘swish and swallow’ is used prophylactically to prevent the oral or
nosa. Gentamicin resistance rapidly develops when used as a topical perineal overgrowth of yeast and fungi in patients receiving two or
antimicrobial agent. A new gentamicin-eluting bioresorbable core/ three systemic antibiotics. In patients with coexisting intestinal can-
shell fiber-structured burn wound dressing shows promise in topical didiasis and vulvovaginal candidiasis, nystatin may be administered
treatment of burns. In initial trials, these drug-eluting fiber structures orally, together with the intravaginal application of an antifungal agent.
have shown a significant decrease in bacterial viability and no survival Most evidence suggests that combined therapy does not substantially
of bacteria after 2 days of treatment. reduce the risk of recurrence of vulvovaginal candidiasis compared
with intravaginal therapy alone. However, limited evidence suggests
■■Bacitracin/polymyxin (Polysporin) that the reduction of intestinal candidal colonization in combination
with intravaginal antifungal therapy may provide some improvement
Topical bacitracin/polymyxin is used to “butter” bolsters that are used in mycological response and reduction in the recurrence rate of vulvo-
to prevent mechanical shearing of newly grafted tissue. This topical vaginal candidiasis. For the treatment of cutaneous or mucocutaneous
ointment barrier has not been shown to control infection. It is com- candidal infections, 100  000  U/g nystatin may be applied topically
monly used as topical coverage for small face burns and for skin graft as a cream, lotion, or ointment to affected areas two to four times
coverage because it is easily applied. It is not documented to reduce daily. The cream or lotion formulations are preferred to the ointment
infections. Prolonged use is associated with hypersensitivity. for use in moist, intertriginous areas. The use of occlusive dressings
and ointment formulations should be avoided in the treatment of
■■Nitrofurantoin (Furacin) candidiasis because they favor the growth of yeast and the release of
its irritating endotoxin. Concomitant therapy should include proper
Topical nitrofurantoin has been used extensively but has had ques- hygiene and skin care. In addition, the affected areas should be kept
tionable therapeutic value. Recent research has shown effectiveness dry and exposed to air whenever possible.
in treating MRSA. Nitrofurantoin has also been shown to be 75% effec- The topical treatment of burn wounds with nystatin powder at a
tive against Gram-negative bacterial isolates other than P. aeruginosa, concentration of 6 000 000 U/g has been shown to eradicate invasive
whereas bacitracin/polymyxin is only 21% effective (Greenhalgh et fungal infections. This topical treatment is effective for superficial and
al. 2007). deep burn fungal wound infections. The powder is easily applied, does
not produce pain or discomfort, and does not impair wound healing.
■■Mupirocin (Bactroban) Nystatin powder may be combined with 1% silver sulfadiazine cream
or 5% mafenide acetate aqueous solution to enhance fungal activity.
Mupirocin was introduced as a topical antibiotic by Fuller et al. (1971).
In vitro studies have established that mupirocin has broad inhibitory
activity against Gram-positive microbes, specifically S. aureus and
■■INFECTION CONTROL
S. epidermidis. Mupirocin has been shown to be efficient in treating BEST PRACTICE
infection or colonization due to S. aureus in various clinical settings.
Rode et al. (1989) have shown that mupirocin is efficacious in the The microorganisms initially populating the burn wound consist of
treatment of established wound infections resulting from S. aureus a mixture of endogenous, airborne, and environmental sources of
that is resistant to systemic meticillin, topical mafenide acetate, and pathogens. The most elaborate methods of isolation have failed to
povidone–iodine. In addition, recent in vitro and in vivo endeavors eliminate infection, although they have significantly reduced the
have shown mupirocin to be equally efficacious in meticillin-resistant incidence of cross-contamination. The most effective means of de-
burn wound infections. creasing exposure of burned patients to exogenous bacteria is strict
observation of appropriate hand washing among the healthcare
■■Acticoat A.B. providers. Universal contact isolation is often a routine practice in
burn centers. Facemasks, waterproof gowns, and gloves should be
Acticoat A.B. Dressing consists of two sheets of high-density poly- worn whenever direct contact with body fluids and wound exudates
ethylene mesh coated with ionic silver and a rayon/polyester core. is possible so that both the patient and the healthcare provider are
Acticoat A.B. Dressing provides broad-spectrum bactericidal coverage protected from inadvertent contamination. All dressing materials
against VREs, MRSA, P. aeruginosa, Candida spp., and many other should be maintained as patient specific. IV pumps and poles, blood
pathogens. This dressing can remain intact on the wound for several pressure devices, monitoring equipment, bedside tables, and beds
days if exudation is minimal. Acticoat must remain moist to be active. should be cleaned with antibacterial solutions at least daily. Decon-
Rewetting with water is recommended. tamination of the patient room after discharge should be undertaken
with detergents. At Shriners Hospitals for Children, Galveston, TX,
■■Nystatin (Mycostatin, Nilstat) Hepa air filters with 99.99% efficiency on 0.3 µm-sized particles are
used and changed regularly. Most units now house major burn patients
Nystatin is an antifungal antibiotic produced by Streptomyces nour- within individual, self-contained positive-pressure isolation rooms.
sei. Nystatin has fungistatic or fungicidal activity against a variety of However, these units contain common bathing or showering facili-
pathogenic and non-pathogenic strains of yeasts and fungi. In vitro, ties. These areas should be conscientiously cleaned between patients
nystatin concentrations of 3 µg/ml inhibit C. albicans and C. guilliert- with an effective bactericidal agent. Disposable liners for cleaning
nondi. Concentrations of 6.25 µg/ml are required to inhibit C. krusei surfaces are encouraged, and sterilizable instruments should be used
and Geotrichum lactis. In general, there is little difference between for debridements.
142 BURN WOUND INFECTION

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Chapter 13 Fungal infections of surgical
significance
Joseph S. Solomkin, Jianan Ren, Donald E. Fry

The contemporary population of surgical patients represents vulner- 2008). Furthermore, in infections occurring after previous intra-
able hosts for the increased frequency of fungal infections. Aggressive abdominal surgery, Candida spp. are cultured from approximately
surgical care in cancer patients and the expansion of transplantation 20% of these patients. In multicenter observational studies, overt
interventions means that more immunosuppressed patients are in the candida infection is encountered in about 0.8–1% of patients in
surgical intensive care unit (ICU). Continued progress in supportive ICUs (Kett et al. 2011).
care, including the development of antibiotics with increasingly broad Candida spp. are the most common fungal pathogens causing
spectra of activity, has increased fungal colonization and resultant serious hospital-acquired infections, especially in patients admitted
rates of infections among injured and other complex postoperative to ICUs (Hidron et al. 2008) (Figure 13.1). A recent study using the
patients. The understanding and treatment of these fungal infections National Hospital Discharge Survey estimated the incidence rate of
are not fully understood, but progress has been made and newer invasive candidiasis to have increased from 23 per 100 000 US popu-
prevention and treatment strategies are evolving. This chapter pro- lation in 1996 to 29 per 100 000 in 2003 (Pfaller and Diekema 2007).
vides an overview of those fungal infections that are most likely to be Candidemia represents about a third of these infections. In addition,
encountered by surgeons in the care of patients. It can be certain that more resistant non-albicans Candida spp. are increasingly identified
additional species of fungal pathogens will be added to those discussed as etiological agents in candidemia. The best incidence data come from
in the upcoming decades. a European study from multiple ICUs examining the point prevalence
of specific infections (Vincent et al. 2009).
■■CANDIDA INFECTIONS Matched cohort and case–control studies in various hospitalized
patient populations, including those in the ICU, report attributable
Candidemia and other candida infection syndromes are diseases of mortality rates for candidemia in the range 20–30% (Morgan et al.
medical and surgical progress. Surgical patients are at considerable 2005, Zaoutis et al. 2005, Falagas et al. 2006). The attributable morbid-
additional risk because perforations of the gastrointestinal (GI) tract ity and mortality of other forms of candida infections have a similar
at any level, but especially of the colon, result in release of colonizing range of increased mortality and an increased length of stay of 5–7
Candida organisms into a previously sterile body site in approxi- days (Prowle et al. 2011). On surgical services, candida peritonitis rep-
mately 20% of cases. Further, there is considerable evidence that GI resents approximately 80% of the candida infection syndromes seen,
dysfunction, including ileus and changes in the intestinal microflora, and has a 30% excess attributable mortality rate (Leroy et al. 2009).
increases the density of candida and the probability of mucosal in-
vasion. All of the other major risk factors, including the presence of
central venous catheters, exposure to broad-spectrum antibiotics,
■■Microbiology of candida infection
and use of parenteral nutrition, are also present. Although there are more than 100 described species of Candida only
Despite the application of prophylaxis and early therapy strate- four are commonly associated with infection: C. albicans, C. tropica-
gies, these infections are not declining, but rather appear to have lis, C. parapsilosis, and C. glabrata (Falagas et al. 2006). Of these, C.
reached a stable plateau (Vincent et al. 1998, Kett et al. 2011). An albicans has long been the most common (>60% of infections); the
important issue is whether these infections are epiphenomena, other three major species are seen at rates varying from 5% to 20%.
appearing in patients who are fated to die, or whether there is the C. tropicalis is a virulent organism and mucosal colonization by this
effect of an attributable mortality that can be reduced by various organism frequently leads to invasive infection.
therapeutic strategies. An evolution of the epidemiology of candidiasis has been re-
Candida albicans, C. glabrata, and other species are pathogens and cently described with a reduction in the incidence of C. albicans in
not commensals requiring failure of host defenses alone to cause infec- favor of the non-albicans species, in particular C. glabrata and to
tion. We provide recommendations for the identification of patients a lesser extent C. krusei (Vincent et al. 1995). This appears to have
at risk to warrant prophylaxis, and then discuss treatment strategies occurred because of wide usage of fluconazole, and is important
in established infection. because several strains of C. glabrata have reduced susceptibility
to fluconazole. C. krusei is highly resistant to all triazoles. In a study
■■Epidemiology of candida infections of 2618 blood isolates, 10% (232/2441) of the patients had recently
(≤30 days) been treated with antifungal drugs. Pre-exposure to
Candida spp. remain the fourth leading cause of nosocomial blood- either fluconazole or an echinocandin resulted in a decreased
stream infection, preceded only by coagulase-negative staphylo- prevalence of C. albicans in favor of less drug-susceptible species
cocci, Staphylococcus aureus, and enterococci (Zilberberg et al. (Lortholary et al. 2011).
144 FUNGAL INFECTIONS OF SURGICAL SIGNIFICANCE

Figure 13.1  (a) The annual hospital discharges

18,000 of patients with disseminated candida infection
16,000 in the USA. (b) Age of patients with disseminated
candida infection who were discharged from
14,000 hospitals in the USA from 2000 to 2009. (Agency for
Healthcare Research and Quality, HCUPnet database,
12,000
Candidiasis cases

accessed March 8, 2012: http://hcupnet.ahrq.gov.)

10,000

8,000

6,000

4,000

2,000

0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
a Year

■■Pathogenicity and virulence

factors for Candida spp.
Four virulence factors have been demonstrated for Candida spp.
(Brown et al. 1999, de Repentigny et al. 2000, Haynes 2001, Naglik et
al. 2003):
⦁⦁ Adherence to epithelial and endothelial cells
⦁⦁ Secretion of proteases that degrade connective tissue proteins and
facilitate invasion
⦁⦁ Production of cell-surface mannans that serve to attach the yeast
to host tissues and suppress host response
⦁⦁ Resistance to oxidative killing by neutrophils.
The transition from yeast (Figure 13.2) to filamentous growth is a criti-
cal step in the subsequent expression of several virulence mechanisms
for C. albicans. The yeast-to-hyphal transition of C. albicans can be
triggered by a wide variety of factors, suggesting that hyphal growth is
a response to nutrient deprivation, especially low nitrogen, and that
filamentous growth enables the fungus to forage for nutrients more
Figure 13.2  A photomicrograph of Candida albicans. (From the Public
effectively (Hostetter 1998, Mitchell 1998, Brown et al. 1999, Naglik et
Health Image Library, Centers for Disease Control, courtesy of Dr Gordon
al. 2003). Of considerable importance to the pathogenicity of candida Roberstad: http://phil.cdc.gov/phil/details.asp.)
infections is the ability of these organisms to produce and participate
in biofilms (Albuquerque and Casadevall 2012, Nobile et al. 2012).
Although C. glabrata is an important human pathogen, its patho- reduced inflammatory responses are observed in animal models.
genicity mechanisms are different, and center on altering events Furthermore, C. glabrata multiplies intracellularly after engulfment by
after phagocytosis by macrophages and neutrophils. Immune eva- macrophages. Similar mechanisms explain C. parapsilosis virulence
sion strategies seem to play key roles during infection, because (Horvath et al. 2012).
 Candida infections 145

■■Clinical aspects of candida infection Prophylaxis is a consideration in transplant recipients. The inci-
dence and mechanism of microbial entry vary in different groups of
The GI tract is an important portal of entry for microorganisms, includ- transplant recipients, depending on the following:
ing yeasts, into the bloodstream. The passage of endogenous fungi ⦁⦁ The organ transplanted
across the mucosal barrier is referred to as fungal translocation (by ⦁⦁ The donor source
analogy with bacterial translocation). There is considerable clinical ⦁⦁ The type of surgical procedure performed
evidence for transmigration of yeast in non-neutropenic humans, and ⦁⦁ The recipient’s age and general condition at the time of the pro-
appears to occur in profoundly immunocompromised patients who cedure.
have received bone marrow transplantation (Blijlevens 2005, Niscola Other influential factors are the conditioning regimen, the type and
2010). Although yeast cells have no intrinsic motility, they are able to duration of immunosuppressive therapy, and the presence or absence
translocate across the intestinal mucosa within a few hours of inges- of organ rejection and graft-versus-host disease. In heart transplant
tion if present in high enough concentrations. recipients, for example, aspergillus infection is a major problem,
Candida spp. are commensals in the gut lumen and on muco- whereas, in other organ transplant recipients, most fungal infections
cutaneous surfaces in the immunocompetent host with normal GI are attributable to Candida spp. (Warnock 1995, Pappas et al. 2006).
colonization. In critically ill patients, colonization with Candida spp. The infection is usually located at the surgical site: an intra-abdominal
precedes and leads to infection. If multiple body sites are colonized, abscess in liver or pancreas transplantation, the mediastinum or the
there will be an increased risk of severe infection in high-risk patients, lungs in heart or heart–lung transplantation, and the urinary tract in
and the chance of invasion can be predicted by the extent of pre- kidney transplantation.
existing colonization. Several studies have documented the efficacy of amphotericin
Pittet et al. (2005) performed a 6-month prospective cohort study B, liposomal amphotericin B, and fluconazole in preventing can-
among patients admitted to surgical and neonatal ICUs. Routine dida infections. The incidence of candida infection in patients not
microbiological surveillance cultures at different body sites were receiving prophylaxis varies between 10 and 20%, and prophylaxis is
performed. A candida colonization index was determined daily as cost-effective, particularly if provided with imidazoles (Avery 2011,
the ratio of the number of distinct body sites colonized with identi- San-Juan et al. 2011).
cal strains over the total number of body sites tested; a mean ratio There is an increasing appreciation of the role of Candida spp. in
of 5.3 was obtained. All isolates (n = 322) sequentially recovered infections after acute pancreatitis (Warnock 1995, Pappas et al. 2006).
were genotyped which allowed strain delineation among Candida A large series of patients undergoing surgery for infected pancreatic
spp. Twenty-nine patients met the criteria for inclusion; all were at necrosis found Candida sp. present in approximately 10% of the pa-
high risk for candida infection; 11 patients (38%) developed severe tients at their initial surgery for infection (Gotzinger et al. 2000). These
infections (8 candidemia); the remaining 18 patients were heavily patients had received prophylaxis with amoxicillin/clavulanate, a
colonized, but never required intravenous antifungal therapy. Candida factor that might explain intestinal overgrowth and translocation of
colonization always preceded infection with genotypically identical Candida spp. This is a particular issue because of the interest in the
strains of Candida spp.. The proposed colonization indexes reached use of broad-spectrum antibiotics, especially imipenem/cilastatin,
threshold values at 6 days before candida infection and demonstrated as prophylaxis for patients with necrotizing pancreatitis. There is
high positive predictive values (66–100%). The intensity of candida consistent and substantial data against this practice, and there are
colonization helps to predict subsequent infections with identical no data on fungal prophylaxis in patients not receiving antimicrobial
strains in critically ill patients. prophylaxis (de Vries et al. 2007). We believe that the appropriate
Prior antibiotic therapy is commonly viewed as an independent prophylaxis strategy is to provide low-dose oral fluconazole.
risk factor for candida infection, but this may not be uniformly cor-
rect. In a case–control study, antibiotic administration was shown to Management of specific infections
be only marginally associated with candidemia, and substantially less Candidemia
important than prior candida colonization (Borzotta and Beardsley Many if not most candidemias seen in the ICU are catheter-related
1999). There are multiple other factors that result in changes in the bloodstream infections (CRBSIs). This is defined as candidemia in one
GI flora. These include intestinal ileus, antacid therapy, and contami- or separate venopunctures, occurring in a patient with an intravascular
nation with hospital flora. The point of emphasis is that appropriate catheter and no other obvious site for infection after careful clinical
anti-infective therapy for a bacterial infection should not be stopped and laboratory evaluation. Several procedures have been developed
because Candida spp. are identified at one or more sites. In intra- to aid in the diagnosis of catheter-associated candidemia. If the
abdominal infections, mixed flora infections with Candida spp. and catheter is removed, a quantitative culture of the tip should recover
bacteria are commonly observed. at least 15 colony-forming units (CFU) of the same Candida spp. as
found in blood culture by the roll-plate technique, or at least 100 CFU
■■Candida prophylaxis of the same Candida sp. as found in blood culture by the sonication
technique. The issue, compared with Gram-positive bacterial CRBSIs,
A meta-analysis of studies employing ketoconazole or fluconazole is the source of the fungi. In most cases, they are not identified at the
prophylaxis has been performed (Cruciani et al. 2005). These authors insertion site, and likely result from hematogenous infection after GI
found 9 studies (seven double blind) with a total of 1226 patients overgrowth. There is compelling evidence that catheter removal is a
that compared ketoconazole or fluconazole to no prophylaxis. Pro- central component of therapy.
phylaxis with azole antifungals was associated with reduced rates of Echinocandins are now considered the treatment of choice for
candidemia, mortality attributable to candida infection, and overall candidemia, with fluconazole added if C. albicans is suspected. This
mortality. From the fluconazole studies, it was apparent that prior recommendation is based on recent IDSA (Infectious Diseases Society
colonization was the major determinant of successful imidazole pro- of America) guidelines (Pappas et al. 2009). Aside from evidence that
phylaxis (Pelz et al. 2001). fluconazole is synergistic with echinocandins, a major concern for
146 FUNGAL INFECTIONS OF SURGICAL SIGNIFICANCE

monotherapy with fluconazole for empirical therapy has to do with the patient groups. Four risk factors for intra-abdominal candida infection
possibility that a resistant strain may be present, and the observation have been identified including failed treatment for intra-abdominal
that the echinocandins are fungicidal, which may be more effica- infection, anastomotic leakage after elective or urgent surgery, surgery
cious in patients with shock or other severe physiological responses for acute pancreatitis, and splenectomy.
to infection. Patients who have previously received fluconazole for Systemic antifungal therapy should be provided for these patients
either prophylaxis or therapy should be treated with an echinocandin. found to have Candida spp. at the site of recurrent intra-abdominal
infection or previous surgery, and those with either fistulae or drain
Choice of antifungal tracts. Antibacterial therapy should be provided if bacteria are identi-
All patients with candidemia should receive antifungal therapy. We fied by either Gram stain or culture. Most of these patients will have
recommend initial therapy with intravenous echinocandin or fluco- polymicrobial infection. Occasionally, Candida spp. may be associ-
nazole for 3 days, particularly if the infecting organism is likely to be ated with acalculous cholecystitis or cholangitis. This is increasingly
C. albicans. If the patient responds rapidly to this regimen, the dosage found in patients with percutaneously placed drainage catheters for
may be decreased and administered orally. For patients with hema- malignancy. Such patients must be given systemic therapy for clini-
togenous candidiasis that are known to be colonized with C. krusei cal evidence of infection, including candidemia, and the drainage
or C. lusitaniae, amphotericin B (0.5–0.7 mg/kg per day) should be catheter must be changed.
the treatment of choice.
Urinary tract infection
Duration of therapy The recovery of Candida spp. from the urinary tract most commonly
Duration of therapy depends on the extent and seriousness of the results from contamination from the perirectal or genital area. Colo-
infection. Therapy can be limited to 7–10 days for patients with nization of the bladder is usually seen with prolonged catheteriza-
catheter-related and low-grade fungemia, without evidence of organ tion, diabetes mellitus, or other diseases associated with incomplete
involvement or hemodynamic instability. Those patients with high- bladder emptying. In addition, Candida spp. usually colonize ileal
grade fungemia, evidence of organ involvement, or hemodynamic conduits. Persistent candidemia in the surgical ICU may, however,
instability need to receive antifungal therapy for 10–14 days after be an early marker of disseminated infection in critically ill high-risk
resolution of all signs and symptoms of infection. patients. Replacing or removing the bladder catheter is preferable.
If candida colonization persists, particularly if the patient has a risk
Candidemia in non-neutropenic patients factor for cystitis (e.g., diabetes mellitus or a disease that leads to
Fluconazole (loading dose of 800 mg [12 mg/kg], then 400 mg [6 mg/kg] incomplete bladder emptying) or hematogenous dissemination (e.g.,
daily) plus an echinocandin (caspofungin: loading dose of 70 mg, then immunosuppression or manipulation of the genitourinary system),
50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose antifungal therapy should be considered. Amphotericin B bladder ir-
of 200 mg, then 100 mg daily) is recommended as initial therapy for rigation provides only temporary clearance of fungemia and systemic
most adult patients. Transition from an echinocandin to fluconazole is treatment is usually needed.
recommended for patients who have isolates with likely susceptibility
to fluconazole (e.g., C. albicans) and who are clinically stable. For in-
fection due to C. glabrata, an echinocandin is preferred. For infection
■■COMMUNITY-ACQUIRED
due to C. parapsilosis, treatment with fluconazole is recommended. FUNGAL PATHOGENS
The recommended duration of therapy for candidemia without obvi-
ous metastatic complications is 2 weeks after documented clearance
of Candida spp. from the bloodstream and resolution of symptoms
■■Blastomycosis
attributable to candidemia. Intravenous catheter removal is strongly Pathogenesis
recommended for non-neutropenic patients with candidemia. Infections with Blastomyces dermatitidis, also known as North Ameri-
can blastomycosis, are principally pulmonary (Smith and Kauffman
Suppurative thrombophlebitis 2010). The fungus is found in the soil primarily in the USA, but is seen
A rare but serious consequence of hematogenous candidemia is sup- in the other continents. The spores are airborne and lodgment is in
purative thrombophlebitis, which results from infection of a vessel the lung (Figure 13.3). Infection occurs 4–6 weeks or longer after
traumatized by prolonged catheterization. Endothelial disruption exposure. Person-to-person transmission is not thought to occur. The
exposes the basement membrane and leads to thrombus formation vigorous inflammatory response results in lesions that are mistaken
and propagation. Suppurative thrombophlebitis is particularly serious for primary lung cancer. The skin is the most common site for extra-
because intravascular infection results in a persistent high-density pulmonary involvement.
fungemia. Management of this disease consists of high-dose anti-
fungal therapy, removal of the central venous catheter, and excision Diagnosis
of the infected vein, when possible. Typically, blood cultures remain Acute pulmonary infection presents with productive cough, fever, and
positive for several days; sometimes, they remain positive for as long pleuritic chest pain. Chronic infections have multiple weeks of cough
as 3–4 weeks despite appropriate antifungal therapy, if the infected and chest discomfort. Chest radiographs will show infiltrates in acute
vein is not excised. infection, and chronic infection shows fibronodular infiltrates that
portray carcinoma. Cavitation and miliary appearances can be seen.
Peritonitis and Intra-abdominal abscess Organisms can be seen from expectorated or bronchoscopic secretions
Systemic therapy is required to eradicate Candida spp. found within by KOH preparation. Cultures require many weeks for growth. Biopsy
intra-abdominal abscesses, peritoneal fluid, or fistula drainage. Can- of suspected skin lesions and lung biopsy will identify the organism.
dida spp. are not uncommonly cultured from intra-abdominal infec- Urine antigen studies have been useful, but cannot replace fungal
tious foci but should be considered a serious threat only in specific identification.
 Community-acquired fungal pathogens 147

Figure 13.3  This annual frequency of inpatient

pulmonary blastomycosis, histoplasmosis, and
coccidioidomycosis from 2005 to 2009. (Agency
for Healthcare Research and Quality, HCUPnet
database, accessed March 8, 2012: http://hcupnet.
ahrq.gov.)

Treatment progress to nodular lesions in the granulomatous phase. Complete

Mild acute blastomycosis requires no antifungal therapy. Oral itra- resolution is the rule for acute pulmonary lesions with only a small
conazole and ketoconazole are used for outpatient therapy of chronic number (<5%) developing calcified or cavitated lesions.
pulmonary infection (Chapman et al. 2008). Severe and disseminated The diagnosis is made by culture of the fungus or by direct histo-
cases of acute and chronic cases are treated with intravenous ampho- pathological identification. Surgical biopsy of solitary lesions may
tericin B. Large lung lesions may be resected in expectation of carcino- be necessary for diagnosis. Skin lesions may have the appearance
ma. If the diagnosis is established before thoracotomy, chemotherapy of basal cell carcinoma and diagnosis is established with excisional
alone is the treatment. In severe cases requiring hospitalization and biopsy. Disseminated disease can be confirmed with cytological or
intravenous treatment, mortality rates are approximately 25% in im- tissue cultures of liver and bone marrow biopsies. Blood cultures may
munocompetent patients and 40% in HIV infection. be positive in immunosuppressed patients. Detection of antibodies
by immunodiffusion complement fixation or ELISA methods is used
■■Coccidioidomycosis by reference laboratories.

This highly infectious dimorphic fungal infection is secondary to Treatment

Cocccidioides immitis and C. posadasii which are endemic to the In immunocompetent patients, no specific therapy for acute pulmo-
south-western USA (Anstead and Graybill 2006) (see Figure 13.3). It nary infection is necessary unless symptoms persist for 4–6 weeks
is caused by inhalation of soil-based fungal spores. There is a vigor- (Limper et al. 2011). Fluconazole or itraconazole is used for persistent
ous inflammatory response with pulmonary lodgment that is similar cases or for pulmonary infection in immunosuppressed patients or
to acute bacterial infection. Subacute infection is characterized by those with risk factors (chronic lung disease) for severe infection.
granuloma formation and even caseation. Scaring and fibrosis replace Diffuse pulmonary disease or disseminated infections are initially
granuloma in the chronic phase, and may result in chronic obstruc- treated with an amphotericin B lipid preparation and followed with
tive lung disease and cavitation. An inadequate host response (e.g., a full year of oral therapy with fluconazole or itraconazole. Surgical
corticosteroid therapy, HIV) may result in dissemination. The systemic resection of pulmonary cavities may be necessary for hemoptysis or
disease may give cutaneous lesions, musculoskeletal manifestations secondary infection of the cavity itself. Occasionally, empyema may
with osteolytic bone lesion, and meningitis. develop and require drainage. Bronchopleural fistulae from ruptured
pleural blebs may require surgical repair.
Diagnosis
The acute pulmonary infection follows a broad continuum of disease
with half the infections being minimally symptomatic. Most severe
■■Cryptococcal infections
acute cases will have fever, malaise, and pleuritic chest pain. In less Pathogenesis
than 10% of cases, symptoms can be severe with myalgias, fatigue, Cryptococcus neoformans and C. gattii are the pathogens most identi-
headache, and weight loss. Respiratory failure can occur in extreme fied with human disease (Li and Mody 2010). This encapsulated fungus
pulmonary infections. Severe or persistent symptoms beyond 4–6 is inhaled and may cause a mild pulmonary infection, but is dissemi-
weeks may herald miliary disease. Skin and bone lesions will occur nated from the lung. Meningitis is the clinical infection of interest.
with dissemination, and meningitis can also be a complication of C. neoformans infection is associated with lymphomas, leukemias,
systemic disease. Endophthalmitis may occur as evidence of dis- transplantation, HIV infection, and patients on high-dose corticoste-
semination. Chest radiographs show alveolar infiltrates initially which roid therapy. C. gattii infections occur in immunocompetent patients.
148 FUNGAL INFECTIONS OF SURGICAL SIGNIFICANCE

Diagnosis ■■Paracoccidioidomycosis
Headache, fever, and meningeal signs are customary and similar
to aseptic meningitis. Symptoms are commonly chronic and per- Pathogenesis
sistent. Skin lesions may rarely be seen. India ink preparation of Also known as South American blastomycosis, Paracoccidioides brasil-
cerebrospinal fluid is usually the best diagnostic method. Special iensis causes acute pulmonary infection after inhalation of airborne
stains are required for identification in tissue biopsies. Cultures of spores (Ramos-e-Silva and Saraiva 2008). Pulmonary paracoccidioido-
infected body fluids will usually be positive, but centrifugation of mycosis is usually asymptomatic but can cause an acute suppurative or
cerebrospinal fluid may be necessary to optimize recovery from the granulomatous infection. Cavitation can occur. Dissemination results
sediment. Negative cultures are common, and repeated cultures in mucocutaneous lesions and head–neck adenopathy. It is endemic
are often necessary. Biopsies of bone or skin lesions will yield an to South America and most cases are in men.
unexpected C. neoformans.
Diagnosis
Treatment Acute infection has non-specific symptoms of fever and cough. Fi-
Mild pulmonary infections in selected patients are treated with fluco- bronodular lesions and cavitation can be seen on chest radiograph.
nazole or itraconazole (Limper et al. 2011). Cryptococcal meningitis Oropharyngeal, cutaneous lesions and cervical adenopathy herald
and disseminated infections are treated with combination therapy disseminated disease. The organism can be seen in sputum and
of amphotericin B and flucytosine, followed by maintenance oral typically requires long incubation times for cultures. Histological
fluconazole. Asymptomatic disease is identified on sputum cultures or identification can be made from oropharyngeal or cutaneous biopsies.
an excised pulmonary nodule and do not require antimicrobial Complement fixation, immunodiffusion, and other antibody detection
therapy. studies are available.

■■Histoplasmosis Treatment
The majority of diagnosed cases have disseminated disease (Limper
Pathogenesis et al. 2011). Systemic amphotericin B is required for severe cases, fol-
Histoplasmosis is caused by H. capsulatum (Kauffman 2009). It is an lowed by 6–12 months of oral therapy with ketoconazole, itraconazole,
airborne pathogen and causes acute pulmonary infections (see Figure or sulfadiazine. Surgical treatment plays a role in the biopsy only of
13.3). The reservoir for the pathogens appears to be wild birds. The lesions or nodes for diagnosis.
pulmonary infection is usually mild or completely asymptomatic. It
has the potential to cause disseminated disease in susceptible hosts.
The spores are ingested by and proliferate within macrophage cells. H.
■■Sporotrichosis
capsulatum forms granulomas in tissue and yields calcified lesions in Pathogenesis
the lung and mediastinal lymph nodes. Most acute cases completely The pathogen of sporotrichosis, Sporothrix schenckii, is found in soil and
resolve. Upper lobe cavitations occur and resemble tuberculosis. on plants. It causes infection after contamination of cutaneous wounds
These cavities may become secondarily infected and are associated and abrasions. Nodular granulomas form at the site of injury, and the
with lung carcinoma. Histoplasma endophthalmitis is a recognized infection spreads as lymphangitis. Satellite granulomas may develop
complication of disseminated disease. The disseminated and chronic along the path of lymphangitis. Deeper wounds can cause tendon and
forms of the disease are associated with chronic steroid therapy, HIV, bone joint infections. Dissemination is uncommon, but is associated with
and immunosuppressed hosts. central nervous system (CNS), pulmonary, cutaneous, or bone infections.

Diagnosis Diagnosis
Acute pulmonary symptoms are fever, chills, and cough. Infiltrates Persistent papular lesions with discharge and ulceration on the upper
are seen on chest radiographs. Acute fulminant disease in children extremity are the common scenario. Culture of the serosanguineous
may lead to severe infection with respiratory distress. Chronic dis- discharge may identify the fungus. Punch or excisional biopsy of
seminated infection may have intermittent fever, weight loss, and cutaneous lesions with culture and identification of granulomas on
hepatosplenomegaly. histology is usually diagnostic.
Excised tissue will demonstrate the microorganisms on hematoxy-
lin and eosin sections. The organisms can usually be cultured from Treatment
sputum specimens and bone marrow aspirates. Similar to many fungi, Itraconazole is the treatment for cutaneous sporotrichosis (Limper
4 weeks may be required for cultures. Blood cultures are positive in et al. 2011). A saturated solution of potassium iodide (SSKI) has been
over 50% of disseminated infections. Antibody and antigen detec- commonly employed for the cutaneous infection, but there is no good
tion methods are used to supplement cultures and histopathological clinical evidence to support this treatment (Xue et al. 2009). Difficult
detection of the fungus. cutaneous infection and extracutaneous sporotrichosis are treated with
intravenous amphotericin B, followed by several months of itraconazole.
Treatment
Acute pulmonary histoplasmosis is a self-limited disease (Wheat
et al. 2007). Mild-to-moderate cases of pulmonary infection and
■■NON-CANDIDA HEALTHCARE-
chronic cavitating disease are treated with itraconazole. Only severe ASSOCIATED INFECTIONS
cases require treatment with amphotericin B, which is followed with
itraconazole for 12 months. Surgical management is not generally
part of the management of histoplasmosis. Solitary lung lesions and
■■Aspergillus fumigatus
cavitating lesions may require surgical resection to rule out the pres- Among the Aspergillus spp., Aspergillus fumigatus is of greatest concern
ence of lung cancer. as a human pathogen. It is a ubiquitous fungus that is an opportunistic
 Non-candida healthcare-associated infections 149

pathogen in hospitalized patients with immunosuppression, neutro- the mucormycoses. This group of opportunistic pathogens includes
penia, and severe debilitation. Mucor, Rhizopus, Cunninghamella, Apaphyhsomyhces, and Absidia
It is an airborne pathogen that is typically associated with cavitat- spp., and many others.
ing infections of the lung, and other associated infections of the upper
airway, including the sinuses and the external/middle ear. The lung Pathogenesis
is the most common site for this unusual infection (Figure 13.4) and Infections of the nasal sinuses and rarely the lung occur by inhala-
forms a matted collection of vegetations commonly referred to as an tion of these ubiquitously-found fungi in immunocompromised or
“aspergilloma.” This fungus has a very low virulence profile, generally diabetic individuals (Sun and Singh 2011). Rarely, burn wounds or
does not demonstrate invasion of adjacent tissues, and does not elicit open traumatic wounds may become secondarily infected after long
a significant inflammatory response from the host. These infections periods of hospitalization and sustained illness.
will result on occasion with endocarditis, solid organ lesions (liver, The nasal infections can result in severe nasofacial necrosis and
spleen, brain), and rarely a metastatic endophthalmitis similar to extension into the orbit, eye, and even the brain (Figure 13.5). Nec-
Candida albicans can be seen. rotizing pulmonary infections result from invasion of the pulmonary
The diagnosis of aspergillus infection is suspected in immunosup- vasculature, with lung infarction and even massive hemoptysis being
pressed patients with hemoptysis and a cavitated lesion of the lung. the consequence. Patients with diabetes are most susceptible because
Hemoptysis can be massive and life threatening. A necrotizing pneu- of the affinity of these microorganisms for a high concentration of
monitis is seen in patients with chronic obstructive pulmonary disease. glucose.
Sinus infections can be very subtle and may have few symptoms. Pro- Dissemination can occur from the lung or nasosinus routes, and
ptosis from adjacent extension of infection into the orbital area from may yield cutaneous or visceral lesions. Even GI and CNS infections
the sinuses can be seen. This can appear similar to mucormycosis. In- can be seen. The invasion of these fungi into arterioles yields the
fections of the external or middle ear require a high index of suspicion. necrotizing feature, which combined with the immunosuppressed
The diagnosis is made by culture identification of Aspergillus or susceptible host leads to a usually fatal outcome for disseminated
spp. from a site with an accompanying clinical picture of infection. disease.
Aspergillus spp. are not difficult to culture and positive lung cultures
may reflect colonization rather than true infection. Sinus aspirates Diagnosis
and cultures from ear specimens are reliable. In selected cases, tis- The diagnosis is usually made by identification of the species on tis-
sue biopsy may be required to definitively establish the diagnosis. In sue biopsy. Black discharge suggests the diagnosis and organisms
pulmonary infections, this may mean transtracheal or lung biopsy. may be seen on KOH preparations. Tissue biopsies with histological
The infection is rarely established from blood cultures. demonstration of invasion of the organism are the most reliable.
Voriconazole is currently the recommended first-line treatment Cultures must be interpreted carefully and are notoriously negative.
for aspergillus infection (Walsh et al. 2008). Lung resection may be When only a few colonies are identified on culture, this may reflect
necessary in cases of severe hemophysis. Drainage and debridement airborne contamination and not infection.
may be necessary in sinus infections.

■■Mucormycosis
Formerly called the phycomycoses and then the zygomycetes, this
collective group of hundreds of different fungi are is collectively called

Figure 13.4  A hematoxylin and eosin stain of avian lung tissue infected Figure 13.5  A case of periorbital mucormycosis. (From the Public Health
with Aspergillus spp. (From the Public Health Image Library, Centers for Image Library, Centers for Disease Control, courtesy of Dr Thomas Sellers,
Disease Control, courtesy of CDC/Dr William Kaplan: http://phil.cdc.gov/phil/ Emory University: http://phil.cdc.gov/phil/details.asp.)
details.asp.)
150 FUNGAL INFECTIONS OF SURGICAL SIGNIFICANCE

Treatment Treatment of pneumocystis pneumonia is managing the underlying

The treatment of mucormycosis is surgical debridement of dead tissue, predisposing illness (e.g., HIV antiretroviral treatment) and specific
medical control of underlying medical conditions, and antifungal che- therapy to target P. jiroveci. Trimethoprim–sulfamethoxazole given
motherapy. There has been considerable study into the development orally or intravenously for 14 days in non-HIV patients, and 21 days
of effective antifungal treatments for this difficult infection (Spellberg for HIV patients, is the current therapy. Primaquine, an anti-malarial
et al. 2009). Lipid formulations of amphotericin B are the standard agent, is used with clindamycin as a second choice. Pentamidine has
systemic treatment. These fungi are usually resistant to the azoles been used but can be given only intravenously for established infec-
and echinocandins. Results are poor with most patients dying from tion. Pentamidine aerosol is used for prevention of recurrent infec-
severe local or disseminated infection. Effective surgical debridement tion. Complications of pneumocystis pneumonia include recurrent
of necrotic tissue is essential for patient survival. infections and pneumothorax. Mortality rates for this infection depend
on the constellation of risk factors in the patient. Improvement has
■■Pneumocystis pneumonia been seen in HIV patients with this infection, but remains at 30–50%
for non-HIV-associated infections (Sepkowitz 2002).
Pneumocystis jiroveci, formerly known as P. carinii, is primarily a pul-
monary pathogen of immunosuppressed hosts that became a source
of considerable interest from infections in AIDS patients in the early
■■ANTIFUNGAL AGENTS
1980s. Considered formerly to be a paracytic pathogen, it is now clas- The number of antifungal agents continues to expand. The dosage
sified as a fungal organism (Figure 13.6). It does not have the typical schedule for the current systemic agents is identified in Table 13.1.
ergosterol within the plasma membrane as other fungi do, and thus has The dosing identified is primarily of adult patients. The frequency and
resistance to those antifungal therapies directed at ergosterol synthesis. amount of drug administered may exceed that noted in the table based
It is acquired by airborne transmission and may reside as a colonist on the degree of illness identified by the clinician.
within the lung for prolonged periods of time (Carmona and Limper
2011). The clinical pneumonitis emerges with immunosuppression
of the host. Many of the pathophysiological features of this pathogen
■■Amphotericin B deoxycholate
are poorly understood because in vitro culture has been elusive and Amphotericin B is an antifungal produced by Streptomyces nodosus.
inhibited effective study. Although initially considered only a pulmo- Despite the many problems that are associated with administration
nary pathogen, P. jiroveci has been identified in lymph nodes, liver, and toxicity of the drug, it continues to be a commonly employed
spleen, bone marrow, and other tissues. Similar to other fungi, it can systemic antifungal agent.
be found in the retina. Amphotericin B binds to the ergosterol component within the
The diagnosis is suspected in vulnerable patients with a non- membrane. Cholesterol in human membranes is also bound, but the
productive cough, fever, shortness of breath, and diffuse bilateral affinity of the drug is much greater for fungal ergosterol. Binding of
infiltrates in the perihilar region on chest radiograph. Histopathologi- amphotericin B to the fungal plasma membrane results in cylindrical
cal identification is required for diagnosis. Cultures cannot be done channels which permit loss of cytoplasmic enzymes (Vertut-Croquin
in the clinical microbiology laboratory. Induced sputum may identify et al. 1983). Amphotericin B is also thought to cause oxidative damage
the pathogen, but bronchoalveolar lavage has yielded the diagnosis in to the fungal cell, and may actually stimulate B-lymphocyte function
up to 90% of cases. Transbronchial biopsy or even open lung biopsy in the host. Changes in the binding characteristics of ergosterol may
has been required in selected cases. Antigen or antibody detection be a mechanism of resistance.
methods have not been successful. Amphotericin B is administered only by the intravenous route, and
has no appreciable absorption from the GI tract when given orally.
The antibiotic is highly protein bound (>90%). It penetrates the CNS
poorly. It has an initial biological elimination half-life of 24 h, but,
after therapy is completed, has a terminal half-life of 15 days. Drug is
identified in the urine for over 6 weeks after cessation of treatment.
The prolongation of drug elimination after treatment is related to cell
membrane binding of the drug to host cells.
Administration of amphotericin B poses some special problems
(Carlson and Condon 1994). The compound is unstable if exposed to
heat, prolonged sunlight, or an acid pH <4.2, and will precipitate in
electrolyte solutions. Acute reactions to amphotericin B are common
and require the administration of a 1-mg test dose. Fever and chills,
dyspnea, and even hypotension can be encountered, with the acute
reaction identified with a peak response by 4 h after administration
due to the release of proinflammatory cytokines (Laniado-Laborin
and Cabrales-Vargas 2009).
Amphotericin B has toxicity that is linked to total dose and duration
of therapy. Renal toxicity secondary to renal vasoconstriction results in
renal tubular damage. Saline loading by the administration of 500 ml
of 0.9% saline before and 500 ml after amphotericin B administration
Figure 13.6  A photomicrograph of Pneumocystis jiroveci in lung with may reduce nephrotoxicity. Additional renal toxicity includes anemia,
toluidine blue stain. (From the Public Health Image Library, Centers for Disease renal tubular acidosis, and renal losses of potassium. Potassium
Control, courtesy of Dr Peter Drotman: http://phil.cdc.gov/phil/details.asp.) supplementation is commonly required.
 Antifungal agents 151

Table 13.1 Antifungal drugs and dosing schedules used in adult patients (unless otherwise indicated) without renal failure.
Drug Dosage Comments
Amphotericin B 0.5–1.0 mg/kg per day This preparation has been used for 50 years in the treatment of severe
deoxycholate fungal infections
Liposomal amphotericin 3–6 mg/kg per day Amphotericin in incorporated into a true liposome for drug delivery
Amphotericin lipid complex 5 mg/kg per day The active amphotericin B is complexed with two separate
phospholipids in this preparation
Amphotericin colloidal 3–4 mg/kg per day Amphotericin is complexed with cholesteryl sulfate. Colloidal complex
suspension is broken down by macrophages to release active drug
5-Fluorocytosine 100–150 mg/kg per day in four divided doses Oral antifungal that is ordinarily used in combination with amphotericin B
Fluconazole 200 mg on day 1, followed by 100 mg daily for Candida Commonly used antifungal that is both an intravenous and an oral
sp.; 400 mg on day 1, and 200 mg daily for cryptococcal preparation
infection
Itraconazole 200–400 mg daily The azole antifungal with a role in the treatment of aspergillus,
blastomycosis, and histoplasmosis infection
Voriconazole 6 mg/kg every 12 h for 24 h; then 4 mg/kg every 12 h Used for aspergillus and candidal infections
Posaconazole 100–400 mg 2–3 times per day Higher doses are used for invasive oropharyngeal infections that are
refractory to other azole antifungal agents.
Ketoconazole 100–200 mg daily in adults; 3.3–6.6 mg/kg daily in Only available as an oral preparation and used for oral pharyngeal
children candida infections with sensitive organisms
Caspofungin 50 mg daily after a loading dose of 70 mg on day 1 Used for invasive candida infections
Anidulafungin 100–200 mg loading dose for day 1, followed by Used for invasive candida infections
50–100 mg daily
Micafungin 50–150 mg daily Used for invasive candida infections

Amphotericin B forms stable complexes with lipids, which permit

the development of new formulations that reduce the toxic profile of
■■Azole antifungal drugs
this treatment. Three lipid formulations of amphotericin B are ap- The azole compounds inhibit cytochrome P450 with resultant reduc-
proved for use: Amphotericin B lipid complex (Abelcet), amphotericin tion in ergosterol and defective membrane synthesis by the targeted
B colloidal dispersion (Amphotec), and liposomal amphotericin B fungal pathogen. They may have a direct action on the cytoplasmic
(AmBisome). Functionally, these lipid formulations are sustained- membrane as well. The inhibition of cytochrome 450 results in a
release methods to maintain drug concentration without excessive large number of drug interactions in using these drugs (Box 13.1)
and toxic peak concentrations. Clinical experience has demonstrated
reductions in both nephrotoxicity and other adverse effects. The daily
dosing of these lipid preparations is much greater than the deoxycho- Box 13.1 Drugs of surgical interest that have significant interac-
late preparation (see Table 13.1). tions with the azole antifungals.

■■5-Fluorocytosine This listing in not complete, but identifies drugs of surgical sig-
nificance.
As the first orally administered antifungal agent, 5-fluorocytosine has Decreased azole serum concentration
been primarily used in the treatment for Candida spp. (not C. krusei) H2 receptor antagonists
and Cryptococcus neoformans. It is ordinarily used in combination Proton pump inhibitors
with amphotericin B. Sulcrafate
The mechanism of action for 5-fluorocytosine requires that the Increased azole metabolism
drug be deaminated to 5-fluorouracil within the target fungal mi- Rifampin
croorganism. The 5-fluorouracil is incorporated into the RNA of the Phenyltoin
fungus and inhibits protein synthesis. The 5-fluorouracil may be Phenobarbital
phosphorylated through a series of reactions which results in the Increased concentration: coadministered drug
inhibition of thymidine synthetase, and the resultant inhibition of Oral hypoglycemics
DNA synthesis. Mechanisms of resistance include loss of perme- Warfarin
ability or failure of mutants to deaminate the parent compound to Ciclosporin
5-fluorouracil. Tacrolimus
Leukopenia and thrombocytopenia are complications directly Phenyltoin
attributable to 5-fluorocytosine and may be amplified by the simul- Benzodiazepines
taneous use of amphotericin B. The drug does not cause renal failure. Statin drugs
Nausea, vomiting, and diarrhea may be seen as consequences of Rifampin
deamination of the parent drug to 5-fluorouracil. Hepatic toxicity has Selected cancer chemotherapy drugs
also been identified. Hypersensitivity can also be seen. Digoxin
152 FUNGAL INFECTIONS OF SURGICAL SIGNIFICANCE

(Brüggeman et al. 2009, Gubbins and Heldenbrand 2010). The mecha- or aspergillus infection. Hypersensitivity, arrhythmias and prolonged
nisms for the emergence of resistance include pathogen development Q–T interval, and hepatic toxicity are the major adverse events.
of efflux pumps to reduce intracellular drug concentrations, point Ketoconazole is an oral preparation that has poorer tissue penetra-
mutations of the gene encoding the target enzyme of drug action, tion and a less desirable adverse event profile than the other azole
and the development of bypass pathways that eliminate drug effects antifungals. It is used for oral candida infections, and can be used for
(Pfaller 2012). The need to maintain drug concentrations above the less severe infections of blastomycosis and coccidioidomycosis. It is
minimum inhibitory concentration (MIC) range and the unpredict- used as a topical cream for cutaneous fungal infections.
able pharmacology of the azoles have led to some recommending
therapeutic monitoring to achieve optimum outcomes (Kontoyian-
nis 2012).
■■Echinocandins
Fluconazole has a broad range of antifungal activity. This com- The echinocandins are large lipopeptide molecules that are inhibitors
pound can be given orally or by intravenous administration. It has of b-1,3-glucan synthesis, an action that results in disruption of the
over a full decade of use in the treatment of candida infections, and fungal cell wall and osmotic stress, lysis, and death of the microorgan-
is approved for use in cryptococcal infections. It has also been used ism (Denning 2003). Available echinocandins include caspofungin,
for coccidioidomycosis. Fluconazole is employed for the preven- anidulafungin and micafungin. They are intravenous drugs. The echi-
tion of candida infections in bone marrow transplantation, and nocandins are fungicidal against most Candida spp. and fungistatic
for patients undergoing chemoradiation. Resistant organisms are against Aspergillus spp. No drug target is present in mammalian cells.
identified with sustained use. Drug-associated adverse events are Results of studies of echinocandins in candidemia and invasive
very low. Elevation of hepatic enzymes and alopecia are seen and candidiasis suggest equivalent efficacy to amphotericin B, with sub-
are reversible with cessation of the drug. Hypersensitivity and ana- stantially fewer toxic effects. The IDSA guidelines for the treatment of
phylaxis are uncommon. candidiasis specifically suggest the use of echinocandins preferentially
Itraconazole is an oral preparation that is used in the long-term among patients with moderate-to-severe disease (Pappas et al. 2009).
management of patients with aspergillosis, blastomycosis, and his- Absence of antagonism in combination with other antifungal drugs
toplasmosis. It is not available as a parenteral preparation. GI com- suggests that combination antifungal therapy could become a general
plaints are the most common adverse events. Similar to other azoles, feature of the echinocandins, particularly for invasive aspergillosis.
hypersensitivity can be seen but is uncommon. Echinocandins exert concentration-dependent killing in many dif-
Voriconazole is an intravenous and oral antifungal preparation. It is ferent in vitro and animal models of disseminated fungal infection.
used in invasive aspergillosis, candida infections in non-neutropenic Fewer than 50 cases of echinocandin-resistant infections with species
patients, and candidal esophagitis. Selection of this drug is always such as C. albicans, C. glabrata, C. tropicalis, and C. krusei have been
confirmed by specific sensitivity validation. Adverse outcomes leading described in limited series or case reports (Lortholary et al. 2011). All
to discontinuation of treatment have been elevated hepatic enzymes, species were found in patients pre-exposed to echinocandins.
rash, and visual disturbances. The echinocandins have few adverse events. They are associated
Posaconazole is an oral suspension that is used for the treatment with histamine release on administration. They do not have the hepa-
of oropharyngeal candida infection, and for prophylaxis in immuno- totoxicity or drug interaction problems that are seen with the azole
compromised patients who are considered at risk for invasive candida antifungals.

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Chapter 14 Viral infections of surgical
significance
Donald E. Fry

The number of viruses that participate in human disease is steadily Transmission of HIV infection is secondary to exposure from blood
increasing. The problem of viral infection has proven to be more or blood products of infected individuals. Transfusion was a significant
elusive than bacterial disease because these microbes have not been cause before effective screening methods were instituted. Intravenous
readily identifiable with conventional microscopy or by culturing drug abuse and sexual exposure remain common modes of transmis-
techniques. Different viral infections share many common clini- sion. Vertical transmission from infected mothers to neonates remains
cal characteristics that make differentiation of disease expression a potential route of transmission, although effective prevention has
very difficult. Antiviral chemotherapy and other treatments of viral been achieved with the third trimester recognition and treatment of
diseases have generally lagged behind those of bacterial infections. HIV-positive mothers. There is no evidence for transmission by saliva
Surgeons need an expanded understanding of those viral illnesses or casual interpersonal contact.
that impact surgical care. Viruses are causes of neoplasia, opportunis- The natural history of HIV infection leads to clinical AIDS. The re-
tic infections in immunosuppressed surgical patients, and important duction of the CD4 lymphocyte count and other immune consequenc-
potential sources of occupational infections for the surgeon. es result in opportunistic infections and neoplasia that constitute the
case definition of AIDS (CDC 1992). These conditions are identified
■■HUMAN IMMUNODEFICIENCY in Table 14.1. The morbidity and deaths from AIDS are generated
by the immunosuppression rather than direct consequences of the
VIRUS clinical infection.
The diagnosis of HIV infection is made by screening individuals
It has been 30 years since the first HIV/AIDS cases were identified with high-risk exposures. The diagnosis is made by detection of spe-
in young males with pneumocystis pneumonia. During the follow- cific antibodies or antigens. The enzyme-linked immunosorbent assay
ing years, HIV infection has been a major international issue with (ELISA) test for HIV-specific antibodies is highly (99%) accurate. A
considerable efforts to understand, prevent, and treat this disease. positive ELISA leads to a western blot evaluation of host antibodies to
Despite this effort, there are 33.3 million people living with HIV specific HIV antigens. The number of indeterminate diagnostic studies
infection in the world, 2.6 million new cases were identified in 2009, requiring direct viral detection has become less frequent.
and 1.8 million people died from HIV during that same year (World Laboratory monitoring of the patient becomes an important
Health Organization 2009). During the last 4 years, an average of feature during management. CD4 cell counts have been most com-
50 000 new cases of HIV infection per year were transmitted in the monly used with <200/µl being the threshold to indicate potential
USA despite attention focused on preventive measures (Prejean emergence of AIDS. Direct measurement of HIV RNA in blood is
et al. 2011). used to monitor therapy. Monitoring warrants quantitative assess-
HIV is a retrovirus. Its primary cellular target is the CD4 lym- ment of viral RNA every 3–4 months. Resistance monitoring of viral
phocyte. Penetration of the target cell results in the synthesis of a strains is commonly done either by evaluating genomic sequences
complementary DNA to the native viral RNA by the enzyme reverse of clinical isolates or by demonstrating inhibition of viral growth by
transcriptase. The complementary DNA becomes the genetic template specific agents in vitro.
for the production of viral proteins. An important clinical feature of the The prevention of HIV infection has been the focus of a large effort
infection is its latency. There is commonly an acute viral syndrome as- by national and international health agencies. Rates of new HIV infec-
sociated with viremia of the acute infection, but the infection may exist tion have declined in developed countries but continue to occur at
for a decade or more before immunosuppression and life-threatening unacceptable rates. In developing countries, safe sex programs have
illness emerge. During this latent period, the virus is replicating and had a small impact and an increasing number of new cases continue
exhausting the host’s reservoir of CD4 cells. During the evolution of to be identified. An effective vaccine has been aggressively pursued
the disease CD8, B cells, monocytes/macrophages, dendritic cells, but not achieved.
and natural killer cells are all affected. The treatment of HIV infection has rapidly progressed over the
An important feature of HIV is hypermutation. This dynamic last 20 years. Highly effective antiretroviral therapy has evolved with
process of constantly changing the viral genome results in specific dramatic prolongation of quality life for many HIV patients (Depart-
antigenic changes. The constantly changing viral antigens have been ment of Health and Human Services 2011). Current therapy is for
a major reason for failure in vaccine development. life, although specific combinations of drugs may be changed over
HIV is identified throughout the world in two types. HIV-1 is most time. Regimens are selected based on the comorbid conditions of the
common and appears to be the most virulent and has the greatest ef- patient (e.g., coexistent hepatitis virus B [HBV] or C [HCV] infection),
ficiency in transmission. HIV-2 is much less common and is identified pregnancy, drug resistance, and other variables. Table 14.2 highlights
primarily in West Africa. HIV-2 is less likely to progress to clinical AIDS the six categories of antiretroviral drugs that are currently available.
(Centers for Disease Control and Prevention [CDC] 2011). Treatment philosophy usually leads to three or more drugs being
156 VIRAL INFECTIONS OF SURGICAL SIGNIFICANCE

Table 14.1 Details the surveillance conditions associated with the diagnosis of AIDS and common diagnostic methods.
Conditions of AIDS surveillance case definition Diagnostic methods
Candidiasis of bronchi, trachea, lungs, esophagus Typical endoscopic appearance; microscopic fungal mycelia filaments; positive
cultures
Invasive cervical carcinoma Biopsy
Coccidioidomycosis Culture or antigen detection
Cryptococcosis Culture or antigen detection
Cryptosporidiosis Histology or cytology
Cytomegalovirus disease (not liver, spleen, or nodes) Culture or antigen detection
Encephalopathy, HIV associated Clinical association in HIV-positive patient
Herpes simplex: chronic ulcer (>1 month), bronchitis, pneumonitis, esophagitis Culture or antigen detection
Histoplasmosis: disseminated or Culture or antigen detection
extrapulmonary
Isosoporiasis, intestinal (>1 month) Histology or cytology
Kaposi sarcoma Histology or cytology
Lymphoma: Burkitt, immunoblastic, or brain primary Biopsy
Mycobacterium avium complex, M. kansasii, or other atypical species Cytology, cultures, typical clinical presentation
(disseminated or extrapulmonary)
Mycobacterium tuberculosis, any site Cytology, cultures, typical clinical presentation
Pneumocystis jiroveci pneumonia Clinical picture without bacteria; biopsy
Pneumonia, recurrent Cultures; clinical recurrent pneumonia
Progressive multifocal leukoencephalopathy Histology or cytology
Salmonella septicemia, recurrent Cultures
Toxoplasmosis of brain Imaging of brain; positive antibody detection
Wasting syndrome due to HIV Clinical association of >10% loss of body mass in HIV-positive patient

used for naïve cases, with agents chosen from groups with a different
mechanism of action. The extensive number of treatment options,
■■Hepatitis A
differences in drug-associated complications, different number of Hepatitis A virus (HAV) continues to be the most clinically identified
associated chronic illnesses (e.g., HBV or HCV), and differences in cause of hepatitis worldwide. HAV is an RNA virus that is transmitted
responsiveness mean that physicians with extensive experience in via the fecal–oral route from contaminated water or food products.
the management of HIV infection are required. The ingested virus adheres to the upper aerodigestive tract mucosa,
In the 1980s and 1990s, there was considerable concern about accesses the circulation, and binds specifically to the hepatocyte. The
occupational risks of HIV infection for surgeons and healthcare work- viral RNA replicates within the hepatocyte cytoplasm, which then
ers. Uncertainty about the efficiency of transmission of HIV infection leads to lysis of the host cell and liberation of new virions to continue
resulted in implementation of universal precautions and reductions the cycle. The bile becomes a rich source of viruses which enter the
in blood exposure during operations. These precautions continue to intestinal tract, and the viral particles are passed from the gut to con-
be recommended and are discussed with hepatitis below (Fry 2007). taminate other food and water sources.
In the USA, 57 documented cases of HIV transmission have occurred HAV causes a severe and incapacitating infection. Fever, malaise,
among healthcare workers and another 139 cases are considered as nausea, vomiting, and marked jaundice are the usual clinical find-
probable transmissions based upon epidemiologic evidence (CDC ings. Mild leukocytosis is usually present with dramatic increases in
2002). No cases have occurred in the sterile environment of the operat- the serum concentrations of aspartate aminotransferase (AST) and
ing room. The current risk of HIV transmission from a percutaneous alanine aminotransferase (ALT). The clinical hepatitis syndrome may
injury is identified at 0.3% (CDC 2003). last 2–3 weeks, but several months may be required for full recovery.
Although the acute hepatitis syndrome is severe, deaths from acute
■■HEPATITIS HAV infection are quite uncommon but can be seen in pregnant
women, elderly people, and immunocompromised individuals.
Hepatitis continues to be an international viral pathogen in millions HAV infection does not have a chronic phase of infection. Resolution
of patients annually. Each hepatitis virus has a unique natural his- of the acute infection results in complete eradication of the virus.
tory and different consequences. For surgeons, hepatitis B and C are There is no post-hepatitis cirrhosis. HAV infection is not a risk for
associated with cirrhosis of the liver, hepatocellular carcinoma, and occupational infection.
portal hypertension. The risks of hepatitis as an occupational infection The diagnosis is customarily made by clinical criteria. Acute and
continue at present. Reported hepatitis viruses of interest are identified convalescent sera for HAV antibody confirm the diagnosis. The virus
in Table 14.3. Each is discussed. can be isolated form blood and stool. Reverse transcriptase polymerase
 Hepatitis 157

Table 14.2 The six groups of currently available antiretroviral agents that are available for the treatment of HIV infection (Department of Health and
Human Services 2011).
Nucleoside/nucleotide reverse transcriptase inhibitors
Generic name Brand name Dosage (adults)
Abacavir Ziagen 300 mg twice daily, or 600 mg four times daily
Didanosine Videx EC 400 mg four times daily
Emtricitabine Emtriva 200 mg four times daily
Lamivudine Epivir 150 mg twice daily, or 300 mg four times daily
Stavudine Zerit 40 mg twice daily
Tanofovir disoproxil fumarate Viread 300 mg four times daily
Zidovudine Retrovir 300 mg twice daily, or 200 mg three times daily
Non-nucleoside reverse transcriptase inhibitors
Delaviridine Rescriptor 400 mg three times daily
Efavirenz Sustiva 600 mg at bedtime
Etravirine Intelence 200 mg twice daily
Nevirapine Viramune 400 mg four times daily
Rilpivirine Edurant 25 mg four times daily
Protease inhibitors
Atazanavir Reyataz 400 mg QD
Darunavir Prezista 600–800 mg four times or twice daily not alone
Fosamprenavir Lexiva 1400 mg twice daily
Indinavir Crixivan 800 mg three times daily
Lopinavir/Ritonavir Kaletra 400 mg/100 mg twice daily, or 800 mg/200 mg four times daily
Nelfinavir Viracept 1250 mg twice daily or 750 mg three times daily
Ritonavir Norvir 100-400 mg four times daily with other protease inhibitors
Saquinavir Invirase 1000 mg twice daily not alone
Tipranavir Aptivus 500 mg twice daily not alone
Fusion inhibitors
Enfuvirtide Fuzeon 90 mg (1 ml) subcutaneously twice daily
CCR5 antagonists
Maraviroc Selzentry 150–600 mg twice daily based on companion drugs
Integrase inhibitor
Raltegravir Isentress 400 mg twice daily
The drugs are given as combinations of multiple agents. Dosages are adjusted depending on companion treatments and patient tolerance. Drug interactions with other therapy and the
toxicities of the agents are complex.

Table 14.3 Those viruses proven or suspected to cause hepatitis in humans.

Hepatitis type Nucleic acid Route of Clinical commentary
transmission
A RNA Fecal–oral Severe acute hepatitis, but infrequently fatal: not associated with chronic hepatitis disease; an
effective vaccine is available
B DNA Blood borne 5% of infections become lifetime chronic disease: associated with end-stage liver disease and
hepatocellular carcinoma; a safe and effective vaccine is available
C RNA Blood borne 60–80% of infections become lifetime chronic infection; a variable natural history of chronic
infection; no vaccine
D RNA Blood borne Requires acute or chronic hepatitis B infection to infect humans; exacerbates severity of chronic
hepatitis B; no vaccine
E RNA Fecal–oral Many common features similar to hepatitis B; not associated with chronic hepatitis disease; no vaccine
G RNA Blood borne Associated with hepatitis B and C patients but unproven to actually cause infection of the hepatocyte
TT DNA Blood borne Transfusion-associated infection but of unproven clinical relevance for hepatitis
SEN DNA Blood borne Transfusion-associated virus: unproven as a hepatitis virus
158 VIRAL INFECTIONS OF SURGICAL SIGNIFICANCE

chain reaction (rtPCR) will identify the viral RNA. No specific treatment antigen confirms that active disease is present. Persistence of the
other than supportive care is required for the acute infection. HAV antigen reflects chronic hepatitis.
infection can be prevented by use of the HAV vaccine which is highly Prevention of HBV infection is an international objective with
effective for international travelers going to endemic areas. the safe and effective HBV vaccine. A three-dose regimen is used via
intramuscular administration, with the second and third dose given
■■Hepatitis B 1 and 6 months after the initial dose. An antibody response should be
documented to identify the 5–10% of non-responders, who should un-
Hepatitis B virus (HBV) infection has traditionally been of greatest dergo a second course of immunization. For non-responders following
concern to surgeons. Chronic HBV infection has been a recognized revaccination, prevention of exposure remains the only recourse. Suc-
cause of end-stage liver disease and its related manifestations. HBV cessful immunization is currently believed to confer lifetime immunity.
infection has been recognized for over 60 years as an occupational Dramatically improved treatment of patients with chronic HBV in-
risk to healthcare workers after blood exposure from infected patients fection has occurred over the last 10–15 years. Seven different drugs are
(Kuh and Ward 1950, Trumbell and Greiner 1951). currently employed in the management of these patients (Table 14.4).
HBV is a DNA virus. It is transmitted by percutaneous or mucous Interferon-a may be used as a conventional formulation or pegylated
membrane exposure to contaminated blood or other body fluids. HBV with polyethylene glycol. All other therapies are nucleoside analogs.
is transmitted by sexual contact and intravenous drug abuse. Blood Interferon-a therapy is used for 48 weeks whereas the nucleosides are
and blood product transfusion has been eliminated as a source of used over many years. Each has different toxicity and different rates
transmission with effective screening methods. Internationally mil- of effectiveness. All require dosing modifications for renal failure. The
lions of new cases occur annually. It is currently estimated that 350 goal of therapy is to reduce the viral load and prevent progression of the
million people have chronic HBV infection worldwide (Dienstag 2008). disease. Current trends in treatment have been to use drugs that have
Following entry of the virus into the circulation, it binds to he- lowest resistance trends and lower toxicity profiles, and yield the best
patocytes. The viral DNA replicates new particles from the infected results in the elimination of HBV DNA. Therapeutic choices are modi-
cell. Only 25% of acute infections are characterized with icterus, fied when patients have concurrent HIV infection. The current treat-
elevated hepatic enzymes (e.g., AST, ALT), and the clinical hepatitis ments are not considered curative and patients must be monitored for
syndrome, whereas all others are subclinical. Unfortunately, 5% of viral breakthrough (Bhattacharya and Thio 2010, Kwon and Lok 2011).
all HBV infections are associated with chronic infection. In chronic Surgeons and other healthcare workers (HCWs) have contracted
HBV infection the patient is positive for the virus for life and remains a occupational HBV infection from percutaneous exposure to blood.
reservoir for infection to others. The chronic HBV patient will progress There is a 30% risk for acute HBV infection after percutaneous injury
to post-necrotic cirrhosis, portal hypertension, and even hepatocel- by needlestick from a chronically infected patient. The generalized use
lular carcinoma. The natural history of chronic infection commonly of the HBV vaccine is reducing the risk in the USA, but occupational
requires over 20 years from acute infection to chronic manifestations HBV infection remains an international risk for surgeons and HCWs.
of the disease. All should be immunized.
The diagnosis is established by the detection of antibodies or HBV When exposure to a known HBV-infected patient occurs, a post-
antigen in the patient. The acute infection will develop both the sur- exposure prophylaxis protocol should be implemented. First, a current
face and core antibody to HBV. Identification of the core antibody is HBV serology should be obtained. If a positive HBV surface antibody
indicative of current or prior HBV infection, because surface antibody is obtained, then the prior immunization is still effective. If the serol-
alone may reflect prior HBV immunization. Identification of the HBV ogy is positive for HBV core antibody, then remote HBV infection

Table 14.4 Drugs currently used or being evaluated for the treatment of patients with chronic hepatitis B infection.
Drug Mode of action Dose Comments
Interferon-α-2a Enhanced immune response 180 µg s.c. weekly for 48 weeks >25% rate of fever, headache, etc.
Contraindicated in decompensated cirrhosis
Eliminates HBV DNA in 30–60% of treated patients
Lamivudine Cytidine analog 100 mg daily Rapid development of resistance
Associated with hepatic steatosis, lactic acidosis
40–70% loss of HBV DNA
Emtricitabine Cytidine analog 200 mg daily High resistance rates
Similar features to lamivudine
Not FDA approved in the USA
Telbivudine Thymidine analog 600 mg daily Similar effects and adverse events as lamivudine
Longer elimination half-life
60–85% loss of HBV DNA
Adefovir Adenosine monophosphate analog 10 mg daily Very nephrotoxic
20–50% loss of HBV DNA
Tenofovir Adenosine monophosphate analog 300 mg daily Nephrotoxicity
75–90 % loss of HBV DNA
Entecavir Guanosine analog 1 mg daily Headaches, diarrhea, arthralgia, lactic acidosis
70–90% loss of HBV DNA
FDA, Food and Drug Administration; HBV, hepatitis B virus; s.c., subcutaneous administration.
 Hepatitis 159

has occurred and no additional preventive measures are necessary. Even though it is an RNA virus, HCV shares many characteristics
However, a positive core antibody requires documentation of cur- of HBV infection. It is transmitted by blood exposure and intrave-
rent antigen status because chronic HBV infection may exist. If the nous drug abuse, and it is associated with multiple sexual partners.
exposed individual is antibody-negative and has not previously been Associations with blood transfusion have largely disappeared with
immunized, then a dose of the HBV immune globulin should be given effective screening of the blood supply. There remain about 15–30%
and the initial does of the HBV vaccine given as the first step in full of HCV infections that do not have identified clinical associations
immunization. If the individual has had prior immunization but is (Rosen 2011). It is not transmitted by the oral route. Similar to HBV,
weakly positive for surface antibody, then a dose of the immune globu- HCV infection is identified with an acute hepatitis syndrome in about
lin and a single booster dose of the vaccine should be administered. 20–30% cases. Unfortunately, HCV infection results in chronic infec-
No recommendations are currently available about routine booster tion in >60% of acute infections. At present over 3 million chronic HCV
doses of the vaccine, but this may be prudent for surgeons in high-risk infections exist in the USA.
specialties to consider. Surgeons with chronic HBV infection and are HCV gains access to the blood, binds to specific receptors on the he-
“e” antigen positive are an infectious risk to patients and should follow patocyte, is internalized into the cell, and replicated viral particles are
the recommendations of the American College of Surgeons (Box 14.1). the result. There are at least six genotypes of HCV, of which genotype-1
is most common in the USA and western Europe. HCV infection has
■■Hepatitis C a worldwide distribution with the greatest prevalence in sub-Saharan
Africa (Cowan et al. 2011).
Before 1989, only HAV and HBV were identified hepatitis viruses. The natural history of chronic HCV infection is quite variable. Se-
A third virus was suspected, and these infections were collectively lected chronic infections will spontaneously resolve whereas others
referred to as non-A, non-B hepatitis. The identification of HCV and result in a persistently positive state of chronic infection with little
the development of the HCV antibody test allowed effective diagnosis clinical progression. About 20–30% of chronic cases develops cirrhosis
and represented the virus of the non-A, non-B hepatitis. Screening over 30 or more years, and are expected to create an enormous future
of blood donations has documented HCV to be more common than disease burden worldwide. Once cirrhosis develops, a 1–3% per year
HBV infection. risk of hepatocellular carcinoma is observed.
The diagnosis of chronic HCV infection is recognized by the identi-
fication of persistent HCV antibody. Chronic infection is validated and
the specific genotype is defined by rtPCR. The degree of liver fibrosis
Box 14.1 The recommendations of the American College of Sur- is best established with liver biopsy, but several liver biomarkers (e.g.,
geons in the Statement on the Surgeon and Hepatitis (www.facs. AST, ALT) are used to estimate ongoing injury to the liver.
org/fellows_info/statements/st-22.html). The treatment for chronic HCV infection is pegylated interferon-a
⦁⦁ Relevant to all blood-borne pathogens: Surgeons should use and ribavirin for 48 weeks. Ribavirin is an orally administered nucleo-
the highest standards of infection control, including the use of side anti-metabolite. It is dosed as 800–1200 mg/day in divided doses.
barriers and practices to avoid blood exposure. This should be Interferon-a treatment has the expected proinflammatory effects of
practiced in all sites where surgical care is rendered. Maximum fever, arthralgias, malaise, and other related symptoms. Ribavirin is
effort should be extended to avoid blood exposure for all mem- associated with hemolytic anemia and an increased rate of myocar-
bers of the surgical team dial infarction. Ribavirin is considered to be teratogenic and effective
⦁⦁ Relevant to hepatitis infected patients: Surgeons have the contraception is recommended for patients of reproductive age. Geno-
ethical obligation to provide care to all patients, including those type-1 patients have a 40% sustained response rate with no detectable
infected with hepatitis viral RNA at 24 weeks after completion of treatment. Response rates
⦁⦁ Relevant to hepatitis B: Surgeons should know their antibody are 70–80% for patients with genotype-2 or -3 infection.
status. Surgeons with natural antibodies without prior im- The introduction of new protease inhibitors have demonstrated
munization should be evaluated for chronic HBV infection improved outcomes compared with interferon-a and ribavirin. Tela-
and if positive should be evaluated for the “e” antigen of HBV. previr (Zeuzem et al. 2011) and boceprevir (Bacon et al. 2011) have
Those surgeons who are “e” antigen positive or have high viral demonstrated overall response rates of 80% and 60% for genotype-1
counts for HBV should have an expert panel convened to make infection. Although these newer treatments are exciting, they have
recommendations about the continuation of clinical practice. introduced a dramatic increase in the cost of therapy. As not all chronic
Surgeons with chronic HBV infection should seek expert medi- HCV infection progresses to cirrhosis and hepatocellular carcinoma,
cal care to receive current treatment for their illness better selection criteria are necessary to define who should be treated
⦁⦁ Relevant to hepatitis B: All surgeons should be immunized and who may not be harmed by observation.
against HBV if they have not previously had HBV infection. Sur- No HCV vaccine is currently approved in the prevention of occu-
geons must know that they have seroconverted at the comple- pational infection. Only uniform precautions to avoid percutaneous
tion of the immunization process. A failed initial immunization or mucous membrane exposure will prevent HCV infection. Percu-
effort requires a second immunization attempt. A failed second taneous needlestick injuries are associated with about a 2% risk of
immunization means particular adherence to practices to avoid seroconversion. As large numbers of patients are unaware of their
blood exposure infection status, uniform application of precautions will provide pro-
⦁⦁ Relevant to hepatitis C: Surgeons should know their antibody tection from HCV and other unappreciated blood-borne pathogens.
status for HCV. Avoiding blood exposure is the only preventive Universal precautions should include personal protective equip-
strategy in the absence of a vaccine against HCV infection. Sur- ment and the avoidance of high-risk operating room behaviors
geons with chronic HCV infection should adhere to strict infec- associated with percutaneous injury. Eye protection should always
tion control practice and use of barrier precautions. They should be worn to avoid splash exposures. Double gloving should be em-
seek expert medical counsel for treatment of their infection ployed in all thoracic and abdominal operations. This is best done
by having the inside glove half a size larger than the external glove
160 VIRAL INFECTIONS OF SURGICAL SIGNIFICANCE

to avoid constriction of the hands and digits. Double gloving will chronic HBV infection. There are multiple different genotypes of
not interfere with tactile discrimination or manual dexterity (Fry et HDV. The presence of HDV infection results in more rapid and severe
al. 2010). Other than the hands, the forearms are the area of highest progression to liver failure than expected from chronic HBV infection
blood “strike through” and warrant the use of sleeve reinforcements alone. The diagnosis of chronic HDV infection requires identification
for trauma, obstetrical cesarean sections, and cardiac surgery. A of the specific antigen or the viral RNA of the virus. The treatment of
reinforced anterior panel of the gown or a water-impervious apron HDV infection has been difficult because it requires the treatment of
under the surgical gown will prevent strike through in high-risk pro- two chronic viruses at the same time. Treatment with interferon-a
cedures, and knee-length foot covers are justified in trauma cases. for 48 weeks has resulted in observed virus-free states followed by
Technical modifications in operating room behavior will reduce relapse. The viral response of HDV appears to be linked to the effec-
rates of intraoperative blood contamination of the surgical team. Wire tive reduction in HBV. The treatment of end-stage liver disease with
suture material should be used only in very specific circumstances combined HDV and HBV infection has been liver transplantation,
(e.g., sternal closure) and must be used with caution to avoid injury. with evidence of effectiveness when the antigenemia of the HBV is
Double gloving will avoid shear injury of the digits from tying large suppressed with HBV immunoglobulin. HDV has not been identified
monofilament suture material (e.g., 0 or no. 1 polypropylene) under as an occupational risk for surgeons and the risk is eliminated by ef-
tension. Palpation of the needle tip in blind suturing techniques should fective HBV immunization.
be avoided. Swaged needles should be removed before tying suture
material. Blunt needle technology appears to potentially reduce in-
juries. A “way” station can be established with a Mayo stand between
■■Hepatitis E
the instrument nurse/technician and the surgeon to prevent direct Hepatitis E virus (HEV) is an RNA virus that is transmitted by the fe-
passing of loaded needle holders. Increased use of the electrocautery cal–oral route. Epidemic outbreaks of this infection are identified in
for opening body cavities has been recommended but may increase Asia and Africa, but clinical infection is a sporadic event in developed
infection at the surgical site. countries and associated with international travel. Clinical epidem-
Despite all the barrier enhancement and technical modifications, ics demonstrate the typical hepatitis syndrome. Acute infection
attitudes about avoiding injury in the operating room remain the most usually resolves without a chronic viral persistence except in very
important area for prevention. Many percutaneous injuries in the immunosuppressed individuals. Acute infection is rarely fatal except
operating room are the result of carelessness. An increased sense of in pregnancy and in very young children. Infection is suspected in
awareness of sharp instruments and needles is essential. Percutaneous patients with an acute hepatitis syndrome who are negative for the
injury is preventable but only when sensitivity to the use of “sharps” conventional hepatitis antibodies. There are four genotypes of HEV
has been increased. but only a single serotype. Commercial assays for anti-HEV antibody
Blood exposure and percutaneous injury continue to occur in are available and detection of the viral RNA occurs at the onset of the
the operating room and require a prompt response. Even though the viral syndrome. A vaccine for HEV is currently not available. Treatment
surgeon may believe that the skin of the hands or forearm is intact, of clinical infection is supportive care only. HEV rarely is transmitted
blood contact from breaks in the gloves or penetration of the surgical by transfusion and is not considered an occupational risk.
gown should be promptly managed. For blood contact or percutane-
ous injury of the hands or forearm, rescrubbing is desirable, but often
not practical because of the circumstances in the operation. Irrigation
■■Other hepatitis viruses
of the local area with povidone–iodine or isopropyl alcohol is recom- The search for additional hepatitis viruses continues. A putative orally
mended because of their known viricidal activity. With percutaneous transmitted hepatitis virus was labeled hepatitis F but has not been
injuries, an acute HCV antibody should be done to establish that validated. As no virus has been identified in up to 20% of patients with
the exposed individual has not previously had HCV infection. Sero- transfusion-associated hepatitis, the search for additional blood-borne
conversion should be documented by periodic reassessments of the hepatitis viruses has continued.
HCV antibody. If seroconversion occurs and the individual is positive Hepatitis G (HGV) was reported in 1996 (Linnen et al. 1996). This
for HCV RNA, then the treatment protocol of active HCV infection virus was associated with chronic hepatitis and was commonly identi-
identified above is recommended. Post-exposure treatment with the fied with HBV, HCV, and HIV infections. HGV is blood borne, and has
HCV antiviral therapy before documentation of actual infection is not been identified in about 2% of studied individuals. At the same time, an
recommended. The administration of HCV immune globulin does not entire group of GB viruses (GBV) were being identified as human and
provide post-exposure prevention. primate pathogens. The “GB” came from the initials of the surgeon with
Are surgeons with HCV infection a threat for transmission of infec- non-A, non-B, non-C hepatitis which was the index case from which
tion to their patients? Although this has been rarely documented, the the virus was recovered. Of the four GB viruses, only GBV-C appears
biggest threat to patients is from contaminated needles or multi-use to cause infection in humans. GBV-C and the aforementioned HGV,
vials of pharmaceuticals that have been contaminated by violations of although potentially having some unique genomic features, are the
infection control practices. The general consensus at this time is that same class of virus (Stapleton et al. 2011). Despite early association with
surgeons who are HCV positive may continue to practice as long as chronic hepatitis, neither GBV-C nor HGV has been proven to infect
they adhere to standards of infection control (see Box 14.1). hepatic cells and may actually infect and replicate within lymphocytes.
Additional viruses have been associated with transfusion-asso-
■■Hepatitis D ciated hepatitis and have been found as potentially additional viral
pathogens with HBV and HCV infection. Both the Torqueteno (TT)
Hepatitis D virus (HDV), or hepatitis D, is an incomplete RNA virus that virus (Hino and Miyata 2007) and the SEN virus (Sagir et al. 2004) are
is solely a pathogen with coexistent HBV infection. HDV is transmitted single-stranded DNA viruses that are transmitted by transfusion but
by the same behaviors as HBV and may be transmitted simultane- have not been documented to cause hepatitis. Both are found in pa-
ously with HBV infection (Hughes et al. 2011). It may occur following tients without clinical disease and may simply be commensal viruses.
 Human papillomavirus 161

■■HUMAN PAPILLOMAVIRUS carcinoma requires the presence of other cofactors. Factors associated
with the malignant transformation are early menarchy, early age sexual
Human papillomavirus (HPV) causes a chronic infection of the human intercourse, multiple child births, multiple sexual partners, other
epithelium and mucosa. It is a double-stranded DNA virus with over sexually transmitted infections, and tobacco use.
100 different strains of differing virulence. These ubiquitous viruses are HPV does not cause acute symptoms from the sexually transmitted
not inactivated with prolonged exposure to the environment. Infection infection itself. The traditional method of evaluating patients has been
occurs in association with traumatic events (e.g., cuts, abrasions) that with the Papanicolaou smear from a cervical scraping, which identifies
permit viral access to the basal cell layer. The complete viral particle the consequences of HPV infection rather than early identification of
is found only in the fully mature keratinocyte where they are released the virus. DNA detection and typing of the virus are done in research
with superficial sloughing of these cells. The different serotypes of HPV settings and have been useful in the identification of specific strains
result in different disease phenotypes. Specific strains are associated (types 16, 18) associated with cervical cancer. Serological tests may
with incorporation of the viral DNA into the host genome and result be positive for antibodies to specific HPV strains, but may reflect the
in malignant transformation. history of infection rather than the infection that is currently active.
Infection with HPV is not associated with the acute symptoms of Positive smears for abnormal cytology necessitate cervical biopsy.
inflammation but rather becomes clinically expressed as neoplasia. The histological change of cervical intraepithelial neoplasia (CIN)
For most patients who acquire HPV, the infection is latent or sub- is the precursor lesion for invasive cancer (Kahn 2009). CIN (formerly
clinical, and becomes a clinical illness only from symptoms attendant known as cervical dysplasia) is graded on the depth of cellular ab-
on local growth of a lesion. HPV infections have varying degrees of normality on the cervical biopsy. CIN-1 involves the lower third of
clinical consequences for the patient and are classified according to the cervical epithelial cells, CIN-2 involves the lower two-thirds, and
the anatomic site where infection occurs. The three major groupings CIN-3 involves the full thickness of the cervical epithelium. CIN-1
of HPV infection are anogenital, upper aerodigestive tract, and non- will spontaneously resolve in >90% of cases, whereas CIN-2/-3 is
genital cutaneous sites. associated with the development of invasive cervical cancer in most
cases. CIN-2/3 cases typically undergo conization or a loop electri-
■■Anogenital HPV cal excision procedure (LEEP). If invasive cancer is identified, then
oncological management of the uterus is pursued. Globally, nearly
Cervical carcinoma 500 000 women have the diagnosis of cervical carcinoma with deaths
Cervical carcinoma is the HPV-associated disease of greatest con- identified in half of them.
cern. Virtually 100% of cervical carcinoma cases are secondary to Enhanced understanding of the role of HPV in cervical carcinoma
HPV infection. Infection of the female genital tract is secondary to has led to the development of an effective vaccine (Harper et al. 2004,
sexual transmission of the virus. The HPV virus infects the squamous Villa et al. 2005). The recombinant vaccine has antibodies for types 6,
epithelium of the cervical canal. Population studies have identified 11, 16, and 18 (Gardasil or Silgard) or for types 16 and 18 alone (Cer-
that 35% of women have HPV virus with differing prevalence by age varix). Both vaccines are administered in three doses over 6 months.
(Figure 14.1) (Dunne et al. 2007). Infection with HPV occurs and then The immunization is recommended for females aged 9–26, and ideally
spontaneously resolves within 2 years among most women. About before first sexual exposure. Infection that is already established with
10% of women have long-term persistence of the sexually acquired types 16 and 18 does not benefit from immunization against these
infection and are at risk for the development of cervical carcinoma. HPV types. Clinical trials have demonstrated a reduction in CIN fre-
Infection may exist with more than one viral strain of HPV. Resolution quency, but a reduction in invasive cervical carcinoma has not been
of infection from one strain does not affect infection from a second documented. As 30% of CIN is caused by HPV types not covered by
strain. Reactivation of HPV infection from immunosuppression the vaccine, and the duration of protection has not been documented,
(e.g., HIV infection) or aging, but without interval sexual exposure, cervical cancer screening is still recommended.
indicates that these infections are not eradicated but rather become
latent within the host. Vulvovaginal carcinoma
HPV infections occur in up to 80% of women studied over a life- Vulvar and vaginal cancers are less common than cervical cancer, but
time. Persistence of the virus or transformation into invasive cervical share many clinical risk factors. In the USA, vulvovaginal squamous

Figure 14.1  Prevalence by age of human

papillomavirus in women.
162 VIRAL INFECTIONS OF SURGICAL SIGNIFICANCE

carcinoma occurs in only 1–2 /100 000 women. About 40% of vulvar penile squamous carcinoma is of interest because current evidence
cancers and 65% of vaginal cancers are secondary to HPV infection. suggests that these subclinical viral infections in men are as frequent
HPV type 16 is most commonly associated with vulvovaginal carci- as they are in women (Smith et al. 2011). HPV immunization of males
noma (Smith et al. 2009). for the prevention of penile carcinoma has not been validated because
Similar to cervical carcinoma, there are premalignant dysplastic of the very low incidence, but it is recommended for the prevention
lesions of vulvar intraepithelial neoplasia (VIN) and vaginal intraepi- of genital warts discussed subsequently.
thelial neoplasia (VAIN). They have similar grading systems of 1–3 with
similar histological criteria to cervical carcinoma. VIN-2/-3 lesions Anal carcinoma
have an 80% association with HPV and VAIN-2/-3 have over a 90% Squamous cell carcinoma of the anal canal has increased in frequency
association. A differentiated VIN variant is seen in older patients with in recent years. There are about 6000 cases per year in the USA. A
vulvar carcinoma that is not associated with HPV and is histologically total of 90% are attributable to HPV disease, and types 16 and 18 are
distinct. VIN and vulvar cancer appear to be increasing with increased identified in these HPV cancers (Parkin and Bray 2006). Risk factors
prevalence of HPV as the putative agent. include anal receptive intercourse, HIV disease, numbers of sexual
Vulvovaginal cancer and premalignant lesions present with partners, anogenital warts, and tobacco use. The diagnosis is by tissue
dyspareunia and pelvic discomfort. Many are asymptomatic and biopsy. Therapy is primarily chemoradiation. As a result of the high
identified with screening examinations. Biopsy confirms the diagno- frequency of type 16 and 18 HPV, prevention may accrue from the use
sis. Surgical excision of invasive cancer and premalignant VIN-2/-3 of the HPV vaccine.
or VAIN-2/-3 lesions has been the treatment. Vulvar cancer has a
better prognosis than vaginal carcinoma, likely because of earlier Genital warts
recognition. Benign anogenital warts (condylomata accuminata) are the most
Imiquimod (Aldara) as a 5% cream is an alternative treatment for common genital lesions attributable to HPV infection. These lesions
VIN-2/-3 lesions and has benefit when compared with a placebo (van can be only a few millimeters in size or very large. The lesions occur
Seters 2008). Additional clinical trials are needed with comparisons at sites of epithelial injury and are usually from an infected sexual
to surgical intervention. As HPV types 16 and 18 are the most com- partner. Lesions occur around the labia in women, on the penis and
mon strains associated with vulvovaginal squamous carcinoma, it is scrotum of men, and in the perianal areas of both sexes. HPV types 6
hoped that the quadrivalent vaccine may impact the frequency of the and 11 are the associated pathogens. Anogenital warts have the same
dysplastic and malignant lesions. risk factors as other HPV infections, but are especially troublesome
for HIV and immunosuppressed patients. The diagnosis is made by
Male genital carcinoma the identification of the typical skin lesion. Biopsy may be necessary
Penile squamous carcinoma is uncommon in the USA and western to eliminate the possibility of squamous carcinoma.
Europe where the incidence is about 1 case per 100 000 adult males The treatment of anogenital warts has many options. Lesions that
per year. About 50% of these carcinomas are associated with HPV DNA. are 1 cm in diameter are best treated with medical options (Table 14.5).
The HPV types identified in penile carcinoma are the same as those Somewhat larger lesions can be treated with liquid nitrogen or electro-
in female cervical carcinoma. Risk factors for penile carcinoma are cautery. Lesions with very board bases and considerable size (>3 cm)
early age sexual activity, multiple sexual partners, anogenital warts, commonly result in the patient being taken to the operating room for
and tobacco use (Giuliano et al. 2010). Circumcision is considered removal by excision or electrocauterization. All treatment options are
protective against penile cancer. The carcinoma begins as erosions employed to manage the symptomatic lesions and are not curative of
or sores on the distal penile skin. These cancers are diagnosed by the underlying HPV infection. Patients should be counseled that the
biopsy. Treatment is surgical excision. The association of HPV with condylomata may recur.

Table 14.5 None of medical therapies is proven safe for pregnant women.
Treatment Commentary
Imiquimod 5% cream Self-administered three times a week for up to 16 weeks. Treated area should be washed 6–10 h after
application. Treatment is immune enhancer and will have local inflammatory reactions
Podofilox 0.5% solution or gel Self-administered application twice a day for 3 days with 4 days off. Repeated for four cycles if necessary. Mild
pain and discomfort. Only for wart burden <10 cm2
Podophyllin resin 10–25% in tincture of benzoin Applied weekly by healthcare provider. Applied to only 10 cm2 per treatment episode. Air drying is necessary
at application to avoid contact with normal skin from clothing. Area of treatment should be washed 1–4 h
after application
Sinecatechin 15% ointment Self-administered green tea extract. Applied three times daily for up to 16 weeks. Local burning and pain. Not
recommended for immunosuppressed (e.g., HIV) patients
Trichoroacetic or bichloroacetic acid 80–90% Chemical coagulation of proteins. Applied by healthcare provider once a week. Must dry to avoid injury to
adjacent tissues. Pain and irritation
Cryotherapy Liquid nitrogen application by healthcare provider. Care must be taken to avoided injury to adjacent tissues.
Effective therapy will have pain. Repeat applications are commonly necessary
Surgical removal Surgical removal by excision or electrocautery is reserved for large burden of warts. Topical therapy may be
required for small residual lesions
From Centers for Disease Control and Prevention. Sexually transmitted diseases: treatment guidelines 2010, genital warts: www.cdc.gov/std/treatment/2010/genital-warts.htm.
 Human herpesviruses 163

The quadrivalent HPV vaccine does have efficacy for type 6 and 11 usually reflect different types of viruses from those identified with
viruses and is approved for use in females and males for the preven- anogenital lesions. The hand warts are associated with HPV types 1,
tion of anogenital warts (Liddon et al. 2010). Prospective randomized 3, 26, and 27, and plantar warts with types 2, 3, 4, 27, and 28.
administration of the vaccine in males aged 16–26 years resulted in The diagnosis of the cutaneous wart is ordinarily made by observing
significantly fewer HPV type 6, 11, 16, and 18 infections, and fewer the typical dry, raised, rough, and crusty lesion of the hands or plantar
anogenital warts (Giuliano et al. 2011). As condylomata are associated surface of the foot. Warts with an atypical or moist appearance may
with other types of HPV, all anogenital lesions will not be prevented. require biopsy. In most cases, the diagnosis is obvious.
Prevention of HPV type 16 and 18 infections in males has the epi- Treatment is necessary when the location (e.g., bottom of the
demiological advantage of potentially reducing the transmission of foot) causes discomfort or functional impairment. Multiple different
these strains to others. preparations of podophyllin resin are available. Podophyllin resin
gives a burning sensation at the site of application. Imiquimod as a
■■Aerodigestive tract HPV infection 5% cream application is effective, well tolerated locally, but very ex-
pensive. Topical salicylic acid, which is at a very high concentration
Of considerable interest to surgeons is the evolving role of HPV infec- in the compound used, has also been used effectively. Many other
tion in the genesis of head and neck squamous cancers. Traditional treatments have been advocated but are usually reserved for refrac-
associations have linked squamous carcinoma of the mouth, tongue, tory cases (Lipke 2006).
pharynx, and larynx to tobacco and alcohol use. Recently, patients Epidermodysplasia verruciformis (EV) is a rare genetic disorder
with head and neck cancers have been identified with reduced or no associated with cutaneous malignancy secondary to HPV infections.
tobacco use, and the results of treatment have been better than histori- These patients have flat, wart-like lesions with a predilection for de-
cal cases. These epidemiological observations led to the identification veloping HPV infection. HPV types 5, 8, and 14 have been associated
of HPV as the etiological agent, and that the type 16 strain associated with the transition of these lesions to invasive squamous carcinoma.
with squamous cancers in the anogenital region was the most common Surgical management of documented squamous cancer is the treat-
HPV identified. Most current squamous head and neck cancers are ment, but many topical agents are used in an attempt to control the
HPV-linked cancers and HPV head and neck cancer is projected to ex- constantly erupting EV skin lesions (Gewirtzman et al. 2008).
ceed cervical carcinoma in frequency by 2020 (Chaturvedi et al. 2011). Bowen disease is an in situ squamous carcinoma of the skin. It is an
Clinical associations with HPV head and neck cancer include mul- irregular, flat erythematous plaque. It is associated with HPV types 16,
tiple sexual partners, oral sexual contact, but less of a tobacco history 18, 31, 33, and 51, but is also linked to solar exposure, carcinogens, and
than has been traditionally noted for these squamous carcinomas. HIV immunosuppression in HIV infection. It can occur over any skin area.
patients are at increased risk for these cancers (Stelow et al. 2010). It is most often seen in women, but is seen in penile skin involvement
The cancers present as primary masses of the head and neck with the (erythroplasia of Queyrat). It is not seen in patients aged <30 years.
usual associated symptoms. The HPV-associated lesion will present Excision is the traditional treatment, but newer treatments include
with neck metastases that have a cystic character. HPV lesions are less photodynamic therapy, cryotherapy, and local chemotherapy (Cox
likely to be multifocal. The clinical management of these carcinomas et al. 2007). Imiquimod treatment is being evaluated.
remains surgical removal with traditional adjunctive measures. HPV
type 16 has been associated with esophageal cancer, although this link
to squamous cancer of the esophagus appears to be identified more in
■■HUMAN HERPESVIRUSES
Asia than in the USA or Europe (Eslick 2010). Although rates of HPV Human herpesviruses (HHVs) are double-stranded DNA viruses
have inconsistently been identified in lung cancers, type 16 virus may that are common human pathogens. Over 90% of adults have been
play a role in squamous carcinoma of the lung (Rezazadeh et al. 2009). infected with one or more of the eight classes of HHV (Fry 2001).
Respiratory papillomatosis is a recurring and difficult disease that They are ubiquitous and commonly transmitted by saliva, airborne
occurs in both children (age <5) and adult populations between ages droplets, or direct lesion contact. They are associated with clinical
20 and 30 (Chadra and James 2010). It consists of papilloma develop- infection in transplant recipients and immunosuppressed patients
ing in the larynx, trachea, and bronchi. It is seldom associated with (e.g., HIV infection). The HHVs have a role in oncogenesis. An im-
invasive cancer (<5%). In children the infection is the consequence portant feature of HHV infection is that the host harbors the virus for
of airway contamination with HPV at birth. It is poorly understood life after the acute infection and clinical events are the consequence
in adults and may relate to sexual practices. It is associated with HPV of remote infection.
types 6 and 11, but has been seen with other types. Clinical symp-
toms consist of hoarseness, stridor, and upper airway obstruction.
Laryngobronchoscopy establishes the diagnosis of usually numer-
■■HHV-1 (herpes simplex)
ous papillomas. The treatment has been endoscopic removal of the Herpes simplex infection is best known for the perioral “cold sore” and
lesions. Systemic antiviral therapies have been used (interferon-a, for acute viral conjunctivitis. The infection typically occurs in the oro-
indole 3-carbinol, cidofovir) and intralesional treatment with ci- pharynx, eyes, and face, and severe cases may extend into the central
dofovir is currently being explored. Photodynamic therapy is also nervous system (CNS). The infection is easily transmitted by contact
being evaluated. with an infected person even though that person may not have current
symptoms. Virus from the initial infection is chronically harbored in
■■Non-genital cutaneous the sensory ganglion cells (commonly the trigeminal ganglion) and is
not eradicated. The acute infection has a broad array of severity, only
HPV infection to be repeatedly reactivated in selected patients.
Cutaneous warts occur in many locations but most predictably on The acute infections clinically present with stomatitis and pharyn-
the digits and palms of the hands, and on the volar surface of the feet gitis of 3 days’ to 3 weeks’ duration. Vesicular perioral lesions proceed
(plantar wart). These are also the consequences of HPV infection, but to a crusted lesion that may persist for several weeks. Occasionally a
164 VIRAL INFECTIONS OF SURGICAL SIGNIFICANCE

herpetic whitlow may be seen after a puncture wound, and have been infection occurs approximately 2 weeks after exposure and the patients
reported with healthcare occupational needlesticks. Herpes gladi- are contagious for 7–10 days until the crusted lesions have separated.
atorum represents mucocutaneous herpetic lesions identified after The pruritic vesicular rash is occasionally the source of secondary
cutaneous skin trauma, with wrestlers being an index group for this streptococcal or staphylococcal infections. The infection can infre-
infection. Herpes simplex keratitis may lead to corneal damage and quently extend to pneumonia, encephalitis, myocarditis, and other
a chorioretinitis may evolve in immunosuppressed or HIV patients. unusual manifestations. In most cases it is a self-limited disease that
Similarly, immunosuppressed patients may develop viral encepha- requires only supportive care. As with all herpesviruses, the virus re-
litis, esophagitis, and pneumonia with herpes simplex. mains dormant in the dorsal root ganglia after acute clinical infection.
The diagnosis of herpes simplex infections is made by identifica- Herpes zoster generally occurs in the sixth decade of life or later. It
tion of the characteristic vesicular lesions of the skin. In adult patients is associated with any acute illness, immunocompromised patients,
the clinical diagnosis is usually confirmed by historical information HIV, or corticosteroid therapy. It can be a spontaneous clinical event
of prior perioral lesions. When a specific viral diagnosis is required without other associated clinical disease. It characteristically occurs
in serious cases, scrapings of the lesions for DNA detection, antigen unilaterally in a thoracic or lumbar dermatome. Pain in the dermato-
detection, or cell culture is used. PCR detection methods are most mal distribution is followed by a maculopapular rash 1–2 days later,
common. When visceral or CNS infections are suspected, then acute which is then succeeded by the vesicular rash. Occasionally zoster
and convalescent sera for antibody detection are employed. will occur in a cranial nerve distribution and is very painful. Ocular
Antiviral treatment of herpes simplex infection is used. Dosing and zoster is a rare but severe reactivation. The duration of pain with herpes
drug selection vary with the severity of the disease. Mucocutaneous zoster is variable and may extend well beyond resolution of the rash.
infection is managed with aciclovir (400 mg by mouth four times daily), Post-herpetic neuralgia can be a longstanding source of chronic pain.
famciclovir (500 mg by mouth three times daily), or valaciclovir (500 The diagnosis of varicella-zoster is made by the distinct clinical
mg by mouth twice daily) for a total of 7–10 days. Other sites of infec- presentation. Viral cultures, PCR detection of DNA, and other antigen
tion and recurrent infection have various other doses and durations, detection techniques can be used but are infrequently necessary. An
and are discussed elsewhere (Cernik et al. 2008). effective vaccine has dramatically reduced the frequency of acute
chickenpox in western societies and is expected to reduce the fre-
■■HHV-2 (genital herpes) quency of herpes zoster.
Clinical chickenpox in children is managed with supportive care.
Genital herpes occurs from HHV-2 which is distinctly different from Adolescents and adults are commonly treated for 5–7 days with aciclo-
HHV-1, even though the two viruses share a 50% genetic homology vir, famciclovir, or valaciclovir to reduce the duration of the rash. For
and have common clinical features (Gupta et al. 2007). Transmission herpes zoster, the use of valaciclovir is more effective at relieving pain
occurs from sexual contact. The virus is harbored in sensory nerves and resolving the rash. Immunization of children with the varicella-
similar to other herpesvirus types. The infected partner may or may zoster vaccine is recommended with one dose at about 1 year of age,
not have evidence of clinical disease because shedding of the virus and a second at age 4–6. Immunization of individuals age >60 years
may be a chronic process. Primary infection may have symptoms of is recommended to prevent the frequency and the severity of zoster.
an acute viral infection but also be associated with sacral pain. Acute
infections may be subclinical, with clinical disease not being expressed HHV-4 (EBV)
until much later. Reactivation occurs with stressor events and may Epstein–Barr virus (EBV) is most frequently associated with mono-
recur for no explainable reason. High rates of reactivation are seen in nucleosis (Oludare et al. 2011). It is also associated with Burkitt
immunocompromised patients. Over 25% of adults are seropositive lymphoma, nasopharyngeal carcinoma, some gastric lymphomas,
for HHV-2. Vertical transmission to neonates with the birthing process and other lymphoproliferative diseases. EBV is transmitted by hu-
is a particular problem with infected mothers. man saliva as the common source of infection. Blood transfusion
The preliminary diagnosis of genital herpes is usually made by and organ transplantation are other causes. Targeted host cells
recognition of the typical vesicular rash of the perineum. The infection include lymphocytes and endothelial cells, with the site of original
needs to be documented because of the common appearance of these transmission occurring in tonsillar tissues. The proliferation of EBV
genital lesions with other infections. A swab specimen is submitted for leads to clinical infection at 5–7 weeks later in most cases. Others
viral culture, antigen detection, or PCR to detect viral DNA. Aciclovir, have a mild or subclinical infection. The patient carries the virus for
famciclovir, and valaciclovir are the antiviral agents chosen. The dos- life within B cells.
ing and duration of treatment are dependent on whether the current The acute mononucleosis syndrome is characterized by mal-
episode is the first episode, a recurrent episode, or a sustained episode aise, fever, fatigue, sore throat, cervical lymphadenopathy, and
requiring suppressive therapy, and whether the patient is immuno- splenomegaly. Hepatic enzyme abnormalities are usually present.
suppressed (Gupta et al. 2007). Vaccines to prevent this infection are Symptoms last for more than 2 weeks. Recovery from fatigue takes
under investigation but have not been validated as beneficial. a longer course. Protracted chronic EBV infection lasting for more
than 6 months is also seen after acute infections. Complications of
■■HHV-3 (varicella-zoster) acute EBV infection may include pancreatitis, parotitis, pericarditis,
pneumonia, and rarely splenic rupture.
HHV-3 causes the infections of varicella (chickenpox) and herpes The diagnosis of acute EBV mononucleosis is made by the hetero-
zoster (shingles). Varicella is the acute infection and herpes zoster phile antibody test. Elevations of AST, ALT, and bilirubin reflect the
is the recurrent infection decades later (Heininger and Seward 2006, hepatitis syndrome that accompanies mononucleosis. In situ hybrid-
Dworkin et al. 2007). The acute infection is acquired from airborne ization and PCR can be used to detect RNA transcripts and DNA of
virus that adheres to the mucosa of the upper respiratory tract, pro- EBV. These viral detection methods are used in transplant recipients
liferates and spreads to regional lymph nodes. The systemic infection and HIV patients with immunosuppression. Aciclovir, ganciclovir,
results in the erythematous vesicular rash known as chickenpox. The and valaciclovir are used for the treatment of established infection.
 Polyoma viruses 165

Oncogenesis from EBV remains an incompletely understood phe- becomes latent and is present for life. Reactivation disease is identi-
nomenon (Grunhe et al. 2009). B-cell lymphoma may be an event after fied in transplant recipients and HIV-infected patients. There are two
acute infection such as Burkitt lymphoma in children, or it may occur variants: HHV-6A and HHV-6B. HHV-6 replicates within the salivary
many years later with immunosuppression such as seen in transplan- gland and saliva is the likely source of transmission. The T lymphocyte
tation or HIV patients. Immunosuppression may lead to an often fatal is the primary target cell and repository of latent virus.
post-transplant lymphoproliferative disorder that is characterized by Primary HHV-6 infection in infants is better known as roseola. It
B-cell and plasma cell hyperplasia, and then the development of lym- is a febrile viral illness that is self-limited in most cases. Its primary
phoma. The successful treatment of this lymphoproliferative disorder source of concern in adults is reactivation disease, in particular among
is to reverse the immunosuppression regimen. transplant recipients (Kumar 2010). Reactivation disease is charac-
Treatment of EBV-associated lymphoma is a combination of che- terized by fever and rash, a hepatitis syndrome, especially if HCV is
motherapy regimens. The monoclonal antibody to CD20 (rituximab) present, myelosuppression, pneumonitis, neurological illness, and an
of the B cell may be added to the chemotherapeutic regimen (Aldoss et increased rate of graft rejection. Ganciclovir, foscarnet, and cidofovir
al. 2008). After tissue diagnosis and staging, localized nasopharyngeal have been proposed as antiviral treatments.
cancer is treated with radiation, whereas locally advanced disease and
cervical metastatic adenopathy are managed with additional chemo-
therapy. Other monoclonal antibodies are being explored.
■■HHV-7
As 90% of patients have latent EBV, prevention of reactivation of HHV-7 is understood the least of any herpesviruses. The primary
the disease is of significance in transplantation recipients. Use of the infection is during childhood and is similar to that of HHV-6. The
aciclovir derivatives covers both EBV and cytomegalovirus infection. lymphocyte is the target cell population but its presence in saliva is
Development of an EBV vaccine to prevent reactivation in transplant established and plays a role in transmission. It remains latent after
recipients and other patient populations with severe immunosup- acute infection within lymphocytes. Definition of the frequency of
pression is being pursued. reactivation disease remains unclear. Transplantation recipients are
considered a population of patients at risk for this reactivation infec-
■■HHV-5 (cytomegalovirus) tion (Shiley and Blumberg 2010). Ganciclovir and foscarnet are the
accepted antiviral treatments.
Cytomegalovirus (CMV) is an infection of relevance in the care of
transplantation and increasingly among critically ill patients with im-
munosuppression (Cook and Trgovcich 2011). CMV is present in over
■■HHV-8
50% of patients from prior clinical infection which results in latency HHV-8 is the virus of Kaposi sarcoma (KS). Transmission is from saliva,
within the salivary glands and other tissues. CMV infection is transmit- but has been documented to be transmitted via blood transfusion and
ted in the birthing process and in breast milk. It is transmitted in saliva, organ transplantation. Serological studies indicate that as many as 25%
by sexual contact, blood products, and transplanted organs. The acute of patients may be positive for this virus. It is latent after acute infection
infection may be analogous to mononucleosis, but for many patients in endothelial cells. HHV-8 is also associated with Castleman disease
the acute infection is subclinical. Severe acute or reactivation disease as an uncommon lymphoproliferative disease. Immunosuppression,
may result in clinical hepatitis, retinitis, encephalitis, pneumonitis, and commonly from HIV disease, is the clinical cofactor that results in KS,
myocarditis. Reactivation disease is associated with gastrointestinal although KS can be seen in transplant recipients and cancer chemo-
hemorrhage or perforation in transplant recipients and HIV patients. therapy patients. The association between KS and HHV-8 is so strong
The clinical diagnosis is difficult because of the absence of char- that viral identification is unnecessary.
acteristic findings. Fever, leukopenia, and hepatosplenomegaly may The treatment of HHV-8 and KS is to control the commonly un-
be present. Reactivation disease in transplantation recipients may derlying HIV disease. Highly active antiretroviral therapy will cause
have clinical features of the systemic inflammatory response syn- regression of the skin lesions but may not affect complete resolution.
drome from any other cause, and requires an index of suspicion. Viral KS is not cured and recurs over time. Interferon-a, rapamicin, inter-
isolation, antigen detection, and PCR identification of DNA are the leukin-12, thalidomide, lenalidomide, cytotoxic agents, and others
usual methods employed. Serological assays have been problematic have been explored for KS (Uldrick and Whitby 2011).
because increases in antibodies may not occur for up to 4 weeks after
the onset of symptoms and antibody titers may remain high from a
prior reactivation.
■■POLYOMA VIRUSES
Prevention of new infection or reactivation of pre-existent CMV The polyoma viruses are double-stranded DNA viruses that are as-
has been an area of interest in transplant recipients. Knowledge of the sociated with experimental neoplasia. The five different polyoma
patient’s status with respect to prior CMV infection is important. Blood viruses that are associated with human disease are identified in
products and transplanted organs from CMV-positive donors into Table 14.6. The BK and JC viruses are most recognized with human
naïve recipients require preventive antiviral therapy for 3–6 months infection (Jiang et al. 2009, Raghavender and Brennan 2010). These
after transplantation. Ganciclovir, valaciclovir, and valganciclovir are two viruses share 75% homology in their respective genomes. The
used to prevent transmission or reactivation events (De Keyzer et al. BK polyoma virus is recognized as a significant pathogen in im-
2011). Ganciclovir and valganciclovir are used for the treatment of munosuppressed transplant recipients. The JC virus is associated
clinical CMV infection. with progressive multifocal leukoencephalopathy (PML). The other
three polyoma viruses (Table 14.6) have been cultured from the
■■HHV-6 human respiratory tract (KI and WU viruses) or from Merkel cell
carcinoma. The role of these latter three viruses in causing infection
HHV-6 clinically infects 95% of people within 2 years of birth (Abdel or neoplasia has not been defined. This discussion focuses on the
Massih and Razonable 2009). Similar to other herpesviruses, it then BK and JC viruses.
166 VIRAL INFECTIONS OF SURGICAL SIGNIFICANCE

Table 14.6 Details for five types of known polyoma viruses and their potential role in human infection.
Polyoma virus type Cellular target Clinical commentary
BK virus Renal and urinary tract epithelium BK polyoma virus nephropathy is associated with over-immunosuppression in renal transplant
recipients, and loss of 50% of kidney grafts when clinical infection occurs
JC virus Lymphocytes, oligodendrocytes, JC polyoma viruses are associated with progressive multifocal leukoencephalopathy seen in
renal epithelium immunosuppressed HIV patients and transplant recipients
KI virus Respiratory epithelium Recovered from the respiratory tract, but of uncertain pathological significance
WU virus Respiratory epithelium Recovered from the respiratory tract, but of uncertain pathological significance
Merkel cell virus Skin Associated with Merkel cell cancer, but has an uncertain role in the causation of the tumor

Current evidence indicates that polyoma virus infection occurs almost 100% sensitivity but only a 20% specificity for detecting active
in childhood, and remains as a chronic but inactive virus in the host. infection. The decoy cells represent sloughed renal tubular epithelial
Routes of transmission remain unclear and may be the result of fe- cells which have viral inclusions. DNA PCR in blood or urine and
cal–oral, airborne, transplacental, or other physical contract with mRNA PCR in urine have higher specificities in the diagnosis.
individuals shedding the virus. Seroprevalence of either JC or BK virus The treatment of BK polyoma nephropathy is to reduce the pa-
is identified in up to 80% of adults, and nearly 20% of individuals will tient’s level of immunosuppression. The obvious risk is to reduce
shed the virus in their urine. The JC virus is more prevalent than the immunosuppression without triggering graft rejection. Reduction or
BK virus. During latency after childhood infection, the JC virus resides elimination of mycophenolate has been one strategy that is employed
within the lymphoid, neural, and renal tissues. The BK virus resides but no standard for reduction in immunosuppression has been estab-
within the epithelial cells of the collecting system of the urinary tract. lished. Early reductions in immunosuppression based on evidence
Primary infection occurs when the polyoma virus binds to mem- from screening the patient yields better results than waiting until
brane receptor sites at the target cell population. Primary infection is nephropathy occurs. Current evidence does not support the use of
thought to be asymptomatic or a mild respiratory infection. The virus is cidofovir or leflunomide to treat BK nephropathy (Johnston et al. 2010).
internalized by endocytosis. Cytoplasmic trafficking results in the virus
residing within the nucleus. It remains in this latent state until immu-
nosuppression leads to reactivation. New virions are produced at this
■■JC polyoma infection
point with resultant lysis of the host cell and release of new particles. PML is a demyelinating disease of the white matter of the brain. Similar
to BK nephropathy, it is seen in patients with severe immunosuppres-
■■BK polyoma infection sion and is most commonly seen in advanced HIV infection. It is also
seen in transplant recipients and in patients receiving monoclonal
Reactivation infection with BK polyoma virus appears as a nephropa- antibody treatment for autoimmune diseases (Tan and Koralnik 2010).
thy, hemorrhagic cystitis, pneumonia, retinitis, hepatic dysfunction, B lymphocytes carry the virus to the CNS with the resultant damage to
or meningoencephalitis. BK nephropathy occurs with profound im- glial cells. Clinical symptoms include mental status changes, ataxia,
munosuppression in transplant recipients, or in those with advanced paresis, and other focal neurological deficits. Asymmetrical brain
HIV infection. Although an association in transplant recipients has lesions are identified by imaging. Toxoplasmosis and lymphoma are
been made with specific immunosuppression agents, it is the degree differential diagnoses. Identification of viral DNA by PCR of the spinal
of immunosuppression and not the agent that is identified with BK fluid may be negative in 20% of PML cases, and will require brain
polyoma nephropathy. biopsy to establish the diagnosis. The treatment of PML in HIV infec-
BK nephropathy occurs in the transplanted kidney, and is highly tion is enhanced antiretroviral therapy to achieve better control of the
unusual in the native kidney of patients who have received non-renal infection. In transplant recipients and other patients on immunosup-
solid organ transplants. The specificity of the transplanted kidney for pressive therapy, reduction or cessation of immunosuppression may
this reactivated infection suggests that the virus may actually be within be necessary. Antiviral chemotherapy against the JC virus has not been
the renal epithelium of the donor kidney and not the recipient. The successful. The prognosis for the PML patient is poor, with survival
disease starts as an interstitial nephritis, is detected about 1 year after being only a few months, although longer survivals are achieved in
transplantation, and results in loss of kidney grafts in 50% of cases HIV patients with successful antiretroviral treatment. Newer clinical
depending on the severity of the infection. syndromes associated with JC virus include granule cell neuropathy
The diagnosis of BK nephropathy is by biopsy of the transplanted of the cerebellum, JC virus encephalopathy, and JC viral meningitis.
kidney, because rejection of the kidney from other causes is clinically
similar. Typical histological changes are observed in the biopsy and
specific immunohistochemistry antibodies confirm the diagnosis. As a
■■Rabies
result of lack of homogeneity in tissue changes, two biopsy specimens Once a common disease among homeothermic animals and humans,
are performed. Urine screening demonstrates the presence of the BK rabies is an uncommon disease in the USA and western Europe be-
virus at 3–6 months after kidney transplantation. The JC virus is identified cause of effective immunization of animal populations at risk (e.g.,
within 5 days but not associated with clinical disease (Saundh et al. 2010). dogs) and effective post-exposure prophylaxis in humans. Rabies is
As clinical reactivation of disease is recognized only with intersti- caused by the single-stranded RNA lyssavirus. However, over 50 000
tial nephritis or failure of the kidney graft, methods for screening the deaths occur worldwide per year, with dogs the most likely source of
patients to detect early viral activation is important in kidney trans- the human infection. Bats, skunks, and raccoons account for rabies
plant recipients during the first 2 years (Hirsch et al. 2005). Detection transmission to humans in the USA, where the annual incidence of
of “decoy” cells in the urine of the kidney transplant recipient has an human infection is only about 1/100 million people (CDC 2009).
 References 167

Human transmission typically follows a soft-tissue bite from an rabies immunoglobulin (20  units/kg) from hyperimmune human
infected animal. Human-to-human transmission can occur from bites donors is infiltrated as much as possible around the soft injury,
from infected patients. A total of 16 cases of fatal rabies have occurred with the remainder given intramuscularly at a site remote from the
after corneal, solid organ, and vascular tissue transplantation from exposure site. The administration of the immunoglobulin is not
infected donors (Manning et al. 2008). Virus from the soft-tissue ex- recommended more than 7 days after exposure. The first dose of the
posure enters into peripheral nerves, and then migrates into the CNS vaccine is given at the time of exposure with four additional doses
where the encephalitis and viral syndrome of the infection evolve. Ex- given on days 3, 7, 14, and 28 after exposure. Current vaccines have
posure to clinical disease commonly requires 2 weeks to 2 months, but replaced the well-chronicled and painful abdominal injections of
longer intervals for infection are seen. Proliferation of the virus within early generations of rabies vaccines.
the CNS leads to the clinical syndrome of confusion, agitation, and The diagnosis of rabies is established from viral cultures or PCR of
hallucinations, and other evidence of cerebral dysfunction. Increased infected brain tissues or body fluids. Skin, cerebrospinal fluid, saliva,
salivation and lacrimation are associated with high concentrations and urine may yield the identification of the virus. The index animal
of the virus. Muscle paralysis leads to ineffective swallowing and the may be a source to confirm that rabies is present. Light microscopic
association of hydrophobia with this infection. methods have been employed to establish the diagnosis in areas
Prevention of infection begins with local wound management. without access to high-tech methods.
Non-viable tissue is debrided and local irrigation with isopropyl Clinical rabies has traditionally been viewed as uniformly fatal.
alcohol or povidone–iodine is used. Irrigation with viricidal solu- Antiviral chemotherapy has not been considered of any benefit
tions is not scientifically validated as preventing infections but is although it has been used. Survivors of rabies have been identified
intuitive and may also avoid other animal bite-associated infections. in the last decade with the so-called “Milwaukee” protocol where
Post-exposure prophylaxis (PEP) is effective and is employed after patients have been treated with a pharmacologically induced coma
exposure events where rabies is suspected (Manning et al. 2008). The and drug therapy of ketamine, midazolam, ribavirin, and amantadine
original vaccine by Pasteur and Roux was attenuated virus derived (Willoughby 2007). Prolonged ventilator supportive care is necessary.
from rabbit tissue. Vaccines in recent years have been derived from Survival with this protocol has been about 8%. Survivors do not appear
human diploid and purified chick embryo cell cultures after viral to have significant neurological sequelae. Survival remains unlikely,
deactivation. PEP is initiated within 10 days of exposure. Human and PEP remains the needed strategy to prevent this infection.

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Chapter 15 Cardiothoracic surgical
infections
Jorge A. Wernly, Charles A. Dietl, Jess D. Schwartz

■■THORACIC EMPYEMA include tumor necrosis factor-a, myeloperoxidase, matrix metallo-

protease-2, neutrophil elastase, interleukin-8, lipopolysaccharide-
■■Definition binding protein, and other biomarkers (Porcel 2010). Bacteriological
and chemical analysis of the pleural fluid is necessary to categorize
An empyema is a collection of pus within the pleural cavity. Empyemas parapneumonic effusions and to identify which require drainage for
follow bacterial contamination of the pleural space. The most common optimal outcomes (Colice et al. 2000).
source of pleural infection is a pneumonic process. Approximately Ultrasonography is the preferred method for guiding thoracocen-
40% of all patients with pneumonia develop a parapneumonic pleural tesis because of loculation of the effusion, and better definition of the
effusion (PPE) but only a small percentage result in a “complicated” diaphragm than with a chest radiograph. Furthermore, ultrasonogra-
empyema (Koegelenberg et al. 2008). Empyemas may also result from phy is extremely helpful for accurate placement of a pigtail catheter
lung abscesses, postoperative contamination, trauma, or extension of drainage or tube thoracostomy. The routine use of ultrasound-guided
an abscess from below the diaphragm. aspiration and drainage should be encouraged, because of patient
Thoracic empyemas have three phases of development: The acute safety and better sampling of the pleural effusion. It also provides
or exudative stage, the transitional or fibrinopurulent stage, and the additional diagnostic and prognostic information, and more effective
chronic or organizing stage. The acute stage is characterized by ac- pleural drainage (Lee et al. 2010).
cumulation of pleural fluid secondary to a contiguous pulmonary Computed tomography (CT) may be helpful to differentiate empy-
infection. If not treated appropriately it may evolve into the fibrino- emas from lung abscesses, and to evaluate effectiveness of a drainage
purulent stage, characterized by bacterial invasion, increased white procedure. A contrast-enhanced CT scan may demonstrate multilocu-
blood cells, and fibrin deposition. The organizing stage occurs when lated effusions, as well as a thick pleural peel or an entrapped lung.
fibroblasts and capillaries grow into a thick, firm fibrin layer known Fluid collections in the fissures or those located in the paramediastinal
as pleural peel. or paravertebral regions may be detected only by CT scan (Heffner et
al. 2010). CT also allows more accurate identification of life-threaten-
■■Clinical presentation and diagnosis ing complications after pulmonary resection, such as empyema and
bronchopleural fistulas that require prompt management. Magnetic
Patients usually present with fever, malaise, pleuritic chest pain, and resonance imaging (MRI) and positron emission tomography (PET)
dyspnea. The diagnosis of empyema must be suspected in patients have limited use in pleural space infections (Heffner et al. 2010).
who describe these symptoms after bronchopneumonia, or a recent
surgical procedure involving the lungs, esophagus, or mediastinum,
recent chest trauma, or an intra-abdominal operation.
■■Pathogenesis and bacteriology
On examination patients usually appear ill and debilitated. Some Fluid in the pleural space predisposes to secondary bacterial contami-
are tachypneic and hypoxic, and present with respiratory distress or nation. Empyema may occur when bacteria in high concentrations
generalized sepsis. Breath sounds are typically decreased on the side access the sterile pleural space. The most common source of pleural
of the empyema. The chest radiograph is characterized by a large infection is a pneumonic process. Bacterial contamination of pleural
pleural effusion, which raises the index of suspicion of empyema. effusions or hemothorax may also follow blunt or penetrating chest
Lateral decubitus films are useful to determine if the pleural effusion trauma. Not infrequently, empyemas follow postoperative pleural
is free flowing or loculated. effusions. This complication is usually secondary to bronchopleural
The diagnosis of empyema should be established by thoracocen- fistulas after lung resection, and anastomotic leaks after esophagec-
tesis and sampling the pleural fluid, which is usually cloudy and foul tomy. Traumatic, iatrogenic, or spontaneous perforations of the tho-
smelling. Gram stain with culture and sensitivity testing is the most racic esophagus may result in empyema and fulminant sepsis which
important initial laboratory test for the diagnosis. However, the pres- are lethal if not managed promptly.
ence of a thin serous fluid or a negative Gram stain does not exclude Bacteriological assessment of pleural fluid is inconsistent.
infection of the pleural space. The pleural fluid should also be analyzed Falguera et al. (2011) observed successful cultures in only 60% of
for neutrophil count, pH, glucose level, and lactate dehydrogenase patients with an uncomplicated PPE and 72% of complicated PPE.
(LDH). If the pleural fluid contains neutrophils (>15 000/mm3), and Streptococcus pneumoniae was the most frequently pathogen identi-
has a low pH (<7.20), low glucose level (<60  mg/dl), or high LDH fied in 36% of uncomplicated PPEs and 48% of complicated PPEs.
(>1000 IU/l), there is strong evidence of pleural infection (Koegelen- Other Gram-positive cocci, (Staphylococcus aureus and Streptococcus
berg et al. 2008). Pleural fluid pH is the preferred study because it viridians), Gram-negative bacilli (Haemophilus influenzae, Pseudo-
has the highest diagnostic accuracy, and requires only a blood gas monas aeruginosa and Klebsiella spp.), and anaerobes (Bacteroides
analyzer. Alternative diagnostic tests for detecting nonpurulent PPE and Fusobacterium spp.) were also identified in complicated PPEs.
170 CARDIOTHORACIC SURGICAL INFECTIONS

Polymicrobial infections were more common in complicated PPEs adequate fluid resuscitation and hemodynamic support including
(Falguera et al. 2011). sepsis management protocols.
The rate of parapneumonic empyemas requiring hospitalization
in the USA from 1996 through 2008 has increased 1.8-fold in adults
(Grijalva et al. 2011). The main reason for this increase was due to a
■■Antibiotic treatment
3.3-fold increase in the rate of staphylococcal empyema. The mean The recommended guidelines of the American College of Chest Physi-
length of hospitalizations was longer for staphylococcal empyema cians for the treatment of parapneumonic effusions are evidenced-
than for other pathogens. The increase in staphylococcal empyema based methods. The initial step is to recognize risk for poor outcome,
may also be responsible for the increased rate of fatal parapneumonic and to identify which patients should undergo a drainage procedure
empyema hospitalizations observed. (see Table 15.1) (Colice et al. 2000). Regardless of the categorizing
Isolation of Candida spp. in patients with empyema is extremely risk, empirical antibiotic therapy should be dictated by the under-
rare, and may be an important clue for suspecting gastrointestinal lying pneumonic process, and modified based on culture results.
tract perforation (Ishiguro et al. 2010). (Koegelenberg et al. 2008).
Whenever possible, empirical antibiotics should be based on the
■■Prevention Gram stain and adjusted for culture/sensitivity results. Gram-positive
bacteria are usually susceptible to a combination of b-lactam/b-
Patients with a small-to-moderate free-flowing pleural effusion, nega- lactamase inhibitors such as intravenous amoxicillin with clavulanic
tive cultures, and a normal pleural fluid (with pH >7.2) are at lowest acid, whereas carbapenem provides excellent coverage for both Gram-
risk of poor outcome, and do not require drainage of the pleural ef- negative and Gram-positive bacteria.
fusion. It will resolve after effective antibiotic therapy of the underly- A combination of intravenous cefuroxime and metronidazole is
ing pneumonia (Table 15.1). Conversely, patients with frank pus on usually recommended for the 30% of cases of community-acquired
aspirate, loculated or large free-flowing pleural effusion, those with culture-negative pleural infections. Hospital-acquired but culture-
positive cultures or Gram stains, or an abnormal pleural fluid (with negative infections require broader-spectrum antibiotic coverage
pH <7.2) are at high risk of poor outcome, and will require effective with intravenous piperacillin and tazobactam (Davies et al. 2003). Ad-
drainage of the pleural effusion, in addition to antibiotics and sup- ditional empirical anaerobic antibiotic coverage with metronidazole
portive measures (Table 15.1) (Colice et al. 2000). is generally advisable because anaerobic organisms are difficult to
Postoperative pleural space infections are the second most com- culture (Chapman and Davies 2004). Aminoglycosides are not recom-
mon cause of empyema. The appropriate preoperative administration mended because of poor pleural penetration. Treatment with vanco-
of prophylactic antibiotics is effective in prevention and cannot be mycin or linezolid is indicated for meticillin-resistant Staphylococcus
overemphasized. However, bacterial contamination of pleural fluid aureus (MRSA) infections. For patients who are allergic to penicillin
after thoracotomy is usually related to bronchopleural fistulas or and cephalosporins, a combination of ciprofloxacin and clindamycin
esophageal anastomotic leaks. Technical prevention of these serious is usually effective. Little evidence supports the duration of antibiotic
postoperative complications is essential. The use of a pedicled inter- treatment. Most clinicians would agree that 3 weeks of intravenous
costal muscle flap to buttress the bronchial stump and the esophago- antibiotics is appropriate, provided that there is adequate drainage
gastric anastomosis may reduce the risk of bronchopleural fistulas after of the pleural fluid (Davies et al. 2003). Similar recommendations are
pulmonary resection and the risk of intrathoracic anastomotic leaks made for postoperative and post-traumatic infections.
after esophagectomy (Cerfolio et al. 2005). Prevention also includes
drainage of retained blood or clots in post-traumatic hemothorax with
a thoracostomy tube or thoracoscopy.
■■Drainage procedures
Thoracocentesis should be used only for diagnosis. Effective drainage
■■Supportive measures should be accomplished with a tube thoracostomy (24 or 28 French
[Fr]) or pigtail catheters (10–14 Fr) inserted under ultrasonic or CT
Patients with empyema are usually catabolic and immunodeficient. guidance (Koegelenberg et al. 2008). The infected pleural space should
Hypoalbuminemia is associated with poor outcome. For this rea- be promptly and effectively drained after diagnosis of a complicated
son, adequate nutritional support should be provided as soon as PPE or empyema (risk category 3 or 4; see Table 15.1). Correct posi-
the diagnosis of empyema is established. Enteral feeding is often tioning of the chest tube or catheter is assured with imaging rather
desirable. Other supportive measures include respiratory care and than blind insertion without radiological guidance, irrespective of
management of associated comorbidities (e.g., diabetes). Patients the drain size (Koegelenberg et al. 2008).
who present with hypoxia and respiratory distress require intuba- There is no consensus on the optimal size of the chest drainage
tion and ventilator support, and those who appear toxic will need tube. A large multicenter prospective study on chest tube size found

Table 15.1 Risk categorization for poor outcome in patients with parapneumonic pleural effusions.
Risk category Radiographic appearance of pleural Bacteriology Chemical analysis Risk of poor Drainage procedure
effusion outcome
1 Minimal free-flowing effusion Unknown pH unknown Very low Not indicated
2 Small-to-moderate free-flowing effusion Negative Gram stain and culture pH >7.2 Low Not indicated
3 Large free-flowing or loculated effusion Positive Gram stain or culture pH <7.2 Moderate Yes
4 Large free-flowing or loculated effusion Frank pus pH <7.0 High Yes
 Thoracic empyema 171

no difference in outcomes between small catheters (<14-Fr gauge) of empyema with lung re-expansion, no sepsis, and no additional
and large bore (>20-Fr gauge) chest tubes (Rahman et al. 2010). In procedures (Wozniak et al. 2009).
addition to providing adequate drainage, the small catheters (12 The only randomized controlled trial comparing VATS with in-
or 14 Fr) are more comfortable and easier to insert (Chapman and trapleural streptokinase showed that VATS was more effective than
Davies 2004). To ensure patency, most clinicians recommend regular fibrinolytics (Wait et al. 1997). Also, a historically controlled series
flushing with 30 ml of saline every 6 h, in addition to connection to showed VATS with the same success as open thoracotomy (Mackinlay
suction (-20 cmH2O). et al. 1996). However, the total patients in these studies were too few
According to evidence-based guidelines of the American College of to support any conclusion.
Chest Physicians the use of drainage procedures alone for complicated Although no significant difference in mortality was observed
PPE is associated with higher mortality when compared to treatment between surgical (10%) versus nonsurgical (16%) management of
plans that include fibrinolytic or surgical approaches (Colice et al. empyema in a retrospective review (Anstadt et al. 2003), deaths from
2000). Patients with PPE who have persistent sepsis or ineffective several randomized controlled trials was significantly lower with open
chest tube drainage should be considered for intrapleural fibrinolytic thoracotomy (1.9%), VATS (4.8%), or fibrinolytic therapy (4.3%) when
therapy or surgical treatment. compared with drainage procedures alone (8.8%) (Colice et al. 2000).
Based on expert opinion, patients should be referred to surgical treat-
■■Intrapleural fibrinolytic therapy ment (VATS or open thoracotomy) for ineffective chest tube drainage
or persistent sepsis (Davies et al. 2003).
Fibrinolytic agents in the pleural cavity can lyse the fibrinous septa- Thoracoscopic debridement may be considered for incompletely
tions within the infection, improve drainage, and are not associated drained or loculated PPE, if performed during the fibrinopurulent
with systemic fibrinolysis or bleeding complications (Koegelenberg stage (Koegelenberg et al. 2008). The objectives of VATS are to evacu-
et al. 2008). In a randomized double-blind study, intrapleural strep- ate purulent collections, disrupt loculations, and remove fibrinous
tokinase (250 000 IU in 100 ml 0.9% saline) and urokinase (100 000 IU deposits to permit lung re-expansion. However, when empyema is in
in 100 ml 0.9% saline) introduced through the chest tube over 6 days the organizing phase, VATS debridement is ineffective to remove the
are equally effective, and both agents reduced the need for surgical visceral peel encasing the lung (Lardinois et al. 2005).
treatment (Bouros et al. 1997). In another study, surgical intervention Open thoracotomy may be indicated at several stages of compli-
was significantly reduced to 13% for the streptokinase group compared cated PPE or empyema (Koegelenberg et al. 2008). During the acute
with 45% for control participants (Diacon et al. 2004). or exudative phase, the main indication for open surgical drainage is
However, a controversial article from the First Multicenter Intra- persistent sepsis from residual pleural fluid collections, despite drain-
pleural Sepsis Trial (MIST-1) showed that intrapleural streptokinase age and antibiotics (Davies et al. 2003). Open thoracotomy should be
did not improve mortality, the rate of surgery, or the length of hospital used liberally for decortication during the chronic or organizing stage
stay (Maskell et al. 2005). A possible explanation for the negative re- (>2 weeks) and for Gram-negative organisms (Lardinois et al. 2005).
sults is that chest tubes were usually inserted without guidance, and Decortication is a major surgical procedure that consists of resecting
fibrinolytic therapy was initiated 8–28 days (median 14 days) after all the fibrous layers causing entrapment to effect lung re-expansion
onset of symptoms. However, a more recent randomized study showed (Koegelenberg et al. 2008). Most patients who undergo decortication
that intrapleural fibrinolytics decrease the rate of surgical interven- can be discharged in 1 or 2 weeks without chest tubes. The reported
tions and the hospital stay, if used early in the fibrinopurulent stage mortality rate of open decortication ranges from 2% to 10% (Colice et
(Misthos et al. 2005). al. 2000, Anstadt et al. 2003).
Improved results have recently been observed in the MIST-2 trial However, in elderly debilitated and immunocompromised pa-
(Rahman et al. 2011) using combined intrapleural tissue plasminogen tients, open decortication is associated with significant morbidity and
activator (tPA) and deoxyribonuclease (DNAase). The DNAase reduces mortality. An open thoracic window is a safer alternative to provide
viscosity in purulent exudates (Maskell et al. 2005). It is necessary to adequate drainage in poor-risk patients. This procedure should be
liquefy the deoxyribose nucleoproteins in the solid sediment of pus delayed until the lung surface is adhered to the parietal pleura to
(Koegelenberg et al. 2008). The MIST-2 trial showed that the combi- avoid pneumothorax. The open thoracic window, or modified Eloesser
nation of tPA and DNAase significantly reduced surgical referral and flap, is usually performed under general anesthesia and consists of
hospital stay, whereas surgical referral was not significantly reduced in resecting portions of two or three ribs, and creating an inverted U-
patients treated with either tPA or DNAase alone (Rahman et al. 2011). shaped flap of skin and subcutaneous tissue to marsupialize the most
In the MIST-1 trial (Maskell et al. 2005) 16% of patients died and dependent portion of the empyema cavity (Thourani et al. 2003). The
16% needed surgery at 3 months in the streptokinase group. However, procedure is safe, effective, and definitive for poor-risk patients with
the MIST-2 trial (Rahman et al. 2011) showed that the mortality rate at chronic empyema. The 30-day mortality rate in this high-risk group
3 months was 8%, and surgical referral was only 4% in patients treated of patients was 5%, with no long-term morbidity from the procedure.
with intrapleural tPA and DNAase. Other surgical indications for the modified Eloesser flap include
post-resectional, post-traumatic, and tuberculosis-related empyemas
■■Surgical treatment (Thourani et al. 2003).
In patients with post-pneumonectomy empyema, the infected
Based on expert recommendations, the American College of Chest pleural space can be initially sterilized with daily antibiotic irriga-
Physicians recommends fibrinolytics, video-assisted thoracoscopic tion of the thoracic cavity as described by Clagett and Geraci (1963),
surgery (VATS), or open surgery for managing patients with category followed by skeletal muscle transposition to obliterate the residual
3 or 4 PPE (Colice et al. 2000). In a recent retrospective study, the pro- pleural space. When a bronchopleural fistula is present, a modified
cedure success rates were significantly lower for chest tube drainage Clagett technique consisting of pedicled skeletal muscle to cover
(38%) and pigtail catheter drainage (40%), when compared with (81%) the stump at open drainage is associated with an 80% survival rate
VATS or open thoracotomy (89%). Success was defined as resolution (Deschamps et al. 2001).
172 CARDIOTHORACIC SURGICAL INFECTIONS

■■STERNAL WOUND INFECTIONS ■■Pathogenesis and bacteriology

■■Definition Infections occur in cardiac surgical procedures because of multiple
incisions and ports, prolonged anesthesia time, and impaired immune
Sternal wound infection is an uncommon but potentially devastating responsiveness among many patients (El Oakley and Wright 1996).
complication of cardiac surgery. Sternal wound infections are classi- An additional risk to increase infections includes reduction of sternal
fied as superficial or deep. Deep sternal wound infections (DSWIs) blood supply from harvesting of the internal mammary artery (IMA),
may involve the sternum, retrosternal space, or both. A precise dis- especially if bilateral IMAs are utilized. Excessive use of electrocautery,
tinction between the two types of infection is crucial, because the foreign bodies (including wax), hematoma, and sternal instability
therapeutic approach is different. Superficial infections have good have been implicated. Blood transfusion increases infections due to
prognosis, whereas DSWIs are associated with significant morbidity transfusion-induced immunosuppression.
and mortality, prolonged hospitalization, and increased costs. Several Most DSWIs are caused by Gram-positive bacteria, particularly
publications in the 1980s included sterile wound dehiscence, and S. aureus and S. epidermidis. Polymicrobial infections are not un-
the terms “sternitis” and “mediastinitis” were used synonymously common, and Gram-negative bacteria may account for up to 35% of
to define sternal wound infections. To standardize the definition of DSWIs. Gårdlund et al. (2002) identified three different types of DSWIs
DSWIs, the Oakley classification of mediastinitis includes five sub- according to the microbiology and pathogenesis:
types: Type I within 2 weeks, type II 2–6 weeks after surgery, type III 1. DSWIs associated with obesity or chronic obstructive lung disease
is the presence of risk factors, type IV is failed prior treatment, and secondary to coagulase-negative staphylococci and with sternal
type V is presentation more than 6 weeks after the operation (El dehiscence
Oakley and Wright 1996). 2. DSWIs caused by perioperative contamination of the mediastinal
space by S. aureus in patients usually with stable sternums
■■Incidence 3. DSWIs caused by spread from concomitant infections, often
secondary to Gram-negative rods (Klebsiella and Enterobacter
The current incidence of DSWIs in large series of patients ranges from spp.).
0.59% to 2.6% (Table 15.2). Most of these are retrospective analyses of Outbreaks of mediastinitis from Gram-negative organisms such as
cardiac operations using midline sternotomy incisions. According to Pseudomona or Serratia spp. are usually secondary to nosocomial
the STS database, the rate of mediastinitis was 0.6% among 331 429 spread (Gårdlund et al. 2002).
coronary artery bypass graft (CABG) cases. However, it primarily Candida spp. infections are very infrequent, and have been as-
captures acute events, and many later infections may not be recorded sociated with prolonged mechanical ventilation, and in those with
(Fowler et al. 2005b). Although some suggest that the rate of DSWIs a reoperation before the diagnosis of a DSWI (Modrau et al. 2009).
may be increasing because of increasing patient risk, recent data sug- DSWIs secondary to candida infection are associated with a very high
gest that DSWIs are actually decreasing due to better management of mortality. The in-hospital all-cause mortality rate was 35% in patients
patient risk (Matros et al. 2010). with candida DSWIs compared with 15% in bacterial infections, and
The Dutch multicenter surveillance study (Manniën et al. 2011) the 1-year all-cause mortality rate was 41% with candida DSWIs com-
found that sternal surgical site infections (SSIs) were more frequently pared with 23% in patients with bacterial infection.
associated with diabetes, obesity, preoperative length of stay, and
reoperations. Multivariate analysis demonstrated the following risk
factors as independent predictors of DSWIs: Diabetes (odds ratio [OR]
■■Prevention
= 1.7), obesity (OR = 2.2), chronic lung disease (OR = 2.3), preopera- The Surgical Care Improvement Project (SCIP) was created in 2006
tive length of stay >3 days (OR = 1.9), respiratory failure (OR = 3.2), with the goal of reducing surgical complications by 25% by the year
combined valve/CABG procedures (OR = 1.9), and re-exploration for 2010 (Bratzler et al. 2006). SCIP is a national campaign and partner-
bleeding (OR = 6.3) (Filsoufi et al. 2009). The same authors observed ship of leading public and private healthcare organizations. Several
that the mortality rate was 14.2% in patients who had DSWIs com- SCIP measures were introduced to reduce the incidence of SSI. Six of
pared with 3.6% in the control group. The 5-year survival rate was the nine performance measures are related to SSI prevention (Bratzler
also decreased in patients who developed DSWIs (55.8% ± 5.6% vs et al. 2006) and five have relevance to cardiac surgery (Table 15.3).
82.0% ± 0.6%) (Filsoufi et al. 2009). Thus, risk assessment and proper
prevention are important.
Table 15.3 SCIP-Infection module and outcome measures.
SCIP-Inf module Core measures
Table 15.2 Incidence of DSWIs in recent series.
SCIP-Inf-1 Prophylactic antibiotic received within 1 h before
First author Year Patients Patients with DSWIs (%) surgical incision
Gårdlund 2002 9557 126 (1.32) SCIP-Inf-2 Prophylactic antibiotic selection for surgical patient
Gummert 2002 9303 134 (1.44) SCIP-Inf-3 Prophylactic antibiotic discontinued within 24 h of
surgery end time (48 h after cardiac surgery end time)
Lu 2003 4228 109 (2.60)
SCIP-Inf-4 Cardiac surgery patients with controlled 6am
Crabtree 2004 4004 73 (1.80)
postoperative blood glucose level (<200 mg/dl)
Friedman 2007 4987 62 (1.33)
SCIP-Inf-5 Postoperative surgical site infection diagnosed during
Filsoufi 2009 5798 106 (1.80) index hospitalization
Ariyaratnam 2010 7602 44 (0.59) SCIP-Inf-6 Surgery patients with appropriate hair removal
DSWIs, deep sternal wound infections. Inf, infection; SCIP, Surgical Care Improvement Project.
 Sternal wound infections 173

Appropriate administration of prophylactic antibiotics is covered in of SSIs may not become evident until the second postoperative week.
the first three SCIP measures (see Chapter 4) (Fry 2008). In a prospective infection control surveillance study at Duke Univer-
In addition to appropriate administration of prophylactic an- sity, mediastinitis occurred in 76.7% of patients with blood cultures
tibiotics, SCIP-4 and SCIP-6 have special significance for cardiac positive for S. aureus, but only in 11.9% patients with blood cultures
surgery. SCIP-4 requires perioperative glycemic control of cardiac positive for other pathogens, suggesting that S. aureus bacteremia
cases because of the increased risk of DSWIs in patients with diabetes after CABG strongly predicts the presence of mediastinitis, whereas
and poorly controlled hyperglycemia. Furnary and associates (2003) other bacteremias did not alter the clinical suspicion of mediastinitis
demonstrated that appropriate glycemic control (<200 mg/dl) with (Fowler et al. 2005).
continuous insulin infusion reduces DSWIs and mortality in patients Mortality rates can be >50% in patients who present with gen-
with diabetes who undergo cardiac surgical procedures. Glycemic eralized sepsis. The risk of death is significantly higher for patients
control before and during the operation, and over the entire postop- with persistently positive bacteremia, non-CABG cardiac surgery,
erative course, should be universally applied to all cardiac surgical and receiving prolonged mechanical ventilation. Mortality is usu-
patients to reduce the risk of SSIs. The increased use of perioperative ally higher with sepsis due to Gram-negative bacteria and S. aureus
intravenous insulin may explain the reduction of DSWIs in recent (Olsen et al. 2008).
studies (Matros et al. 2010). Thus, a timely diagnosis is essential. Unfortunately, imaging studies
Another core measure, SCIP-6, refers to appropriate hair removal such as CT and radioisotope scans are usually non-diagnostic during
with electric clippers immediately before the skin incision. Advanced the early stages. Mediastinal fluid collections or free gas bubbles are
hair removal should not be done and straight razors should not be not specific during the early postoperative period, because these find-
used at all because microbial growth in skin abrasions may lead to ings may be present in patients without mediastinitis. However, these
wound colonization. observations could be indicative of mediastinitis when present >21
An association between SCIP performance and clinical outcomes days after surgery (Yamashiro et al. 2008). Clinical correlation with
has not been demonstrated on individual SCIP measures. However, imaging may dictate the need to explore the wound to obtain multiple
adherence to all-or-none SCIP-Inf measures was associated with de- cultures and tissue sampling to confirm the diagnosis. Multiple tis-
creased likelihood of developing an SSI (Stulberg et al. 2010). sue samplings before administration of antibiotics are necessary to
In a recent retrospective study, Trussell et al. (2008) observed that ensure a microbiologically correct diagnosis that identifies the primary
timely perioperative antibiotic administration, tight blood glucose pathogen (Tammelin et al. 2002).
control, and hair removal with clippers significantly decreased SSI A more common scenario for presentation of DSWIs is between the
rates in CABG patients. second and sixth postoperative weeks (types II, II, or IV), usually with
As the patient’s skin is a major source of pathogens that may cause purulent drainage and sternal instability. These physical findings are
SSIs, effective skin decolonization can be accomplished with a 4% usually diagnostic. However, in some patients fever and leukocytosis
chlorhexidine shower the evening and morning before surgery, fol- may be the only clinical manifestations during several days before
lowed by a chlorhexidine–alcohol scrub instead of a povidone–iodine the diagnosis can be established. Other non-specific symptoms may
scrub or paint for skin preparation in the operating room (Darouiche be increasing wound pain, with localized redness and tenderness. A
et al. 2010). CT scan combined with granulocyte antibody scintigraphy may be of
A well-controlled, multicenter, randomized study by Bode et al. help to distinguish between deep and superficial sternal infections
(2010) demonstrated the efficacy of preoperative screening of nasal (Bitkover et al. 1996).
carriers of S. aureus followed by decontamination with intranasal Sternal wound infections may also present more than 6 weeks
mupirocin twice a day over 5 days, in addition to daily baths with postoperatively as chronic or recurrent osteomyelitis (type V). Imaging
chlorhexidine soap. According to the Society of Thoracic Surgeons’ studies are important to confirm or exclude the diagnosis of chronic
practice guidelines, routine mupirocin administration is recom- osteomyelitis. MRI and CT lack specificity in chronic osteomyelitis
mended for all patients undergoing cardiac surgical procedures in (Prandini et al. 2006) and, although leukocyte scintigraphy has ac-
the absence of a documented negative testing for staphylococcal ceptable accuracy to diagnose chronic osteomyelitis in the peripheral
colonization. In fact, most cardiac surgical programs have instituted skeleton, fluorodeoxyglucose (FDG) PET has the highest diagnostic
a routine protocol for intranasal mupirocin beginning at least the day accuracy for detecting chronic osteomyelitis in the axial skeleton
before surgery (sooner, if elective) and continuing for 2–5 days after (Termaat et al. 2005) (Figure 15.1). In addition, PET is a valuable tool
surgery (Engelman et al. 2007). that allows accurate assessment of residual activity after medical or
In addition to the SCIP measures, the avoidance of blood transfu- surgical treatment (Prandini et al. 2006).
sions, the judicious use of electrocautery, and selective use of bilateral
IMA are practices that should decrease DSWIs. Sternal ischemia may
be minimized by skeletonization of one or both IMAs during harvest-
■■Treatment
ing, which has been associated with a reduction in DSWI rates. The Type I mediastinitis can usually be treated with thorough debride-
application of topical vancomycin to the cut sternal edges may also re- ment and a closed mediastinal irrigation–suction system. A safe and
duce postoperative DSWI, although evidence is currently not available. effective initial step for rapid control of sepsis consists of reopening
the entire incision, removal of all sternal wires, and debridement
■■Clinical presentation and diagnosis of necrotic tissue. However, in mediastinitis types II and III, wound
debridement and closed mediastinal irrigation have been associated
Sternal wound infections may present acutely with generalized sepsis with high failure rates and up to 35% mortality rates, whereas open
during the first or second week after the operation (type I). The diag- wound packing followed by pedicle flap closure has a significantly
nosis of mediastinitis may be difficult to establish during the early lower mortality. More recently the vacuum-assisted closure (VAC)
stages. After cardiac surgery, patients who present with septicemia and device has been applied to open sternal wounds to facilitate granu-
positive blood cultures frequently have mediastinitis, and evidence lation tissue formation after aggressive sternal debridement or total
174 CARDIOTHORACIC SURGICAL INFECTIONS

a b

a b

Figure 15.2  Computed tomography (CT) scan of the chest shows

satisfactory reconstruction. The study was performed 7 days after chest wall
reconstruction using a pedicled omental flap (OM) and bilateral pectoralis
major muscle flaps (PM). Scanning was performed after administration of
100 ml Isovue-300 intravenous contrast. Images were reconstructed at 3-mm
increments. (a) Axial view; (b) coronal view.
c d

Figure 15.1  CT/PET scan performed 6 weeks after coronary artery into acute and chronic categories. Acute mediastinitis is often the result
bypass graft demonstrates infection (using intravenous 15.1 mCi
of iatrogenic injury or spontaneous perforation of the aerodigestive
fluorodexoyglucose [FDG]; computed tomography (CT)/positron emission
tomography (PET) fusion images were obtained 1 h after FDG administration). tract. Chronic infections tend to be self-limiting but may progress
(a,b) The CT scan fails to reveal involvement of the sternum. (c,d) PET scan into the clinical entity of chronic fibrosing mediastinitis as a result of
shows FDG-avid soft tissue phlegmon and sternal involvement, with phlegmon fungal or tubercular infections.
extending into the mediastinum. The low incidence of these infections and their clinical heterogene-
ity precludes the scrutiny of large, stratified, double-blind, placebo-
controlled, clinical trials to help the clinician with treatment options.
sternectomy (Scholl et al. 2004). Some have identified improved sta- To obtain sufficient material to allow statistical testing, “contempo-
bilization of open sternal wounds and decreased need for paralysis rary” reviews span decades of evolving clinical experiences (Freeman
and mechanical ventilation with the VAC. et al. 2000, Richardson 2005). The literature about the management of
Definitive treatment requires flap reconstruction with viable patients with mediastinitis in the past was therefore often anecdotal,
tissue after debridement or sternectomy, whether the wound is ini- confusing, and controversial. Finally, the clinical picture of these
tially packed open, or temporarily covered with a VAC device. Staged infections is changing. Once the exclusive domain of the thoracic
sternectomy and delayed flap reconstruction are also indicated after surgeon, mediastinal infections are now often treated by minimally
other treatment methods have failed (type IV), or in chronic sternal invasive means. Advanced endoscopy, invasive radiology, and par-
infections (type V). The choice of flap closure depends on the experi- ticularly video-assisted thoracic procedures are altering currently
ence of the surgical team, and plastic surgeons familiar with these held paradigms.
procedures. Bilateral pedicled pectoralis major muscle flaps have
been used successfully to cover the entire wound (Scholl et al. 2004).
However, coverage of the lower third of the open sternal wound may
■■Anatomic considerations
not be feasible using pectoralis muscles only. of the mediastinum
Other reconstructive options include the use of a pedicled rectus The mediastinum is defined as the space between the two lateral
abdominis muscle flap as an adjunct to a unilateral pectoralis major pleural sacs, posterior to the sternum and anterior to the vertebral
muscle flap (Roh et al. 2008), or a combination of omental flap and column, inferior to the thoracic inlet and superior to the diaphragm.
pectoralis major flaps (Kobayashi et al. 2011) (Figure 15.2). Omental Important anatomic considerations include the fact that the fascial
flaps have the advantage that they are technically easy to harvest and planes in the neck are continuous with those in the mediastinum
the procedure can be performed by cardiac surgeons (Van Wingerden and allow extension of infection from the neck to the chest. Deep
et al. 2011). Furthermore, omental transposition flaps are significantly cervical fascial layers separate the neck into three compartments:
less likely than muscle flaps to require a reoperation in patients with Retrovisceral, pretracheal, and perivascular. Each of these fascial
diabetes. In our experience, the use of a pedicled omental flap and planes allows direct extension downward into the mediastinum.
partial mobilization of bilateral pectoralis muscles to cover the omen- Gravity, respiration, and negative intrathoracic pressure are all
tum have been very effective to treat DSWIs. believed to facilitate intrathoracic spread of the infectious process.
The posterior mediastinum is also continuous with the retroperi-
■■INFECTIONS OF THE toneum inferiorly. Mediastinal infections can spread to the retro-
peritoneum via this route, whereas spread from the mediastinum to
MEDIASTINUM the neck is unusual. Spread of infection from the retroperitoneum
or subphrenic areas to the mediastinum has been described for
Mediastinal infections are some of the most vexing and challenging many years and remains an important though infrequent cause of
problems that a physician can face. Effective treatment requires an acute mediastinitis. Finally, the lack of an esophageal serosa allows
understanding of the anatomy and pathophysiology, and a thorough bacteria and alimentary contents direct access to the mediastinum
knowledge of the literature. Infections of the mediastinum can be divided when a perforation occurs.
 Infections of the mediastinum 175

■■Descending necrotizing findings are likely to demonstrate soft-tissue edema with distortion
of normal fascial planes. As mentioned above, pleural and pericar-
mediastinitis dial fluid collections are also often present. Clinical findings have
Descending necrotizing mediastinitis (DNM) is a form of acute me- been categorized by (1) widening of the retrocervical space with or
diastinitis spreading from the cervical region to the mediastinal con- without an air–fluid level, (2) anterior displacement of the tracheal
nective tissue via the cervical facial planes. Pearse (1938) described air column, (3) mediastinal emphysema, and (4) loss of the normal
110 patients with suppurative mediastinitis from descending cervical lordosis in the cervical spine (Figure 15.3). These same authors also
infection and recorded 21 instances secondary to oropharyngeal recommended addition of thoracotomy to cervicotomy whenever the
infection. This report had an overall mortality rate of 55% with 86% inflammatory process descended to the level of the carina anteriorly
occurring in nonsurgical patients and 35% in surgical patient. Although or the T4 vertebra posteriorly. Repeat neck, chest, and abdominal CT
uncommon, this condition remains a life-threatening form of acute scans are recommended for any patient with clinical deterioration,
mediastinitis. Until the introduction of modern antimicrobial therapy, even if an adequate surgical intervention was undertaken to identify
CT, and aggressive surgical intervention, this form of mediastinitis has disease progression.
continued to produce reported mortality rates between 25% and 40%
(Freeman et al. 2000).

Etiology and incidence

Acute mediastinitis may results from oral, odontogenic, and periton-
sillar infections that cause oropharyngeal abscesses (Ludwig angina)
with severe cervical infection spreading along to the fascial planes
into the mediastinum (Estrera et al. 1983). Inadvertent iatrogenic
esophageal intubations, instrumentation, and penetrating trauma may
cause cervical infections which may also extend to the mediastinum.
Furthermore, any surgical procedure on the neck, including lymph
node biopsy, thyroidectomy, tracheostomy, and mediastinoscopy,
can rarely cause subsequent mediastinitis.
The bacteriological features of DNM have been well documented as
polymicrobial with both aerobic and anaerobic bacteria reflecting the
flora of the oral cavity (Brook et al. 1996). A synergistic effect occurs as
the aerobes cause a change to the local blood supply to the deep tissues
of the neck thereby allowing anaerobes to grow without oxygen. In
this sense, these infections are similar to other aggressive necrotizing
infections such as necrotizing fasciitis and Fournier gangrene, in which
aggressive surgical debridement and drainage is life saving (Freeman
et al. 2000). Antibiotics alone will not suffice. Furthermore, conditions a
that predispose certain patient populations to this serious infection
have been characterized and include: Diabetes (13.3%), alcoholism
(17.7%), neoplasm (4.4%), and radiation necrosis (3.3%).

Diagnosis
In 1983, Estrera et al. (1983) formalized the description of an acute
purulent mediastinal infection arising as the result of a severe oropha-
ryngeal infection as “descending necrotizing mediastinitis.” Inclusion
criteria for such a diagnosis include the following:
1. Clinical manifestation of severe oropharyngeal infection
2. Demonstration of characteristic radiological features of mediasti-
nitis
3. Documentation of necrotizing mediastinitis at surgery or postmor-
tem examination or both
4. Establishment of relationship between oropharyngeal infection
and development of necrotizing mediastinal process
Diagnosis of DNM mandates that the relationship between medi-
astinitis and oropharyngeal infection be clearly established. A high
index of suspicion in any patient with a deep cervical infection is
warranted and should prompt rapid evaluation with the appropriate
diagnostic studies. Clinical features that may help the clinician include
substernal chest pain, stridor, brawny or pitting edema overlying the b
neck and chest, and crepitus. With progression of the disease, pleural
Figure 15.3  Computed tomography (CT) scan of the neck and chest with
and pericardial effusion occur which may lead to diminished breath
intravenous contrast demonstrates descending necrotizing mediastinitis
sounds and oxygen saturations, and even pericardial tamponade. CT from cervical pharyngeal infection. (a) Representative neck images showing
is the most useful test to rapidly establish a diagnosis of a deep cervical large retropharyngeal collection. (b) Chest image showing extensive air
infection from one of the previously mentioned causes. Radiographic infiltration of all mediastinal compartments.
176 CARDIOTHORACIC SURGICAL INFECTIONS

Treatment al. (1979) and this has expanded endoscopic and minimally invasive
The treatment of DNM includes broad-spectrum antimicrobial therapies over the last three decades. With greater experience, im-
therapy with the intention to cover both aerobes and anaerobes of proved technologies and critical care recent series report mortality
oropharyngeal origin. In addition, particular care must be placed on rates ranging from 2% to 20% (Kuppusamy et al. 2011).
ensuring and maintaining an adequate airway because there may
be respiratory embarrassment with the ongoing swelling within the Etiology and incidence
cervical region. These measures alone will not, however, suffice, and In the USA and Europe most esophageal injuries (60%) are iatrogenic
appropriate and aggressive surgical debridement and drainage are (Brinster et al. 2004). Most have acute presentations, but subacute
essential to reduce mortality. There is consensus that an aggressive and chronic courses have been reported. Different inclusion criteria
cervical approach by either a unilateral or bilateral sternocleidomas- prevent concrete statements regarding incidence, but two conclu-
toid muscle incision or a collar incision is appropriate. Important sions appear to be justified: (1) Esophageal disruptions are rare and
surgical pearls of such an approach are to open all three compartments (2) they are most often caused by medical intervention usually as part
of the neck, i.e., pretracheal, prevertebral, and perivascular. Whether of an endoscopic procedure as therapy for a stricture or achalasia.
to add a transthoracic approach is a bit more controversial. Estrera Although the rate of injury from esophagoscopy alone is very low
et al. (1983) have championed the concept that, if the preoperative (0.03%), perforations after dilation for peptic stricture occur in 1% of
radiological findings demonstrate infection at or below the level of the patients, and 5% after balloon dilation of achalasia (Silvis et al. 1976).
carina anteriorly or the T4 vertebrate posteriorly, then a transthoracic Barotrauma or Boerhaave syndrome account for 15–30% of cases
approach is mandated. with trauma, foreign body ingestion, and surgical injury making up
Since the 1990s, however, most authors, including Temes et al. the remaining benign causes of perforations. Non-iatrogenic rupture
(1998) from our institution, have reported superior outcomes with of a normal esophagus usually follows forceful vomiting (Boerhaave
a combined transcervical and transthoracic approach. Corsten et syndrome), but is also associated with defecation, lifting, seizure,
al. (1997) solidified this view with a comprehensive literature review pregnancy, and childbirth. Any instrument placed in the pharynx,
over the era beginning with the availability of CT scans. This consisted especially in emergency situations, can perforate the esophagus.
of 36 previous reports including a total cohort of 69 patients. When Thus, nasogastric, Sengstaken–Blakemore, and endotracheal tubes
subjected to meta-analysis, this study found that 47% of patients died in high-risk populations (elderly, bedridden, swallowing impaired
when surgery was limited to transcervical drainage alone, whereas patients) can be responsible. Even ingestion of certain pills (antibiot-
the mortality rate was only 19% when a thoracic incision was added ics, anti-inflammatory agents, potassium, and quinidine) can lead to
(p <0.05). Freeman et al. (2000) published their results on 10 patients esophageal perforation.
with zero mortality. They attribute their results to an aggressive multi- Anastomotic leaks account for most of the esophageal problems
disciplinary effort involving head and neck, thoracic, and oral–maxil- associated with surgical procedures (Richardson 2005). Inadvertent
lofacial surgeons. The mean number of surgical procedures was 6 ± 2 injuries during thyroidectomy, pneumonectomy, vagotomy, and anti-
procedures per patient, reflecting aggressive attitudes toward reopera- reflux procedures have been reported. External trauma can involve the
tion. The preferred thoracic approach to use, whether posterolateral esophagus, but in salvageable patients it is usually limited to the cervi-
thoracotomy, sternotomy, clamshell, or VATS appears to be of less cal region. Traumatic injury to the thoracic esophagus most often in-
importance, so long as all the compartments of the mediastinum are volves serious associated injuries that preclude survival. An abnormal
widely debrided and drained. But, clearly, a standard posterolateral esophagus is at increased risk of perforation. Malignant perforation is
thoracotomy provides very good exposure to the pleural cavity, and ominous and usually rapidly fatal, although under certain conditions
the pericardium prevertebral and paraesophageal planes without it can be palliated. Perforations after lye ingestion or during fulminant
the risk of sternal osteomyelitis. This aggressive approach has lead to esophageal infections are also well documented. With caustic injuries
a decrease in the overall mortality rate to 19% (Corsten et al. 1997). it is important to distinguish between acid and alkali ingestion: Alkali
typically injures the esophagus and spares the stomach; acid does the
■■Esophageal perforation opposite. Although mediastinitis can occur after acid ingestion and
esophagogastrectomy may be required, gastric rather than esopha-
Esophageal perforation is a rare but potentially catastrophic event geal injury is the hallmark of acid ingestion. An impressive variety of
with mortality rates in the past as high at 80% (Kuppusamy et al. 2011). foreign bodies accounts for a large percentage of esophageal perfora-
The successful management requires prompt recognition and sound tions. Innocuous items such as carbonated beverages or tortilla chips
clinical judgment, because the consequences of delayed or incorrect have caused perforations in patients with occult esophageal disease.
decisions can be devastating. Brinster et al. (2004) reported in 559 patients that 59% were caused
Care of these patients therefore requires a thorough understanding by esophageal instrumentation, 15% were spontaneous perforations,
of both esophageal pathophysiology and anatomy. The esophagus foreign body ingestion in 12%, trauma in 9%, surgical injury in 2%, tu-
is a unique structure that lies within the cervical, mediastinal and mor in 1%, and others were 2%. This compared similarly with the prior
abdominal compartments of the body. Unlike other viscera of the di- comprehensive review of 511 perforations of Jones and Ginberg (1992).
gestive tract it has no mesentery and lacks a serosal layer, which allows They found 43% were secondary to instrumentation, 19% by trauma,
perforation to develop into an extensive infection. This results from the 16% spontaneous, 7% by foreign bodies, 8% from surgical injury, and
leakage of ingested material and gastrointestinal secretions leading to 7% from other causes. In this review, endoscopy alone accounted for
an intense combined chemical and infectious mediastinitis. Injuries 35% of perforations by instrumentation, pneumatic dilation caused
to this organ that go unrecognized or are not treated expeditiously can 25%, and bougienage caused 20%. Faulty endotracheal intubation,
lead to extremely high mortality rates. Historically, surgical therapy Sengstaken–Blakemore tubes, nasogastric tubes, sclerotherapy, and
was considered the standard of care with improved outcomes linked endoesophageal prostheses caused 20% of iatrogenic perforations.
to surgical interventions within the first 24 h after injury (Brinster et It is important to maintain the distinction between esophageal
al. 2004). Nonsurgical management was first reported by Cameron et perforation and mediastinitis, because it is the potential source of
 Infections of the mediastinum 177

considerable confusion. An esophageal perforation may or may not

develop into mediastinitis. Small mucosal rents can usually heal
spontaneously. Although large tears that communicate with the pleura
often require surgical intervention, leaks associated with slow erosion
such as foreign bodies are more likely to be contained by local inflam-
matory reaction without invasive mediastinitis. A subset of lesser
perforations, if discovered early, can be prevented from progressing
to mediastinitis by non-invasive or endoluminal stenting. Further-
more, the mere presence of mediastinal air (pneumomediastinum)
does not necessarily equate with mediastinitis. This entity is typically
the result of some form of barotrauma and, although an expeditious
diagnostic workup with an esophagram is indicated in any patient
with pneumomediastinum to rule out a perforation, very often these
studies are negative (Caceres et al. 2008). Again, the preceding history,
inciting events, and clinical presentation can help aid diagnostic and
treatment decision-making.
Finally, bacteriology is non-specific. Cultures are usually polymi-
crobial reflecting normal oral flora and can include Gram-negative,
Gram-positive, aerobic, anaerobic organisms, and even yeasts. The
most common are streptococci, Pseudomonas spp., and Candida spp.
(Brook et al. 1996).

Diagnosis
Clinical presentation depends on the cause and site of injury along
Figure 15.4  Barium swallow showing esophageal perforation. Image
with the length of time from perforation. The diagnosis of esophageal revealed large collection of barium outside the lumen of the distal esophagus.
perforation should obviously be considered in any patient presenting
with suspicious symptoms after endoscopy or instrumentation. Chest
pain, dyspnea, odynophagia, and dysphagia are often present. Associ-
ated fevers and signs of sepsis or shock are particularly ominous. The
differential diagnosis includes myocardial infarction, pulmonary em-
bolism, pneumonia, spontaneous pneumothorax, aortic dissection,
pancreatitis, peptic ulcer, and esophagitis. Pain is the most frequent
symptom. It varies with the location of injury and may be found in the
neck, chest, back, or abdomen. It can be constant or pleuritic. A his-
tory of dysphagia, vomiting, or dyspnea may be present and physical
findings are usually non-specific. Cervical crepitus is common with
cervical injuries (Pate et al. 1989). Surprisingly, leukocytosis and fever
are not uniform findings. Pleural effusion with a strongly acid pH, bile,
or gross food particles establishes the diagnosis.
During the initial evaluation it is critical to determine the physi-
ological stability of the patient. This is done together with treatment
of any pain, and resuscitation of any hypotension or sepsis before
Figure 15.5  Computed tomography (CT) scan of the chest showing large
choosing the necessary diagnostic workup. Once resuscitation has
left pleural effusion. There is mediastinal air next to the esophagus and a
commenced and stability has been assured, diagnostic radiology large effusion with compression of the lung.
with an esophagram (Figure 15.4) and/or a CT scan (Figure 15.5) is
extremely valuable. Chest radiographs appear abnormal in >90% of
patients although they must be carefully interpreted (Han et al. 1985). swallows and CT scans. Most authors recommend an initial study with
Common findings include pneumothorax, pleural effusion, medias- water-soluble contrast followed by a barium study only for patients
tinal emphysema, air–fluid levels, and foreign bodies. Mediastinal who had negative findings (Brinster et al. 2004, Strauss et al. 2010).
widening may be present. Pneumothorax is usually on the left, but A CT scan immediately after a contrast swallow may be valuable if
right or even bilateral accumulations are reported. Although these the esophagram is equivocal in patients whose clinical presentation
non-specific findings are common, they represent advanced manifes- is consistent with perforation. Furthermore, they are often neces-
tations. Definitive diagnosis can be made with a contrast esophagram sary in patients with intubation and septic shock in whom a contrast
in 90% of patients. In the past controversy existed as to whether to esophagram cannot be performed. In addition to demonstrating the
use a water-soluble contrast such as Gastrografin or barium should perforation, the CT scan may also demonstrate the site of perforation
be employed (White and Morris 1992). However, barium contrast is and assist in decisions about the surgical approach.
22% more accurate than water-soluble contrast (Buecker et al. 1997). In the past, the diagnostic utility of esophagoscopy was controver-
Although there are concerns that barium contamination increases sial. Certain authors found that it adds little to the esophagograms
mediastinal or pleural inflammation, these have been found to be inac- (Bladergroen et al. 1986). However, with the increasing use of non-
curate. Barium should not, however, be used as the first-line contrast operative endoluminal treatments, esophagoscopy has become
simply because large-volume extravasation can impair subsequent extremely important as a means of both diagnosis and therapy.
178 CARDIOTHORACIC SURGICAL INFECTIONS

Certainly, patients with a trapped foreign body that has perforated 4. Injury not in neoplastic tissue, not in abdomen, not proximal to
benefit from endoscopic removal. Intraluminal assessment of the obstruction
extent of injury defines whether minimally invasive management 5. Symptoms and signs of septicemia absent
is appropriate. Panendoscopy is also part of the standard workup 6. Contrast imaging and experienced thoracic surgeon available.
for evaluation of patients with penetrating neck trauma. Several The last decade has seen a rapidly increasing interest and use of
series of such patients have found that the sensitivity and specificity minimally invasive and endoscopic management of esophageal per-
are >90% (Arantes et al. 2009). These results are much better than foration. These newer treatment strategies include stent placement,
barium contrast swallow studies, which have a 10% false-negative tube thoracostomy, feeding gastrostomy, and/or jejunostomy. The
result (Wu et al. 2007). Lastly, if pleural fluid seen can be drained outcomes without traditional surgical repair have been encouraging.
by thoracocentesis, finding undigested food, a pH <6, or salivary Historically, endoluminal stenting began as a treatment for malignant
amylase confirms the diagnosis of perforation in the proper clinical esophageal strictures decades ago. Newer covered metal and plastic
setting (Attar et al. 1990). stents have been used to treat a variety of benign conditions including
The diagnosis can be difficult and is often delayed beyond 24 h in esophageal perforations.
up to half of all patients (Pate et al. 1989, Jones and Ginsberg 1992, Recent data would suggest that the development of esophageal
White et al. 1992). The most common reasons for delay are failure to stent technology has been a significant advance in minimally invasive
recognize symptoms (55%), misinterpretation of chest radiographs management of esophageal perforation. Vogel et al. (2005) reported
(25%), and atypical or mild symptoms (9.5%) (Jones and Ginsberg no deaths among 32 patients (4 with cervical, 28 with thoracic per-
1992). False-negative water-soluble and barium swallows do occur, foration) treated without surgical repair. Utilizing an “aggressive
and a negative test does not definitively mean that there is not a leak. conservative” approach with repetitive radiographic studies and
However, it does support an initial nonsurgical approach unless image-guided drainage, as well as surgical intervention when indi-
there are severe signs and symptoms. Exploration is justified despite cated, they documented esophageal healing in 96% of patients and
negative radiological and endoscopic findings if the clinical suspicion an impressive overall survival rate of 96% (n = 47). Even in the group
remains high (Bladergroen et al. 1986). with spontaneous perforation, they achieved a remarkable 93% sur-
vival rate. Notably, 30% of the patients required surgical intervention
Treatment for drainage or esophageal repair. In contrast, van Heel et al. (2010)
Immediate, aggressive supportive therapy should be instituted in reported the largest series of stenting benign perforations, including
all patients with esophageal perforation. This includes ensuring an 10 patients with Boerhaave syndrome, in which healing of the perfora-
adequate airway, intravenous hydration, empirical broad-spectrum tion occurred in 23 of 33 patients. There was an overall perforation-
intravenous antibiotics, gastric decompression, pharyngeal aspiration, related mortality rate of 21%, mostly due to sepsis. This experience
and chest physiotherapy (Jones and Ginsberg 1992). It is unfortunate confirms that minimally invasive therapy is not appropriate in all
that this high level of active intervention is commonly called “conser- patients. Sepesi et al. (2010) reviewed the use of esophageal stents
vative management” in the literature. Goals of therapy for esophageal and found the mortality rate ranged from 0% to 16%. Most patients
perforations of any type include the classic principles of: had iatrogenic injuries that were recognized early, and, although open
⦁⦁ prevention of further contamination surgical therapy was not the primary treatment, stenting was often
⦁⦁ elimination of infection done together with an attempted primary repair and/or debridement/
⦁⦁ restoration of gastrointestinal integrity if possible decortication and drainage. Freeman et al. (2009) reported treatment
⦁⦁ provision of nutritional support, ideally enteral. via placement of silicone-coated stents in 17 patients with iatrogenic
This of course can include wide debridement of infected and necrotic esophageal perforation after endoscopy or surgery. Patients with ma-
tissue, removal of distal obstruction, broad-spectrum antimicrobial lignancy were excluded from the study; 94% of leaks were successfully
therapy, and either closure or diversion of the perforation (Pate et al. sealed on barium esophagogram. Complications included respiratory
1989). Although certain general principles may exist, treatment of an failure, myocardial infarction, and deep venous thrombosis in three
individual patient must be directed by specific analysis of the cause, patients; there were no deaths. After a mean of 52 days, all stents were
anatomic location, diagnostic delay, underlying pathology, and physi- successfully retrieved. This “hybrid approach” warrants a randomized
ological condition (White et al. 1992). controlled trial.

Nonsurgical management Surgical management

Nonsurgical management of esophageal perforation is appropriate Although small, contained, minimally symptomatic perforations can
in select patients with well-contained perforations and minimal me- be treated nonsurgically, frank mediastinal suppuration, major leak, or
diastinal and pleural contamination. Expectant nonsurgical therapy perforation through an ulcer or tumor requires urgent, complete drain-
limited to aggressive supportive measures alone should be reserved age in addition to aggressive supportive care. When one considers the
for patients with small, contained, minimally symptomatic esophageal therapeutic options, the condition of the esophagus is of paramount
perforations that drain back into the esophagus (Cameron et al. 1979). importance. This is obviously influenced by any underlying pathology
These patients do not have mediastinitis; rather they have contained in addition to the local inflammatory reaction. Local inflammation
processes that may or may not progress to fulminant infection. As can increase rapidly over time, precluding direct repair in as short a
such, therapy is intended to prevent, rather than treat, mediastinitis. period as 12–36 h. Finally, careful judgment is required for the elderly
Criteria for nonsurgical management have been suggested (Altorjay or seriously compromised patient. Contemporary therapeutic options
et al. 1997) including: include primary or reinforced primary repair, wide debridement with
1. Early diagnosis or leak contained if diagnosis delayed irrigation and drainage, exclusion and diversion, T-tube drainage, and
2. Leak contained within neck or mediastinum, or between medias- esophagectomy with or without immediate reconstruction.
tinum and visceral lung pleura Patients with cervical perforations down to the level of the carina
3. Drainage into esophageal lumen as evidenced by contrast imaging can usually be treated with wide surgical drainage and irrigation of
 Infections of the mediastinum 179

the retrovisceral and pretracheal spaces because these perforations tant when one considers that secondary reconstructions have been
will heal without repair (Bladergroen et al. 1986). Although the large associated with a mortality rate as high as 10% (Skinner et al. 1980).
majority of cervical perforations do not spread to the mediastinum, Debridement, irrigation, and drainage are appropriate when local
the surgeon should be aware of “descending necrotizing mediastinitis,” inflammatory reaction or the physical condition of the patient con-
discussed above. With mediastinitis, a cervical approach alone may tradicts more definitive options (Skinner et al. 1980, Pate et al. 1989).
prove to be inadequate and may require additional transthoracic In patients with acute perforations and pleural contamination, inter-
drainage. A cervical CT scan, performed before initial exploration, is costal drainage can be an important temporizing measure. Drainage
recommended to identify patients with superior mediastinal exten- includes multiple pleural catheters, distal (naso)gastric drainage, and
sions of cervical infections. proximal pharyngoesophageal aspiration. Drainage may or may not
The preferred approach is primary repair. Collis et al. (1944) were require thoracotomy and may be facilitated by CT-guided placement
early champions of primary repair for esophageal perforations. They of percutaneous catheters. Decortication is generally indicated in
demonstrated the need for wide debridement of necrotic tissue, my- patients with extensive collapsed lung and intrapleural contamination.
otomy to expose the full extent of the mucosal injury, complete closure If adequate (extensive) communication exists between the pleural
of the mucosal injury, and adequate drainage of the contaminated space and the esophagus, the proximal esophageal catheter can be
area. Mucosal repair is critical and additional myotomy may be re- used for topical and continuous antibiotic irrigation (Santos and Frater
quired for adequate exposure. In most cases, primary closure, usually 1986). Treating the esophagus through the rent with a 10- to 12-mm
with buttressing of the suture line, is recommended. Reinforcement Montgomery tracheal T-tube together with pleural, nasogastric, and
of the repair has been found to be essential for success and primary gastric drainage has been reported to be successful (Linden et al.
reinforced repair within 24–26 h of rupture is usually successful (Grillo 2007). This approach is reasonable if the diagnosis has been delayed
et al. 1975, Gouge et al. 1989). The choice of the pedicle tissue flap can and primary repair is not feasible.
include pleura, intercostal muscle, pericardial fat, or gastric fundus. Finally, an intermediate approach of esophageal diversion has
Alternatively muscle pedicles from the diaphragm, latissimus dorsi, been suggested. In this procedure, the perforated but “nonfunctional”
or sternocleidomastoid can be very effective in reinforcing the repair, esophagus is left in situ. This is accomplished by complete occlusion
depending on the location of the perforation. Our preference is a vas- of the esophagogastric junction and creation of a cervical esopha-
cularized pedicle of intercostal muscle if available. Wright et al. (1995) gostomy. Theoretically, the retained nonfunctional remnant is not
validated buttressing primary repair of thoracic esophageal perfora- a source of continued contamination. Gastrointestinal continuity is
tions with the pedicled intercostal muscle flap. They achieved primary re-established after several weeks of healing. Suggested advantages
healing in 89% of the 28 patients, 13 of whom were treated more than include esophageal preservation and reduced surgical insult. Although
24 h after perforation. In the seven patients with postoperative leaks, some authors have been satisfied with this technique in selected
only one required reoperation. circumstances (Urschel et al. 1974, Pate et al. 1989), others have
Intrinsic esophageal pathology can be found in at least half the abandoned it (Orringer et al. 1990, Richardson 2005). Reconstruc-
patients and merits thoughtful consideration. Moghissi and Pender tions following this controversial procedure may be quite challeng-
(1988) identified a 100% mortality rate if repair of proximal perfora- ing. Thoracoscopic approaches for the management of esophageal
tions was undertaken without addressing distal obstruction. Perfora- perforations have been limited (Brinster et al. 2004).
tions associated with achalasia are found in 5% of patients and can Finally, although delay in the repair of an acute perforation may
be directly repaired when combined with a myotomy (Urbani and create increased soilage and subsequently greater fibrosis, it is this
Mathisen 2000). Perforations associated with simple “anatomic le- degree of fibrosis/necrosis that matters most and not the exact num-
sions” such as diverticula, webs, and rings occur in 10% of patients ber of hours that have passed (Wang et al. 1996). Surgical judgment is
and can be treated with excision and reanastomosis if found early. paramount when deciding whether to undertake primary repair versus
When perforations occur in the presence of severe gastroesophageal drainage alone, diversion and exclusion, or resection.
reflux, an antireflux procedure should be performed to enhance the
repair. A Belsey Mark IV is recommended for thoracic perforations, Results of treatment
whereas a Nissen fundoplication is the procedure of choice for an Esophageal perforation remains a lethal condition. The mortality rate
intra-abdominal perforation (Brinster et al. 2004). varies widely, with a mean of 18% from one meta-analysis from 1990
Perforations more than 24–36 h old and those associated with and 2003 (Brinster et al. 2004). However, standards for expected sur-
previous surgery or significant esophageal pathology may not be vival are difficult because homogeneous series do not exist. Mortality
amenable to direct repair. If the patient is an acceptable surgical risk, statistics for esophageal perforations decrease with the inclusion of
and if the esophagus has extensive irreversible changes (cancer, previ- cervical lesions and minor instrumentation tears or with the exclusion
ous surgery, or caustic injury), total thoracic esophagectomy, cervical of malignant disruptions. There is, however, uniform agreement that
esophagostomy, closure of gastric cardia, gastrostomy, and feeding (1) delay from time of perforation to repair multiplies mortality fivefold
jejunostomy with delayed reconstruction are indicated These can be to ninefold for any procedure and (2) when primary repair is attempted
accomplished by a either a left or a right thoracotomy or transhiatal ap- the suture line should be buttressed with a vascularized pedicle flap
proach. Tunneling a long segment of viable proximal esophagus onto (Bladergroen et al. 1986, Attar et al. 1990, Richardson 2005).
the anterior chest wall, rather than a short cervical esophagectomy, Gouge et al. (1989) reviewed 10 series of primary suture of thoracic
can simplify postoperative care and facilitate future reconstruction perforations: Fistulas developed in 39% of 158 patients, with a 25%
(White et al. 1992). mortality rate. This included patients repaired before and 24 h after
Esophagectomy with immediate reconstruction has, however, been perforation. In those operated on 24 hours after perforation, the
very successful in treating this same population (Orringer and Stirling esophageal repair leaked in 50% of cases. In contrast, in 99 patients
1990). Although this increases the complexity of the initial procedure, who had a buttress repair, the leakage rate was 13% and the mortality
it can be accomplished safely, reduces postoperative morbidity, and rate 6%. They also reported mortality rates as 36% for T-tube drainage,
eliminates a second major reconstructive procedure. This is impor- 35% for exclusion–diversion, and 26% for resection.
180 CARDIOTHORACIC SURGICAL INFECTIONS

Abbas et al. (2009) published the largest single institution ex- valve endocarditis (PVE). Factors that determine the clinical presenta-
perience of 119 esophageal perforations over an 11-year period; tion are the infecting organism, the presence of pre-existing cardiac
44 patients presented with Boerhaave syndrome. Most of these abnormalities, and the source of infection (Box 15.1).
patients (34/44 or 77%) were treated with surgical primary repair. The incidence of IE is between 1.8 and 6.2 per 100 000 persons per
Although not statistically significant, they demonstrated better
outcomes for those treated nonsurgically (4% vs 15%, p = 0.19). In
addition, length of stay (24 days vs 13 days, p = 0.032) and overall Box 15.1 Common definitions of infective endocarditis (IE).
complications (62% vs 6%, p = 0.018) favored nonsurgical therapy.
In addition they identified a higher mortality rate (18% vs 3%, p = IE according to localization of infection and presence or absence
0.18) with T-tube drainage. of intracardiac material
Kuppusamy et al. (2011) reported on 81 patients presenting from ⦁⦁ Left-sided native valve IE
1989 to 2009; 48 patients (59%) were treated surgically, 33 patients ⦁⦁ Left-sided prosthetic valve IE (PVE)
(41%) nonsurgically, and 10 patients received a hybrid approach; 57 –  Early PVE: <1 year after valve surgery
patients were treated <24 h and 24 patients >24 h from presentation. –  Late PVE: >1 year after valve surgery
Overall length of stay was less in the early treatment group (11 days ⦁⦁ Right-sided IE (RSIE)
vs 20 days, p = 0.003), but overall mortality was the same. Similarly, ⦁⦁ Device-related IE (permanent pacemaker or cardioverter–de-
mortality was not significantly different in those treated surgically fibrillator)
versus nonsurgically. IE according to the mode of acquisition
Ultimately, optimal results will come from the timely application ⦁⦁ Healthcare-associated IE (HCA)
of the technique most appropriate for the specific situation, rather – Nosocomial: IE developing in a patient hospitalized >48 h
than adopting a standard approach. Increasing experience with tho- before the onset of signs/symptoms consistent with IE
racoscopy may dramatically change management of these patients. – Non-nosocomial: Signs and/or symptoms of IE starting <48 h
after admission in a patient with healthcare contact defined
■■Chronic fibrosing mediastinitis
as:
1. home-based nursing or intravenous therapy, hemodi-
Chronic fibrosing mediastinitis represents a benign proliferation alysis, or intravenous chemotherapy <30 days before the
of dense fibrotic tissue deposition within the visceral mediastinal onset of IE
compartment from chronic infection. The most common cause of 2. hospitalized in an acute care facility <90 days before the
chronic infections of the mediastinum is pulmonary granulomatous onset of IE
disease, although incompletely treated acute infections may also be 3. resident in a nursing home or long-term care facility
a cause. Fungi such as Histoplasma capsulatum and Coccidioides ⦁⦁ Community-acquired IE: Signs and/or symptoms of IE starting
immitis have replaced tuberculosis as the major causative organism. <48 h after admission in a patient not fulfilling the criteria for
Clinically these chronic infections encase and entrap mediastinal healthcare-associated infection
structures such as the superior vena cava, trachea, and esophagus. ⦁⦁ Intravenous drug abuse-associated IE: IE in an active injection
Chronic deposition leads to restriction or local erosion of these struc- drug user without alternative source of infection
tures. Diagnosis is suggested by calcified mediastinal lymph nodes or Active IE
a wide mediastinum. The extent of involvement is defined by CT or ⦁⦁ IE with persistent fever and positive blood culture or
MRI. Etiology of the causative organism is established by skin tests, ⦁⦁ Active inflammatory morphology found at surgery or
serum antibodies, and culture. Treatment is appropriate systemic ⦁⦁ Patient still under antibiotic therapy or
antifungal agents and corticosteroid. As reported by Mathisen and ⦁⦁ Histopathological evidence of active IE
Grillo (1992), this approach is supported by case reports and small Recurrence
series, with no prospective, randomized controlled trials. Surgical Relapse: Repeat episode of IE caused by the same microorganism
procedures are usually reserved for diagnostic purposes, but can be <6 months after the initial episode:
directed toward reopening occluded or stenotic airways, pulmonary – Reinfection: Infection with a different microorganism or
arteries, or the vena cava. – Repeat episode of IE caused by the same microorganism >6
months after the initial episode
■■INFECTIVE ENDOCARDITIS
Infective endocarditis (IE) is usually caused by bacteria but fungal, year and increases significantly over age 50 (Acar and Michael 2010).
rickettsial, chlamydial, and even viral infection can occur. Although The incidence of PVE is between 0.3 and 1.2% during the first year,
any endothelial surface can be affected, valves are most common. with a subsequent annual risk of late IE of 0.5%. Epidemiology of IE
Endocarditis has traditionally been classified as acute or subacute has geographic variations driven by factors such as access to dental
based on the pathogenic organism and clinical presentation. The term and medical care, the prevalence of intravenous drug abuse (IVDA),
“acute bacterial endocarditis” refers to virulent infection that rapidly and HIV (Habib et al. 2009).
destroys the valve and often seeds to other areas of the body. It most The overall impact of endocarditis is quite significant. Approxi-
commonly is caused by S. aureus. Subacute bacterial endocarditis is a mately 20 000 patients are hospitalized each year (8000 new patients)
more indolent process that evolves over weeks to months and is caused at an estimated cost of $100 million in direct medical expenses alone
by more indolent pathogens such as S. epidermidis or Streptococcus (Baddour et al. 2005). Before antibiotic therapy, IE was a uniformly
viridans. This distinction is not, however, clear and the general term fatal disease. Even with current treatment, there is a 30–38% risk of
“infective endocarditis” is more commonly used. More importantly, IE death within 1 year of diagnosis. Prevention of IE is of paramount
is subcategorized into native valve endocarditis (NVE) and prosthetic importance (Acar and Michael 2010).
 Infective endocarditis 181

■■Pathogenesis indicate that 50–75% of IE IVDA patients were HIV positive (Moss
and Munt 2003). Patients with chronic inflammatory bowel disease,
IE begins with sterile vegetations composed of extracellular matrix, alcoholism, poor dental hygiene, and diabetes mellitus are also at
platelets, and fibrin. This subclinical condition is called non-bacterial increased risk (Wilson et al. 2007).
thrombotic endocarditis (NBTE). Endothelium damage can be caused Age is another important host factor. Not only valve disease is more
by high-velocity turbulent blood flow secondary to valvular or struc- prevalent in elderly people but also more patients with prosthetic
tural abnormalities, electrodes, or catheters, or local inflammatory or valves or prior CHD repair are surviving into old age. In addition, older
degenerative changes. The vegetation can be seeded by microorgan- patients make up a disproportionate share of hospital admissions; they
isms. Infected vegetations contain a large inoculum of bacteria often have more invasive monitoring catheters and more invasive proce-
enclosed in a layer of polysaccharides that hampers antibiotic pen- dures that predispose to HCA endocarditis (Acar and Michael 2010).
etration. Experimentally it is nearly impossible to produce IE without Transient bacteremia is relatively common after dental procedures
pre-existing vegetations. However, it is unknown whether the presence but also occurs after gastrointestinal, urological, or gynecological
of vegetations is essential to the development of IE in humans. The diagnostic or surgical procedures. More importantly, spontaneous
degree of valvular destruction depends on the bacteria, duration of bacteremia frequently occurs with tooth brushing, flossing, and chew-
the infection, and anatomic site. Lesions include ulcerations, tears, ing, particularly in patients with poor oral health and in many other
perforation, rupture, and abscess formation. situations. This explains why less than a quarter of all patients with IE
Current clinical reports indicate that left-sided IE constitutes 85% (excluding IVDA) have an identifiable origin of bacteremia.
of cases (isolated aortic lesions in 55–60%, isolated mitral lesions in
25–30%, and mitral and aortic lesions in 15% of cases). Right-sided
IE (RSIE) accounts for only 10–15% of all cases, and is commonly the
■■Bacteriology
tricuspid valve (80%) (Acar and Michael 2010). The infecting organism is usually a single species, most commonly
As virtually all IE cases are seeded by venous bacteremia, what a Gram-positive coccus. The typical IE pathogens adhere to dam-
explains the predilection for left-sided endocarditis? Is it just the aged endothelium, trigger local procoagulant activity, and nurture
increased mechanical stress associated with the higher pressure of the infected vegetations in which they survive. They are consistently
the left heart? Several pathogenic differences have been identified in resistant to platelet microbicidal proteins. The continuing evolution of
laboratory animals: antimicrobial resistance, the increased rates of HCA S. aureus bacte-
⦁⦁ After catheter-induced endothelial trauma and inoculation with remia, and the large number of patients with cardiac or intravascular
bacteria, the left-sided valves are more susceptible to bacterial access devices have changed the epidemiology of IE. In many areas
contamination than those on the right side. of the world, staphylococci have surpassed streptococci as a cause of
⦁⦁ The density of bacteria per gram of tissue is much higher in left- NVE (Baddour et al. 2005, Fowler et al. 2005a). Coagulase-negative
sided valves. staphylococci, the most common cause of PVE, are now a recognized
⦁⦁ Antibiotic inhibition and killing of bacteria were significantly de- occasional cause of NVE. Streptococcus viridans, a normal component
creased at an oxygen pressure (PO2) of 80 mmHg (10.6 kPa) than at of oropharyngeal flora, continues to account for more than half of
a PO2 of 40 mmHg (5.3 kPa), conditions simulating the PO2 tension all streptococcal IE. Enterococci are frequently implicated in HCA
of the left and right sides, respectively. endocarditis in elderly people (Mylonakis and Calderwood 2001).
⦁⦁ More exopolysaccharide in the bacterial capsule is produced at Endocarditis in IVDA results mainly from skin contaminants,
a higher PO2, perhaps explaining the reduced antibiotic efficacy. because approximately 60% of cases are caused by S. aureus. Strep-
Although RSIE may occur in association with congenital heart disease tococci, enterococci, and Gram-negative organisms make up the
(CHD) and the implantation of medical devices, it is overwhelmingly rest of the usual isolated agents. Pseudomonas spp., a rare cause of
a disease associated with IVDA which accounts for most cases (Moss endocarditis, are almost always associated with IVDA, as are cases
and Munt 2003). Damage from particulate material, and the direct with fungi. Polymicrobial IE is infrequent.
toxic effect of the illicit drug or diluents on the right-sided valves,
make them more susceptible (Habib et al. 2009). Valvular damage
by a previous IE is a recognized risk factor in many of the RSIE cases.
■■HCA endocarditis
In the last decade endocarditis caused by HCA infections accounts
■■Host susceptibility for 15–25% of all cases. HCA infection is defined as nosocomial or
non-nosocomial depending on well-established criteria (see Box 15.1).
Spontaneous cases of IE have underlying cardiac disease (often un- Risk factors include intravascular/intracardiac devices, hemodialysis,
diagnosed), although this is frequently not the case with IVDA and genitourinary or gastrointestinal procedures, and surgical wound in-
healthcare-associated (HCA) infections. Structural abnormalities fections. Predominant pathogens are S. aureus (frequently meticillin
predisposing to IE include congenital and valvular heart disease. resistant) and enterococci (often multidrug resistant). Overall mortal-
Degenerative valve disease is becoming more important as the inci- ity is high (Baddour et al. 2005, Fowler et al. 2005a).
dence of rheumatic disease continues to decline. A previous cardiac
operation such as a valve replacement or other intracardiac implants,
or prior NVE, is a significant risk factor.
■■PVE
IVDA is an important risk factor. The probability of IE in this PVE is a devastating complication that accounts for 5–15% of all cases
population is several times higher than with any other predisposing of IE. It has been divided into early infections (within 60 days of opera-
factors (1.5–5% per year). Other important non-cardiac risk factors tion) and late infections (>12 months after surgery). Early infections
include indwelling intravascular catheters, chronic hemodialysis, and are commonly due to S. epidermidis and S. aureus, with an increasing
advanced HIV disease. In many urban centers, IE in IVDA is now the number being meticillin resistant. A variety of Gram-negative aerobic
dominant form of the disease (Fowler et al. 2005a). Recent reports organisms, fungi, and streptococci cause the remainder (David et al.
182 CARDIOTHORACIC SURGICAL INFECTIONS

2007). In late PVE the bacteriology is characteristic of community-

acquired NVE and is usually due to Strep. viridans or Staph. epider- Box 15.2 Modified Duke criteria for the diagnosis of infective
midis. Cases presenting between 2 and 12 months, still frequently endocarditis (IE) (adapted from Li et al. 2000).
called early PVE by many authors, are a mixture of less virulent HCA Major criteria
infections and community-acquired episodes. Blood cultures positive for IE:
The risk of PVE clearly shows an early peak at about 6 weeks after ⦁⦁ Typical microorganisms consistent with IE from two separate
operation and then declines sharply over the next 6 months. After the blood cultures:
first year, the risk of PVE remains low (0.2–0.5% per year) throughout – Viridans streptococci, Streptococcus bovis, HACEKa group,
the remainder of the lifespan of the valve. No specific mechanical or Staphylococcus aureus; or community-acquired enterococci,
bioprosthetic valve has been associated with any increased infectious in the absence of a primary focus, or
risk. Allograft aortic valves are unique in that they are not associated ⦁⦁ Persistently positive blood cultures with microorganisms con-
with early risk of IE, and have a low risk of infection throughout the sistent with IE from:
valve’s lifespan. The most important risk factors for PVE are valve – at least two positive blood cultures of blood samples drawn
operations for NVE and prosthetic valve reoperations. >12 h apart; or
– all of three or a majority of four or more separate cultures of
Diagnosis blood (with first and last sample drawn at least 1 h apart), or
The clinical manifestations of IE are varied, from acute and fulmi- – Single positive blood culture for Coxiella burnetii or phase
nant to chronic and indolent. Symptoms develop within 2 weeks of I IgG antibody titer >1:800
infection. Most patients present with a febrile illness. Nonspecific Echocardiographic evidence of endocardial involvement
symptoms such as shaking chills, night sweats, fatigue, and anorexia ⦁⦁ Echocardiography findings typical of IE:
are common. Weight loss, diffuse arthralgias, and myalgias are not –  Vegetation – abscess – new partial dehiscence of prosthetic
infrequent in patients with subacute IE. Occasionally patients will valve
follow a prolonged course with few specific signs or symptoms, mak- ⦁⦁ New valvular regurgitation
ing recognition difficult. Heart murmurs are almost always present Minor criteria
except with acute infections, mural infections, or RSIE. A number ⦁⦁ Predisposing heart condition or injection drug use
of microembolic manifestations have been described, ranging from ⦁⦁ Fever: temperature >38°C
stroke to splinter hemorrhages of the nail beds to splenomegaly. Clini- ⦁⦁ Vascular phenomena: Major arterial emboli, septic pulmonary
cally apparent emboli occur in 15–35% of patients but autopsy studies infarcts, mycotic aneurysm, intracranial hemorrhages, conjunc-
detect emboli more frequently. CHF is the most serious presentation tival hemorrhages, Janeway lesions
of IE and usually indicates valve destruction (Acar and Michael 2010). ⦁⦁ Immunological phenomena: Glomerulonephritis, Olser nodes,
Emboli are more likely with large mobile vegetations and especially Roth spots, rheumatoid factor
when the mitral valve is affected. Embolic complications tend to be ⦁⦁ Microbiological evidence: Positive blood culture but does not
recurrent if vegetations persist on echocardiography. Up to 65% of meet a major criterion or serological evidence of active infection
embolic events involve the central nervous system, most involving with organism consistent with IE
the middle cerebral artery, and have a high mortality rate (Sila 2010). Diagnosis of IE is DEFINITE in the presence of
Patients with RSIE present with multiple pulmonary emboli, fol- ⦁⦁ 2 major criteria, or
lowed by infarcts, lung abscesses, and pleural effusions. Hemoptysis ⦁⦁ 1 major and 3 minor criteria, or
can be fatal. Peripheral emboli and immunological vascular phe- ⦁⦁ 5 minor criteria
nomena are unusual in right-sided disease. Their presence suggests Diagnosis of IE is POSSIBLE in the presence of
left-sided involvement or paradoxical embolism. ⦁⦁ 1 major and 1 minor criteria, or
In acute endocarditis, leukocytosis is common; in subacute IE, ⦁⦁ 3 minor criteria
anemia and a normal white blood cell count are the rule. Hematuria, Diagnosis of IE is REJECTED if:
proteinuria, and renal dysfunction may result from emboli, immuno- Firm alternate diagnosis for manifestations of endocarditis, or
logically mediated nephritis, or antibiotic toxicity. resolution of manifestations of endocarditis with antibiotic therapy
for ≤4 days or less, or no pathological evidence of IE at surgery
Blood cultures or autopsy after antibiotic therapy for ≤4 days, or does not meet
The mainstay in establishing the diagnosis of IE is the demonstration criteria as above
of bacteremia or fungemia by blood cultures. Blood cultures are posi- aHACEK group: Haemophilus spp.: Hemophilus parainfluenzae,

tive in 90–95% of patients not already receiving antibiotics. In general H. aphrophilus, and H. paraphrophilus, Actinobacillus actinomy-
three sets of cultures should be obtained from different sites 60 min cetemcomitans, Cardiobacterium hominis, Eikenella corrodens,
apart, irrespective of body temperature, to prove that the bacteremia and Kingella kingae
is continuous. Antimicrobial therapy should not be delayed more
than a few hours. Several microorganisms such as the HACEK group
(Box 15.2), Brucella spp., and anaerobes may require special culture antibiotic discontinuation. A frequent cause of culture-negative (CN)
techniques. Fungal organisms can be extremely difficult to grow in IE is infections caused by nutritionally variant streptococci, fastidi-
culture media and in fact some may never be isolated from the blood ous organisms of the HACEK group, and Brucella and Candida spp.
(Baddour et al. 2005). that do not grow in commonly used media. Importantly, the blood
Negative blood cultures have been reported in 5–10% of patients cultures of IE caused by intracellular bacteria such as Bartonella,
with IE often delaying diagnosis and treatment. Failure to isolate the Coxiella, Chlamydia, and Aspergillus spp. are constantly negative and
organism is usually prior antibiotic therapy (Acar and Michael 2010). considered true CNIE. In patients suspected of having IE, cultures in
Importantly, the suppression of bacteremia persists for many days after special media to recover fastidious organisms, long incubation times,
 Infective endocarditis 183

cell cultures, and serological tests for Coxiella, Bartonella spp. should NVE caused by meticillin-sensitive S. aureus (MSSA) usually re-
be performed if there is no growth after 7 days. sponds to 4–6 weeks of a nafcillin and gentamicin. For patients with
MRSA infections, vancomycin is used and may be combined with
Echocardiography gentamicin. S. epidermidis is meticillin resistant and rifampicin is
The most important diagnostic study is echocardiography which often added to vancomycin. It is important that vancomycin is not
should be done as soon as possible to establish diagnosis and identify an effective agent for MSSA. Patients with Gram-positive bacteremia
patients at risk of complications. By demonstrating vegetations as should receive both nafcillin and vancomycin in addition to genta-
small as 5 mm in diameter, the echocardiogram can indicate which micin, until proper identification of the organism has been obtained.
valve is involved and the degree of valve dysfunction. Myocardial and No standard therapies exist for MRSA or S. epidermidis resistant to
valve ring abscesses also can be identified. Serial examinations provide vancomycin
prognostic and management information. Most HACEK organisms are ampicillin resistant but are suscep-
The increased accuracy of transesophageal echocardiography tible to a third-generation cephalosporin given for 4–6 weeks. Other
(TEE) over transthoracic echocardiography (TTE) is accepted (Li Gram-negative bacilli such Enterobacteriaceae and Pseudomonas spp.
et al. 2000). TEE has the relative disadvantage of being a somewhat cannot be treated with antibiotics alone. Valve replacement after 7–10
invasive, uncomfortable and time-consuming procedure. However, it days of therapy in combination with prolonged combination therapy
is the diagnostic method of choice in patients with suspected IE and has been recommended for these difficult infections.
negative or inconclusive TTE. Guidelines for unusual organisms include bartonella IE treated
with a b-lactam and aminoglycoside. Brucella endocarditis requires
Coronary angiography. prolonged therapy with doxycycline and rifampin for at least 8 weeks.
Cardiac catheterization not routinely is performed in IE patients but Q fever sometimes responds to a combination of doxycycline and
also is of value in patients with risk factors or history of coronary dis- hydrochloroquine for prolonged periods of time until the antibody
ease. Alternatively, high-resolution CT cardiac angiography may be titers decrease. Fungal infections usually require surgery in addition
used in patients with large aortic vegetations. to amphotericin B.
Culture-negative IE patients should be treated empirically based
Diagnosis criteria of IE on epidemiological features and the course of infection. Usually a
Diagnostic criteria for integration of clinical, echocardiographic, and combination of penicillin (or vancomycin or ceftriaxone) with an
laboratory information have evolved and modified (Li et al. 2000). aminoglycoside is recommended. Therapy should be adjusted if re-
These “Duke criteria” have been validated by many studies. Cases sults of serology and special cultures techniques reveal another cause.
are defined as definite IE if they fulfill two major criteria, one major Alternatively, if fever persists after empirical therapy, surgery should
plus three minor criteria, or five minor criteria; cases are defined as be considered for debridement and obtaining microbiological and
possible IE if they fulfill one major and one minor criterion or three pathological specimens.
minor criteria, or they are rejected if they do not meet above criteria. There is significant debate about the duration of therapy. Advo-
The definitions of these criteria are summarized in Box 15.2. The Duke cates for shorter treatments cite compliance and cost issues, whereas
criteria are meant to be a clinical guide for diagnosing IE and should proponents of longer regimens focus on efficacy and emphasize the
not replace medical judgment. consequences of relapse. The duration of therapy varies with the
organism but usually is a minimum of 2 weeks and often 6 weeks
■■Medical management (Baddour et al. 2005).

The principal treatment for IE is antimicrobial therapy, which should

be initiated on an empirical basis as soon as the presumptive diagnosis
■■Outcome considerations
has been made and blood cultures have been drawn. Isolation of the Although 70% of patients with NVE can be cured with appropriate an-
organism and determination of antibiotic susceptibility are extremely tibiotics, as many as 60% of “cured” patients eventually require repair
important in choosing the proper agent and for monitoring therapy. or replacement of a damaged cardiac valve. For PVE, the prognosis is
Once the results of the cultures are available treatment can be modi- much worse. Early PVE is a much more virulent disease and carries
fied appropriately. a 75–80% overall mortality rate with medical treatment alone (David
Cure of IE requires sterilization of the vegetations; any surviving et al. 2007). Late PVE has a better prognosis but still carries a 20–50%
bacteria will rapidly repopulate the vegetations. This generally requires mortality rate. Late PVE is often due to S. epidermidis or streptococci,
parenteral therapy in order to ensure high serum concentrations and which occasionally can be cured by antibiotics alone if there is no
tissue penetration. The exact choices of drug, dosage, and duration of periprosthetic infection.
treatment are based on the antimicrobial susceptibility of the organ- The response to medical treatment of IE in IVDA depends on the
ism responsible. organism and location. A right-sided infection with Gram-positive or-
Most Streptococcus viridans and S. bovis organisms are suscep- ganisms can be cured in 90% of patients, whereas left-sided lesions are
tible to penicillin. Medical treatment with penicillin or ceftriaxone significantly worse. Gram-negative infections are significantly worse,
for 4 weeks can be expected to cure 98% of the patients. Treatment with only a 20% cure rate. Relapse usually occurs within 2 months of
for enterococci is more difficult. Most strains are resistant to penicil- treatment (Mylonakis and Calderwood 2001).
lin alone. Susceptibility to penicillin derivatives, vancomycin, and Overall mortality depends on the pathogen and the presence of
gentamicin should be determined in order to select therapy. Standard complications or coexisting conditions. Representative mortality rates
recommendations consist of penicillin or ampicillin plus gentamicin are 4–16% for Streptococcus viridans and S. bovis; 15 – 25% for entero-
for 4–6 weeks. Relapses can occur in 8–20% of cases. Newer agents cocci, 25–40% for staphylococci, and >50% for Enterobacteriaceae,
such as linezolid are indicated in multidrug-resistant enterococci. Pseudomonas spp., and fungi.
184 CARDIOTHORACIC SURGICAL INFECTIONS

■■Surgical management destruction is variable but extension of aortic annular abscess to

involve the mitral valve is not uncommon. The conduction system is
The accepted indications for surgical intervention in IE are congestive another nearby structure sometimes involved and new-onset heart
heart failure (CHF), myocardial or valve ring abscess, uncontrolled block in the patient with PVE should raise the suspicion for IE with
infection, prosthetic valve dysfunction or dehiscence, and infections abscess. There is increased mortality in patients with annular or
caused by fungal or Gram-negative organisms (Box 15.3). Other myocardial abscess (Baddour et al. 2005). Early and repeated TEE in
relative indications for surgery include all cases of PVE, emboli (or patients not responding to medical therapy permits earlier diagnosis
recurrent emboli), large vegetations (particularly when vegetations of annular or myocardial abscess and should result in lower mortality
remain after an embolic episode or increase in size despite therapy), rates through earlier surgical intervention (David et al. 2007)
and infections caused by S. aureus (Di Salvo et al. 2001). Although infrequent, persistent sepsis despite appropriate treat-
ment is the second most common indication for surgical treatment.
The blood cultures of patients who respond to medical therapy
Box 15.3 Accepted Indications for surgical treatment of Infective typically become sterile within 2 weeks. Patients who have persistent
endocarditis. bacteremia should be considered for surgical intervention despite
lack of other indications. Patients with CNIE and a continuing septic
Native valve endocarditis state associated with clinical and echocardiographic findings of IE
⦁⦁ Heart failure due to valve dysfunction should undergo surgery for both diagnostic and therapeutic reasons.
⦁⦁ Evidence of perivalvular extension of infectiona Fungal and Gram-negative organisms are unusual causes of IE
⦁⦁ Aortic, mitral regurgitation, or both, with hemodynamic (Figure 15.6). These patients are seldom cured with medical therapy
evidence of elevated left ventricular end-diastolic or left atrial alone. Although a few less aggressive Gram-negative bacilli may
pressure, or moderate or severe pulmonary hypertension respond to combination therapy based on susceptibility and synergy
⦁⦁ Persistent infection after 7–10 days or adequate antibiotic testing, fungal and most Gram-negative organisms are virtually an
therapy, infection due to fungal or other resistant organisms absolute indication for valve replacement.
with a poor response to antibiotic treatment Other surgical indications of large vegetations, emboli, or recur-
⦁⦁ Recurrent embolism and persistent vegetation despite appropri- rent emboli, S. aureus infection, and non-streptoccocal PVE are more
ate antibiotic therapy controversial. The data on these conditions are not as clear but there
Prosthetic valve endocarditis is certainly a significant body of data to justify an aggressive approach.
⦁⦁ Heart failure due to prosthetic dysfunction The correlation between size of vegetation and risk of emboliza-
⦁⦁ Evidence of periprosthetic extension of infectiona tion is controversial, with some studies showing no correlation and
⦁⦁ Prosthetic valve with evidence of increasing obstruction or others showing an increased risk with larger vegetations. Several have
worsening regurgitation reported a vegetation diameter >10 mm to be an independent predic-
⦁⦁ Prosthetic valve with dehiscence evident by cinefluoroscopy tor of a new embolic event, especially at the mitral valve (Mugge et
or echocardiography al. 1989, Di Salvo et al. 2001, Thuny et al. 2007, 2011). The risk is even
⦁⦁ Persistent infection after 7–10 days or adequate antibiotic higher with very large (>15 mm) and mobile vegetations.
therapy, infection due to fungal or other resistant organisms PVE is usually considered a surgical disease. However, conserva-
with a poor response to antibiotic treatment tive management can be offered in patients with streptococcal infec-
⦁⦁ Recurrent emboli despite appropriate antibiotic treatment tion, small or absent vegetations, and no periprosthetic abscesses.
⦁⦁ Prosthetic valve with relapsing infection
aEvidence of perivalvular extension: Heart blocks; annular or aortic

abscess; destructive penetrating lesions; sinus of Valsalva to right

atrium, right ventricle, or left atrium fistula; mitral leaflet perfora-
tion with aortic valve endocarditis S. epidermidis
10% - 15%

The presence of shock or severe CHF is an ominous development, Enterococci

with a reported mortality rate of almost 90% with medical therapy 5% - 10%
Streptococus species
alone. It can result from a variety of causes such as sepsis, valve dys- 30%–40%
function, intracardiac shunts, and myocardial dysfunction. Echocar-
Culture negative
diography can give a rapid assessment of cardiac hemodynamics, 10%
providing valuable preoperative information. TEE is especially well
suited for this because of its better accuracy for IE manifestations, and
it can also be used intraoperatively to assess the adequacy of repair.
The general consensus is that IE with CHF is best treated by sur- Gram-negative bacilli Staphlococus aureus
gery. Cautious delay should be considered in patients who have not 5% 30%–40%
yet received any antimicrobial treatment, to allow for better control
Miscellaneous and fungi
with antibiotics for at least 72 h. However, in many emergency cases, 5%
it is not always possible.
Abscesses of the annulus or myocardium occur most often in pa-
tients with PVE (40–75%) compared with NVE (26–30%). The aortic Figure 15.6  Relative prevalence of different microorganism causing
position is the most common site in either PVE or NVE, accounting infective endocarditis (IE). The pie chart depicts the relative prevalence of
for the majority of all abscesses. The extent of annular or myocardial different microorganisms causing IE-based on reports from last decade.
 Infective endocarditis 185

Bioprostheses in the mitral position are more likely to respond to renal failure, and early PVE. The risk of PVE after valve replacement
medical therapy than aortic or mechanical p. The presence of perian- performed for NVE is between 3 and 7%.
nular extension, fistulas, new onset of heart block, S. aureus, Gram- The overall problem of IVDA-induced IE is significant. Sadly, many
negative, or fungal infection mandates early surgical intervention. IVDA patients continue using drugs and recurrence of IE is common
Aortic root abscesses and combined mitral and aortic ring ab- (Habib et al. 2009). Return to drug use is one of the most important
scesses are a challenging problem. Surgical mortality ranges from factors in long-term survival which is only 10% over 5–10 years.
22% to 33% (David et al. 2007). Many surgeons advocate aortic root Prognostic information for those IVDA patients who are also HIV
replacement using homograft valves after radical debridement (David positive is limited. Although some reported no significant difference
et al. 2007). Homografts are ideal for the reconstruction of the aortic in outcome of IE in HIV-positive and HIV-negative drug users, others
root, the intervalvular curtain, and the anterior leaflet of the mitral noted markedly increased early postoperative mortality in HIV-posi-
valve. Alternatively, aggressive debridement and reconstruction fol- tive patients with active infection at the time of operation, particularly
lowed by valve replacement with conventional prosthetic valves have those with a CDC 4 count <200 cells/mm3). Most of these patients died
been successfully used. of persistent or early recurrent IE, which may be a sign of immunode-
ficiency despite the clinical absence of AIDS (Moss and Munt 2003).
■■Special situations
Patients with septic cerebral emboli from IE present a difficult clinical
■■Long-term outcome of IE
problem. Brain imaging helps direct the timing of surgery. Patients There are two types of recurrences: Relapse and reinfection (see Box
with ischemic infarcts without hemorrhage, midline shift, or clinical 15.1). Relapse refers to a repeat episode caused by the same organism.
coma can be safely operated on within a week. The presence of a hem- Reinfection is used to describe infection with a different organism.
orrhagic infarct indicates a very high risk of perioperative neurological Molecular techniques help identify a true relapse when the new organ-
complications. The operation should be delayed at least for three weeks ism is of the same species. Relapses are most often due to insufficient
following repeat brain imaging (Sila 2010). CT angiography and MRI duration of the original treatment, suboptimal choice of antibiotics, or
can reliably recognize the presence of intracranial mycotic aneurysms. a persistent focus of infection. Reinfections are more frequent in IVDA,
RSIE in IVDA generally responds well to medical therapy alone, PVE, and patients undergoing chronic dialysis. With the exception of
especially with Gram-positive infections. However, patients with homographs in their first year, it is generally agreed that the type of
Gram-negative or fungal infections are rarely cured with antibiotics valve implanted has no effect on the risk of recurrence.
alone (Moss and Munt 2003). There are at least three surgical options A small number of studies have addressed the overall long-term
to consider in tricuspid valve IE: Valvectomy, repair, and valve replace- prognosis of IE patients after hospital discharge. The reported survival
ment. Simple excision of the valve and debridement of periannular rate after NVE is approximately 90%, 80%, 65%, and 50% at 1, 5, 10, and
abscesses without replacement are a fast and somewhat simpler 15 years, respectively, whereas for PVE it is 78%, 70%, 50%, and 25% for
operation that avoids placing any prosthetic material in an infected the same intervals (David et al. 2007, Martinez-Selles et al. 2008). Fac-
field. Prosthetic valve implantation can be electively performed later. tors associated with better long-term prognosis are age <55 years, lack
Replacement of the tricuspid valve with a mechanical prosthesis is of heart failure, NVE, and early surgical treatment (Habib et al. 2009).
problematic due to issues of compliance with anticoagulation and
the high rate of valve thrombosis. Accordingly, the authors prefer
the use of a bioprosthesis. The third option in this group of patients
■■Prophylaxis
is vegetectomy and tricuspid valve repair, which should always be Although prevention would appear to be the best way to deal with
preferred when technically feasible. the problem of IE, several factors contribute to the failure of this ap-
As mentioned previously, IE in IVDA patients who are also HIV proach. Overall, less than half of IE patients have a previously recog-
positive is becoming a more frequent problem. Reasonable indica- nized cardiac risk and, excluding IVDA patients, less than a quarter
tions for operation in these patients include urgent conditions such have an identifiable cause of bacteremia (Nishimura et al. 2008). It
as a ruptured valve, shock, or cardiac failure. is estimated that less than 10% of IE cases are avoidable and only a
fraction of them are caused by dental procedures. Updated guidelines
■■Surgical outcome have recently published by several professional societies from the USA
and Europe (Wilson et al. 2007, Stokes et al. 2008, Habib et al. 2009).
Outcome depends on the indication for surgery, the valve(s) infected, Interestingly, although based on the same body of evidence, each
the type of replacement valve, and the infecting organism. Early versus guideline significantly differs in its recommendations. In common
late infection is important in PVE. The surgical mortality rate for all there is a general trend against empirical use of antibiotics, limit-
types of IE ranges between 4.8 and 8.7% for NVE and 4 and 20% for ing prophylaxis to patients “with the highest risk of IE undergoing
PVE (early 25% and late 15%) (David et al. 2007). CHF remains a grim the highest risk procedures.” Current American Heart Association
prognostic finding, with a recent series reporting a 41% surgical mor- (AHA) guidelines are summarized in Box 15.4. The reader is referred
tality rate in these patients. Other indicators of poor prognosis include to the excellent review article on the rationale for revised guidelines
persistent fever, extra-annular extension, non-streptococcal infection, (Gopalakrishnan et al. 2009).
186 CARDIOTHORACIC SURGICAL INFECTIONS

Box 15.4 Summary of American Heart Association infective endocarditis prophylaxis recommendations.

High-risk cardiac conditions in which prophylaxis is reasonable

⦁⦁ Prosthetic cardiac valve or prosthetic material used for cardiac valve repair
⦁⦁ Previous infective endocarditis
⦁⦁ Congenital heart disease (CHD):
– unrepaired cyanotic CHD, including shunts and conduits
– completely repaired congenital heart defect with prosthetic material or device, during the first 6 months after the procedure
– repaired CHD with residual defects at or adjacent to site of prosthetic patch or device inhibiting endothelialization
⦁⦁ Post-cardiac transplant valvulopathy
High-risk procedures for which prophylaxis is reasonable, only in patients with above listed high-risk cardiac conditions
⦁⦁ All dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of oral mucosa
⦁⦁ Invasive procedure of the respiratory tract that involves incision or biopsy of respiratory mucosa
⦁⦁ Procedures involving infected skin, skin structures, or musculoskeletal tissue
Antibiotic prophylaxis solely to prevent infective endocarditis is not recommended for gastrointestinal or genitourinary tract procedures

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Chapter 16 Head–neck infections
Francisco O. M. Vieira, Mitchell Challis, Shawn M. Allen

■■ CERVICAL SPACE INFECTION down to the shoulders and thorax (Figure 16.1a). Although the area
contained within this fascial plane is not considered a deep neck space,
■■Anatomy it may serve as an additional barrier for containing edema and pres-
sure caused by infections in the underlying compartments of the neck.
Complex head and neck anatomy often makes early recognition of The deep cervical fascia is divided into three layers – superficial,
cervical space infection challenging and delay in treatment poses a middle, and deep. These envelope the contents of the head and
potential for severe complications. Multiple layers of cervical fascia neck and form the potential deep neck spaces. The superficial layer
encase anatomic contents to form superficial and deep cervical spaces. encloses the inferior aspect of the skull base to the face and com-
These fascial planes constitute barriers for the spread of infection or pletely surrounds the neck. It is traditionally called “investing fascia”
serve to direct infectious spread once their natural resistance has been (Figure 16.1b). Above the hyoid bone level it encloses two muscles
overcome. Aggressive monitoring and management of the airway is (anterior belly of the digastric and masseter), two salivary glands
the most critical aspect of care, followed by appropriate antibiotic (parotid and submandibular), and two fascial compartments (parotid
coverage and surgical drainage. A growing number of patients with and masticator spaces). The middle layer encloses the anterior neck
immune dysfunction are at risk for atypical and more complicated contents and has two divisions: The muscular division surrounds
cases of deep cervical space infections. the infrahyoid strap muscles and extends from the thyroid cartilage
and hyoid bone down to the sternum, clavicle, and scapulae (Figure
Superficial and deep 16.1c, division M); the visceral division envelops the trachea, larynx,
cervical fascial planes pharynx, esophagus, and thyroid gland (Figure 16.1c, division V), and
posteriorly the anterior wall of the retropharyngeal space. The carotid
The superficial cervical fascia underlies the skin of the head and neck in sheath receives connective tissue contributions from all three layers
a continuous plane from the zygoma and muscles of facial expression of deep cervical fascia, forming an anatomically independent com-

Figure 16.1  (a) The superficial

cervical fascia. (b) The superficial
layer of deep cervical fascia
‘investing fascia’. (c) M represents
the muscular division and V the
visceral division of the middle
layer of deep cervical fascia. C
Represents the carotid sheath.
(d) The deep layer of deep
cervical fascia.

a b

V
C

c d
190 HEAD–NECK INFECTIONS

partment (Figure 16.1c, division C). The deep layer originates from the parapharyngeal space, anterior visceral space, or carotid space.
vertebral spinous processes and encloses the posterior neck (Figure Infections often present with induration, swelling, and tenderness
16.1d). It also divides and forms the prevertebral fascia and the alar of the floor of the mouth. Protrusion and elevation of the tongue
fascia. The alar fascia forms the posterior wall of the retropharyngeal may occur as the swelling progresses, causing airway obstruction.
space. The alar fascia also serves as the anterior boundary of the dan- The inframylohyoid compartment contains submandibular glands,
ger space, which extends inferiorly into the posterior mediastinum. lymph nodes, and digastric muscles. The central segment between the
The prevertebral fascia forms the posterior wall of the danger space. anterior bellies of the digastric muscles forms a subdivision known as
Deep neck spaces are formed by cervical fascial planes and they submental space. Inframylohyoid infections cause induration, swell-
functionally contain the infectious processes. Anteriorly, strong fascial ing, and tenderness below the mandible. They can also lead to eleva-
attachments to the hyoid bone restrict downward infectious spread tion and protrusion of the tongue, causing respiratory obstruction.
(Figure 16.2). Consequently, the deep neck spaces are classified into Posterior dental infections can spread directly into this compartment.
three anatomic groups: Suprahyoid, length of the neck, and infrahyoid. The parapharyngeal space approximates an inverted pyramid
extending superiorly from the base of the skull down to the hyoid
Suprahyoid spaces bone. It is divided into two compartments by the styloid process.
The peritonsillar space lies between the palatine tonsil and superior Prestyloid compartment infections result from dental and pharyngeal
pharyngeal constrictor, and is also bounded by the tonsillar pillars. It infections. Clinically they present with fever, chills, neck pain, tris-
is contiguous with the parapharyngeal and retropharyngeal spaces. mus, and bulging of the palatine tonsil. To avoid complications from
Infections often present with fever, sore throat, dysphagia, odynopha- rapid spread into adjacent neck spaces, prompt surgical drainage is
gia, muffled voice, and cervical adenopathy. A contrast computed required. An external approach along the anterosuperior border of
tomography (CT) scan can define the presence of abscess. Cooperative sternocleidomastoid is used to gain adequate exposure, and avoid
patients can usually have these abscesses drained at the bedside with injury to the carotid sheath contents and spinal accessory nerve.
local anesthesia. Uncomplicated infections without airway compro- Poststyloid compartment infections commonly cause no obvious pain
mise can be treated with an initial course of intravenous antibiotics or swelling. However, involvement of the carotid sheath can lead to
for 12–36 h. septicemia, Lemierre syndrome, carotid artery aneurysm or rupture,
The mandibular space extends from the mandible to the hyoid Horner syndrome, and palsies of cranial nerves IX–XII. Management
bone. It is divided horizontally by the mylohyoid muscle into two begins with imaging to determine the extent of spread, and proxim-
compartments: Supramylohyoid and inframylohyoid. These two ity to the carotid sheath. Abscesses of the poststyloid compartment
compartments communicate at the posterior end of the mylohyoid require external drainage.
muscle insertion. The roots of the second and third molars lie below The masticator space lies between the medial pterygoid and masse-
the attachment of the mylohyoid muscle and in the inframylohyoid ter muscles. It includes the temporalis muscle, parotid gland, divisions
compartment. The supramylohyoid compartment contains loose of the mandibular nerve (V3), and the internal maxillary artery. Most
areolar tissue, sublingual glands, the Wharton’s duct, geniohyoid infections originate from the posterior mandibular molars. The initial
muscles, and lingual and hypoglossal nerves. Anterior dental infec- presentation is usually trismus, sore throat, dysphagia, and pain sur-
tions above the mylohyoid level can potentially spread directly into rounding the mandible or preauricular region. An extraoral approach
avoids the facial nerve and the internal maxillary artery. An intraoral
approach at the retromolar trigone may be attempted for draining
abscesses medial to the mandible.
The parotid space is formed by the superficial layer of deep cervical
fascia. The fascia on the medial aspect of the gland is thin and provides
little resistance to spread into the adjacent parapharyngeal space.
Infections often result from parotid duct obstruction and occasionally
from odontogenic sources. They present with severe pain and swell-
ing at the angle of the mandible, but little or no trismus. An external,
parotidectomy-like approach is used to drain a parotid space abscess.
The buccal space contains the buccal fat pad, parotid duct, and
facial artery. Most buccal space infections are odontogenic in ori-
gin and present with a warm and tender swelling within the cheek.
Trismus may be present if the infection spreads posteriorly to the
masticator space.

Entire length-of-neck spaces

The retropharyngeal space lies between the posterior pharynx and the
alar fascia. Laterally, it is bounded by the carotid sheaths (see Figure
16.2, arrow 1). Retropharyngeal infection can result from trauma or
as an extension from parapharyngeal space infection. It presents with
neck pain, fever, anorexia, snoring, and dyspnea. The most feared
complications of retropharyngeal infection are airway obstruction and
Figure 16.2  The freeway spaces to mediastinum and the hyoid bone
rupture of abscess with aspiration. Patients with airway compromise
level, which oppose as an anatomic barrier to the mediastinum
represented by the pink upside-down triangle and the infectious process should be intubated with the patient in the Trendelenburg position.
by the red short arrows. (1) The retropharyngeal space, (2) the carotid or Needle aspiration should be attempted preceding intraoral incision
vascular space, (3) the prevertebral space, and (4) the danger space. and drainage.
 Cervical space infection 191

The danger space lies between the alar and prevertebral fascias. It mon symptoms are dysphagia, odynophagia, trismus, dysphonia, and
extends from the skull base into the posterior mediastinum to the level dyspnea. A discriminating manual physical examination is vitally im-
of the diaphragm. Involvement of this space may result from the spread portant to identify the severity of the process and to make sure that the
of retropharyngeal, parapharyngeal, or prevertebral space infections. airway is secure. Aspirates for culture of aerobes, anaerobes, fungus,
Infection has the tendency to spread inferiorly into the thorax result- and acid-fast bacilli should be obtained before antibiotics are insti-
ing in mediastinitis, empyema, and sepsis (see Figure 16.2, arrow 4). tuted if possible. Negative cultures, despite the presence of organisms
The prevertebral space is between the prevertebral fascia and on Gram stain, may suggest an anaerobic infection or atypical sources.
the vertebral bodies (see Figure 16.2, arrow 3). Sources of infection
include trauma to the posterior pharynx, and secondary spread Imaging studies
from infectious discitis, retropharyngeal, or danger space infections. Management of cervical space infection is highly dependent on the
Complications include spinal osteomyelitis and spinal instability. location and extent of deep neck involvement. Appropriate diagnostic
Staphylococci are the most frequent bacteria. Once identified by a imaging is essential in many cases. The imaging method of choice is
CT scan, prevertebral space abscesses should be drained externally dependent on availability, operator skill, anatomic locations, and
to avoid a persistent draining fistula in the posterior pharynx. patient conditions. Choice of imaging modality will also depend on
The carotid space lies within the carotid sheath and encases the whether image-guided needle drainage or open surgical drainage is
carotid artery, internal jugular vein, cervical sympathetic chain, and considered. Plain radiography is of limited utility for the evaluation
cranial nerves IX, X, XI, and XII (see Figure 16.2, arrow 2). The carotid of deep cervical space infections.
sheath can potentially serve as a ‘‘highway’’ for infectious spread. Ultrasonography can identify mainly superficially localized masses
Infections present with stiffness, swelling neck, fever, chills, Horner and fluid collections. It is readily available and has relatively low
syndrome, or vocal fold paralysis. An external approach is used for operational costs. It is also portable and does not expose patients to
incision and drainage. radiation. Ultrasonography is more accurate than CT in differentiating a
drainable abscess from cellulitis, and should be used to supplement CT
Infrahyoid space or MRI when deep neck abscess is uncertain. It is also useful for image-
The anterior visceral space lies between the infrahyoid strap muscles guided diagnostic and therapeutic needle aspiration. Ultrasonography
and the esophagus. It contains the thyroid gland, trachea, and anterior is limited by its inability to penetrate bone or air-filled structures, and it
esophageal wall. It extends from the thyroid cartilage into the superior may not visualize deeper lesions. It can be difficult to interpret, and is
mediastinum. Infections of this space often originate from traumatic subject to operator skill level with variable reproducibility. It does not
perforation of the anterior esophageal wall. Clinically, they present provide the anatomic detail of a contrast CT scan which is necessary for
with neck swelling, sore throat, dysphagia, odynophagia, hoarseness, planning surgical approaches to deep space collections.
and dyspnea. Perforation of visceral contents may cause crepitus in A contrast CT scan is the imaging modality of choice and the
the neck, mediastinitis, or pneumothorax. standard for the diagnosis and management of deep cervical space
infections. CT scans are fast, relatively inexpensive, and widely avail-
■■Risk factors able. A contrast CT scan can reliably localize a process and define its
extent. It is particularly superior when evaluating cellulitis or abscess
Diabetes mellitus is the most common risk factor in cervical space within the mediastinum (Stalfors et al. 2004). When combined with
infection. Uncontrolled hyperglycemia causes changes in immuno- physical examination, CT has a reported accuracy of 89% in dif-
logical responses and decreases the ability to confine infection. Older ferentiating a drainable abscess from cellulites. Abscesses are seen
patients with diabetes respond poorly to conservative medical therapy as low-density lesions with rim enhancement, occasional air–fluid
and develop frequent complications (Huang at al. 2005). Other sources levels, and loculations. A discrete hypodensity >2 ml in volume on
of immunosuppression – such as HIV infection, intravenous drug use, CT is more predictive of a deep neck abscess than just the presence
chemotherapy, chronic renal failure, hepatic disease, and chronic of a ring-enhancing lesion.
steroid therapy – also increase risk for severe and atypical infections. MRI provides better resolution of soft tissues than CT. It is useful
Cervical space infections can present as the initial manifestation of for assessing the extent of soft-tissue involvement and for delineating
HIV infection. vascular complications. It also avoids radiation exposure, has less in-
Congenital lesions should be considered in immunocompetent terference from dental fillings, and uses less allergenic contrast mate-
patients with recurrent cervical space infections. Contrast CT can be rial. However, it requires a lengthy scan time, is limited in emergency
useful to identify infected cystic lesions and help with surgical plan- settings, and is more expensive.
ning. Infected congenital cysts may respond well to antibiotic therapy.
However, progression of the infection may require needle aspiration or
incision and drainage. Once the infection has resolved complete surgical
■■Microbiology
excision will prevent recurrent infections. Cultures of aspirates from deep neck abscesses are commonly poly-
Head and neck malignancy can initially present as cervical space microbial and reflect the oropharyngeal and odontogenic bacterial
infection. Patients with such infections can present with lymphade- flora. Frequently isolated aerobes include Streptococcus viridans and
nopathy refractory to treatment. Workup should include fine needle Staphylococcus aureus. Less frequently, Strep. pneumoniae, Strep.
aspiration of the lymph nodes and panendoscopy. pyogenes, Klebsiella pneumoniae, Neisseria spp., and Hemophilus
influenzae are isolated. Common anaerobic isolates include pepto-
■■Diagnosis streptococci, Bacteroides fragilis, and Fusobacterium spp. Eikenella
corrodens is a resistant anaerobe frequently isolated from intravenous
In the initial assessment of cervical space infection the airway is the drug abusers. In addition, meticillin-resistant Staph. aureus (MRSA),
first priority. Early identification of immunocompromised patients is once considered a nosocomial infection, is seen with increasing
also important to minimize potential complications. The most com- prevalence as a community-acquired cause of cervical space infections
192 HEAD–NECK INFECTIONS

especially in intravenous drug abusers and immunocompromised without surgical drainage. It has been found that conservative treat-
patients. K. pneumoniae is the most common cause of cervical space ment does not increase mortality or length of hospitalization in these
infections in patients who have poorly controlled diabetes mellitus. patients. Steroids with antibiotic treatment may reduce the need for
surgical intervention by minimizing airway edema, inflammation,
■■Treatment and the progression of cellulitis into an abscess (Mayor et al. 2001).
Parenteral antibiotic therapy should be continued until the patient
Airway management has been afebrile for at least 48 h and then switched to oral therapy.
Careful monitoring of the airway is the first priority when initiating Patients on intravenous antibiotic without improvement in 24–36 h
management of a cervical space infection. The supine position in a will require surgical drainage.
patient may precipitate complete airway obstruction and should be
considered when sending a patient for CT or MRI. Airway obstruction Surgical management
occurs most often in cases with multiple space involvement, Ludwig’s Surgical intervention remains the mainstay of treatment for more
angina, retropharyngeal, parapharyngeal, or anterior visceral space severe or complicated cases of deep cervical space infections. Aggres-
abscesses. Indications for airway control include dyspnea, stridor, sive management of blood pressure, fluid resuscitation, and treatment
retractions, or expected airway compromise. Monitoring of the airway of associated comorbidities is necessary before a surgical approach
should continue for at least 48 h after surgical intervention for swelling. when possible.
Endotracheal intubation is difficult with distorted airway anatomy, Minimally invasive techniques such as image-guided needle
immobility of the soft tissues, or trismus. In less severe infections, aspiration and indwelling catheter placement have been used for
trismus may be overcome with the use of general anesthesia. However, well-defined, unilocular abscesses in patients without airway com-
general anesthesia in more advanced infections can precipitate com- promise. Multilocular abscesses usually require incision and drainage.
plete airway obstruction, resulting in an emergency surgical airway. Ultrasound guidance is effective for locating and draining abscesses.
Fiberoptic nasotracheal intubation is especially useful in patients who CT guidance is helpful for needle aspiration of deep fluid collections.
have severe trismus. In a study of fiberoptic-assisted nasotracheal Unilocular abscesses <3  cm have been successfully treated using
intubation in patients with cervical space infection, titration of intra- ultrasound-guided percutaneous needle drainage (Yeow et al. 2001).
venous diazepam or midazolam with or without fentanyl was shown Failure of improvement by percutaneous treatment requires conver-
to reduce laryngeal spasm before the application of topical anesthesia sion to open drainage
(Ovassapian et al. 2005). Surgical indications for open drainage are in Box 16.1. The exter-
Tracheotomy under local anesthesia is indicated for impend- nal cervical approach is most often used when draining the anterior
ing airway obstruction when trismus or massive soft-tissue edema visceral, submandibular, parapharyngeal, prevertebral, and carotid
precludes endotracheal intubation, or when repeated attempts at spaces, and for complicated retropharyngeal abscesses that cannot be
intubation have failed. Separate incisions for tracheotomy and drain- fully drained using an intraoral approach. Wounds requiring extensive
age procedures of the anterior neck should be used. The advantages debridement of necrotic tissue should be left open and packed with
of tracheotomy include airway security, less sedation, and earlier antimicrobial dressings. In cases involving descending infections,
transfer to a non-critical care unit. The disadvantages of tracheotomy
include bleeding, pneumothorax, and the potential for causing tra- Box 16.1 Indications for surgical management of cervical space
cheal stenosis. infections.
Cricothyrotomy can provide urgent airway access under emergency
circumstances. Potential complications include trauma to the poste- ⦁⦁ Emergency airway compromise
rior wall of the trachea, esophagus, or subglottic stenosis. Cricothy- ⦁⦁ Cervical space necrotizing fasciitis
rotomy should be converted to a standard tracheotomy within 12–36 h. ⦁⦁ Uncontrolled diabetes mellitus
⦁⦁ Septicemia, bacteremia, or systemic inflammatory response
Antibiotic management syndrome
Once aspirates have been collected empirical antibiotic therapy should ⦁⦁ Descending infection to mediastinum from the retropharyngeal,
be started until culture and sensitivity results are available. Antibiotic carotid, danger, prevertebral or anterior visceral spaces
therapy should be started against aerobic and anaerobic bacteria that ⦁⦁ Failure of clinical improvement within 36–48 h of the initiation
are more commonly involved (polymicrobial organisms and strepto- of conservative treatment
cocci). Either a b-lactamase penicillin inhibitor (such as amoxicillin or ⦁⦁ Abscesses >3  cm in diameter that involve the prevertebral,
ticarcillin with clavulanic acid) or a b-lactamase-resistant antibiotic anterior visceral, or carotid spaces
(such as cefoxitin, cefuroxime, imipenem, or meropenem) in combina- ⦁⦁ Pre-existing congenital anomaly
tion with a drug that is highly effective against most anaerobes (such as ⦁⦁ Abscesses that involve more than two spaces
clindamycin or metronidazole) is recommended for optimal empirical ⦁⦁ Failure of previous minimally invasive techniques
coverage. Vancomycin should be considered for empirical therapy
in intravenous drug abusers at risk for infection with MRSA and in cervical drainage is sufficient as long as the infection remains above
patients who have profound neutropenia or immune dysfunction. the carina. Transthoracic drainage is necessary when infection spreads
Ceftriaxone and clindamycin have been recommended as empirical below that level to the mediastinum.
therapy against community-acquired MRSA to ensure adequate cov-
erage and avoid resistance to vancomycin (Naidu et al. 2005). Once
available, the results of the culture and sensitivity tests should guide
■■Complications
further antibiotic therapy. Mediastinitis results from extension of infection from spaces that ex-
In selected cases, an uncomplicated deep neck abscess or cellulitis tend the length of the neck or the anterior visceral space. The causative
can be effectively treated with antibiotics and careful monitoring, organisms are mostly combined aerobes and anaerobes. Patients will
 Nosocomial sinusitis 193

have increasing chest pain or dyspnea, and chest radiography or CT Recurrent infections are commonly found with pre-existing con-
may demonstrate a widened mediastinum or pneumomediastinum. genital abnormality or head–neck cancer. Imaging is useful in making
Transthoracic drainage is necessary for infection below the carina. the diagnosis when recurrent infections occur in the same cervical
Mortality rates for patients who have mediastinitis are 40% (Huang spaces. The second branchial cleft cyst is the most common congenital
et al. 2004). neck abnormality (Nusbaum et al. 1999).
Lemierre syndrome is suppurative thrombophlebitis of the inter-
nal jugular vein from extension of infection into the carotid space.
Findings include swelling and tenderness at the angle of the jaw and
■■NOSOCOMIAL SINUSITIS
sternocleidomastoid, signs of sepsis, and evidence of septic pulmonary Nosocomial sinusitis (NS) is an important hospital-acquired infection.
emboli. Confirmation is obtained by use of high-resolution ultrasonog- In contrast to community-acquired sinusitis, NS may be difficult to
raphy, CT scan, or MRI/MR angiography (MRA). Treatment involves diagnose. Often these patients are intubated, unconscious, and do not
prolonged antimicrobial therapy directed by culture and sensitivity, complain of sinus symptoms. However, NS can be associated with seri-
and anticoagulation for 3 months. Most cases resolve with medical ous complications including the development of ventilator-associated
management and do not require surgical ligation or resection of pneumonia and septicemia. Thus, timely diagnosis and treatment of
the internal jugular vein. Fibrinolytic agents may be used if jugular this condition are important.
thrombosis is recognized within 4 days of onset, but have a higher
risk of hemorrhage than anticoagulation.
Carotid artery aneurysm can present as a pulsatile neck mass with
■■Anatomy
four cardinal signs: The paranasal sinuses are mucosa-lined cavities that are contiguous
1. Recurrent sentinel hemorrhages from the pharynx, nose or ear with the nasal cavity. They have several proposed roles including pro-
2. Protracted clinical course (7–14 days) viding the brain protection from trauma, acting as resonating cham-
3. Hematoma of the surrounding neck tissues bers for voice production, humidifying inspired air, and reducing the
4. Hemodynamic collapse. weight of the facial skeleton. The maxillary and ethmoid sinuses are
Endovascular stenting or vessel occlusion is an option in less present at birth, whereas the sphenoid sinus begins to form at about
urgent cases. 3 years of age and the frontal sinus at 5–6 years.
Ludwig’s angina is the result of rapidly progressive bacterial infec- The sinuses drain into the nasal cavity through several ostia. The
tion in the supramylohyoid and inframylohyoid spaces. It is caused frontal, maxillary, and anterior ethmoid sinuses drain into the area
by firm indurated cellulites rather than abscess formation. Patients underneath the middle turbinate known as the middle meatus. The
present with odynophagia, dysphagia, drooling, and displacement area where these ostia open is known as the osteomeatal complex.
of the tongue superiorly and posteriorly, which may lead to airway This is a bottleneck area for sinus drainage and obstruction can lead
compromise. If the airway is stable at presentation, intravenous to mucus stasis, which predisposes to bacterial growth. The posterior
broad-spectrum antibiotic coverage should be initiated. If the pa- ethmoids and sphenoid sinuses drain into the superior meatus. Sinus
tient develops airway compromise, then an oropharyngeal airway drainage can be blocked by a variety of abnormalities such as a devi-
(oral airway or Guedel cannula), nasopharyngeal airway (trumpet), ated septum, inflammatory processes such as allergic rhinitis, and
nasotracheal fiberoptic intubation (if anatomic conditions are favor- foreign bodies in the nose.
able), or trachesotomy or cricothyrotomy should be considered. These The sinuses and nasal cavity are lined with ciliated pseudostratified
procedures should be attempted with the patient in a sitting-up posi- columnar epithelia. The cilia play an essential role in mucus clearance
tion under close pulse oximetry monitoring. If conservative measures by beating the mucus blanket toward the ostia of the sinus. There is
fail, a surgical tracheotomy is required. Ludwig’s angina may invade very little passive drainage from the sinuses. The function of the cilia
the retropharyngeal or danger space. This can result in mediastinitis, can be impaired by factors including tobacco smoke, infection (viral
pleural effusion, empyema, and infection of carotid sheath structures. and bacterial), and low humidity.
Surgical debridement of necrotic tissue is necessary for compartment Knowledge of the close anatomic relationship of the paranasal
decompression. Currently Ludwig’s angina with aggressive airway sinuses to the orbits and brain is paramount, because of related ma-
management, intravenous antibiotics, and surgical decompression jor complications of sinusitis. The lamina papyracea is a paper-thin
carries a mortality rate of <10%. portion of the lateral ethmoid bone that separates the sinuses from
Necrotizing cervical fasciitis is a fulminant infection that spreads the orbit and may serve as a route for the spread of infection. The roof
along fascial planes. Patients are acutely ill with high fevers, and the of the nasal cavity is formed by the cribriform plate of the ethmoid
skin overlying the necrosis may be tender, edematous, and erythema- bone, which also serves as the floor of the anterior cranial fossa and
tous, with indistinct transition to normal skin. Soft-tissue crepitus is another potential route for the spread of infection.
may be present. In more advanced cases, the skin becomes pale,
anesthetic, and dusky, with blistering and sloughing. CT may demon-
strate diffuse cellulitis with infiltration of the skin and subcutaneous
■■Risk factors, pathogenesis,
tissues, myositis, compartmental fluid, and gas (Palacios and Rojas and bacteriology
2006). Managing necrotizing fasciitis is best accomplished in an in- Nasal foreign bodies including nasoendotracheal tubes, nasogastric
tensive care unit (ICU) and involves parenteral antibiotics, along with tubes, and nasal packing are thought to be the most important risk
early and frequent surgical debridement of any devitalized tissue. The factor in the development of NS. Multiple studies have shown that NS
wound should be left open and packed with antimicrobial dressings rarely develops without a foreign body in the nose (Rouby and Laurent
until the infection has subsided. Hyperbaric oxygen has been used 1994). Several studies have attempted to further elucidate risk factors
as an adjunctive treatment in hemodynamically stable patients. The associated with development of NS. In a large study of 2368 trauma pa-
condition is often accompanied by mediastinitis and sepsis, which tients NS was identified in 32 (1.4%) of these patients. Predisposing risk
increase mortality rates. factors were mechanical ventilation, nasogastric tubes, corticosteroid
194 HEAD–NECK INFECTIONS

therapy, prior antibiotic use, facial trauma, nasoendotracheal tubes, Figure 16.3  CT
scan showing
and nasal packing (Caplan and Hoyt 1982). Most of these infections complete
occurred during the second week of hospitalization. In a prospec- opacification
tive study of 366 patients in an ICU for at least 48 h, risk factors were of the ethmoid
sedative use, nasoenteric feeding tube, Glasgow Coma Scale (GCS) sinuses.
score ≤7, and nasal colonization with enteric Gram-negative bacteria
(George et al. 1998).
The pathogenesis of NS relates to a decrease in nasal patency with
osteomeatal complex obstruction. The aforementioned foreign bodies
in the nasal cavity can apply pressure against the osteomeatal complex,
cause inflammation of the nasal mucosa, and lead to occlusion of the
sinus ostia. Increases in central venous pressure, positive pressure
ventilation, and supine position also play a role in inducing nasal
congestion by increasing jugular venous pressure.
Occlusion of the sinus ostia predisposes the patient to NS. Mucus
stasis, hypoxia, and bacterial toxins all play a role in disrupting cilia
function, further complicating sinus drainage. In addition, tubes and
the damaged mucosa surrounding them provide a surface for bacte-
rial adhesion. This leads to the formation of biofilms which promote
bacterial resistance to host defenses and antibiotic therapy.
Colonization of the paranasal sinuses occurs from endogenous
flora or exogenous pathogens acquired from the hospital environ-
ment. S. pneumoniae, H. influenzae, and M. catarrhalis are the most infection. They identified 84 sinuses that were positive for disease.
common causes of community-acquired sinusitis. In contrast, these Transantral punctures were then performed and confirmed sinus
organisms are rare in NS. NS has a polymicrobial etiology that is of- disease in 78 (93%) of the sinuses. Using these criteria, a sensitivity
ten ICU specific. P. aeruginosa, S. aureus, Acinetobacter spp., E. coli, of 100% and a specificity of 86% were achieved in detecting NS with
Proteus mirabilis, and streptococci are the most common isolates ultrasonography (Vargas and Bui 2006).
(Riga et al. 2010). Mixed anaerobes and fungal pathogens are less Imaging studies have limitations. Radiographic sinusitis does not
commonly isolated. always correlate with microbiological sinusitis. Imagining cannot differ-
The normal sinus flora in critically ill patients is rapidly replaced entiate purulent secretions, blood, mucus, or serous effusions. Further-
by enteric Gram-negative bacilli. Colonization of the nasopharynx, more, imaging studies do not provide information for antibiotic therapy.
oropharynx, and oral cavity (especially gingival plague) plays an Performing a sinus puncture by intranasal approach is more
important role in the colonization of the sinuses. Some contend that invasive and limited to the maxillary sinuses, but it does have advan-
gastroesophageal reflux may lead to gastric colonization of the sinuses tages. First, in adults this can usually be performed at the bedside
(Korinek et al. 1993). with local anesthesia, which saves transportation to the CT scanner.
Second, sinus irrigation can be therapeutic as well as diagnostic.
■■Diagnosis Importantly, it provides a microbiological specimen for cultures and
sensitivities.
NS presents with a wide range of signs and symptoms, including face Vandenbussche and De Moor (2000) performed a retrospective
pain or pressure, nasal obstruction, rhinorrhea, postnasal drip, and review of 53 patients who underwent a total of 105 punctures. They
fever. On physical examination the sinuses may be tender to palpa- noted no complications from these procedures other than minor
tion, the nasal mucosa may be erythematous and edematous, and bleeding, which required no further intervention. They diagnosed 21
there will likely be purulent drainage. Most commonly this is found (39.6%) patients with NS. They conclude that sinus puncture is safe,
in the middle meatus. Anterior rhinoscopy should be performed in inexpensive, and effective for the immediate diagnosis of NS in ICU
patients with suspected NS. In many patients with NS, only fever may patients.
be present. Thus, a high index of suspicion and further studies may be
required in order to make the diagnosis.
Historically, plain films were the most common radiographic study
■■Prevention and treatment
used for diagnosis of NS. However, they have low sensitivity and a Prevention of NS begins with removal of unnecessary nasotracheal
high false-positive rate. CT has replaced conventional radiographs, and nasogastric tubes, semi-recumbent positioning, and strict adher-
and is particularly useful in diagnosis of NS in the unresponsive ence to hand washing and oral hygiene. Pharmacological prevention
patient. CT also has the advantage of delineating sinus anatomy, and of NS was studied in a randomized placebo-controlled trial to evalu-
can identify any abnormalities or variants that may be important in ate a topically applied α-adrenergic agonist and corticosteroids in 79
surgical planning. polytrauma ICU patients who were anticipated to be intubated for at
Diseased sinuses will show mucosal thickening or opacification least 3 days. The treatment group received two drops of xylometazo-
(Figure 16.3). It is important to identify the osteomeatal complex and line twice daily and 100 µg budesonide nasal spray. CT-diagnosed NS
evaluate its patency. Isolated mucus retention cysts may be identi- was detected in 54% of the treatment group compared with 84% of the
fied within the sinuses but these rarely have clinical significance. A control group. NS diagnosed by transnasal puncture and culture was
prospective study evaluated ultrasonography in detecting NS. The found in 8% of the treatment group and 20% of the control group. This
authors examined 120 maxillary sinuses in ICU patients who had was not a statistically significant result, but results may suffer from
been nasotracheally intubated for ≥48 h and had clinical signs of sinus an inadequate sample size (Pneumatikos et al. 2006).
 Parotitis 195

Treatment of NS requires removal of any foreign bodies from the nasotracheally intubated patients. The treatment group received CT
nose if possible. Management of blood glucose levels in patients with sinus scans if the temperature was >38°C. The control group received
diabetes, repair of facial fractures, and early mobilization of the patient standard fever workup without CT scan. NS in the treatment group
are also important. was treated with intravenous antibiotics and sinus lavage without
Antibiotics remain the first-line treatment for NS. Empirical choice removal of the nasotracheal tube. Ventilator-associated pneumonia
of antibiotic depends on probable infecting pathogen and bacterial was identified in 34% of the treatment group and 47% of the control
antibiotic resistance patterns. Broad-spectrum coverage should be group (p = 0.02). It was concluded that early diagnosis and treatment
started initially and then tailored to cultures and sensitivity results. of NS decreases the risk of ventilator-associated pneumonia (Holza-
Adjunctive treatments include nasal saline irrigations, mucolytics, pfel et al. 1999).
and topical/oral decongestants. Topical decongestants should be used
sparingly and for no longer than 72 h in order to prevent the rebound
effects of rhinitis medicamentosa. Nasal steroid sprays can also be used
■■PAROTITIS
as local anti-inflammatory agents in severe NS. Although their role in the In 1881 US President, James Garfield, suffered an abdominal gunshot
acute setting is somewhat controversial, some studies have shown that wound and subsequently died of complications related to suppurative
they are beneficial in reducing acute NS symptoms (Meltzer et al. 2005). parotitis. The parotid is the salivary gland most affected by inflam-
Failure to improve with medical management is an indication for mation. Acute parotitis (AP) usually afflicts very young children, the
surgical intervention. Sinus puncture with irrigation is the first-line elderly or immunocompromised or otherwise debilitated patients.
surgical intervention. However, puncture is limited to the maxillary Historically, AP has been associated with significant morbidity and
sinuses. Endoscopic sinus surgery allows complete access to the mortality. However, contemporary medical and surgical treatments
paranasal sinuses. Endoscopic surgery permits direct visualization have improved results. The incidence of AP has been estimated at
of the sinus ostia and removal of obstruction. Furthermore, the ostia 0.01–0.02% of all hospital admissions and 0.002–0.04% of postoperative
can be widened to permit further drainage. patients (Fattahi et al. 2002). Understanding AP and the importance of
timely diagnosis and treatment is important for favorable outcomes.
■■Complications
Complications of NS are similar to those of acute rhinosinusitis. In-
■■Anatomy
fection can penetrate the thin lamina papyracea to involve the orbit. The parotid is the largest of the major salivary glands. It is located in
This extension leads to pre- and postseptal orbital cellulitis (Figure the preauricular region deep to the skin and subcutaneous tissue.
16.4). Left untreated this infection will progress to formation of a sub- Anteriorly, it is located lateral to the masseter muscle and it extends
periosteal abscess and eventually an orbital abscess. A patient with posteriorly over the sternocleidomastoid muscle and behind the
orbital extension may present with proptosis, chemosis, pain with angle of the mandible. The gland is artificially divided into deep and
extraocular movement, and decreased visual acuity. Patients with superficial lobes by branches of the facial nerve. Stensen’s duct courses
loss of extraocular movement or decreased visual acuity should have anteriorly from the gland over the masseter muscle. It pierces the
emergency drainage of the sinuses and involved orbit. buccinator muscle to enter the buccal mucosa, usually opposite to
Infection that spreads posteriorly can lead to intracranial complica- the second maxillary molar. The average length of the duct is 4–6 cm.
tions, including epidural abscesses, cavernous sinus thrombosis, and The parotid secretes only a thin watery saliva, under the control of
brain abscesses. All these complications require surgical drainage of the parasympathetic nervous system via the glossopharyngeal nerve.
the affected sinus.
To evaluate the relationship between NS and ventilator-associated
pneumonia, a randomized controlled trial was conducted with 399
■■Risk factors
AP occurs most commonly in elderly patients associated with systemic
illness or surgical procedures. Obstructed or altered salivary flow from
dehydration or malnutrition predisposes to AP. No oral intake com-
promises the stimulatory effects of mastication on the salivary glands.
Diuretics, anticholinergics, and antihistamines can also reduce sa-
liva production. Sialoliths, tumors, and trauma to the duct can lead to
obstruction and salivary stasis. Radiation therapy, Sjögren syndrome,
and other autoimmune disorders are all associated with reductions
in salivary secretions. Poor oral hygiene and immunocompromise
are also risks for AP.

■■Pathogenesis and microbiology

The current understanding of the pathogenesis of AP is that retrograde
migration of bacteria in the Stensen duct leads to AP. The continuous
flow of saliva normally prevents retrograde bacterial movement but
decreased salivation with dehydration, starvation, or the postoperative
state permits microbial movement.
Anaerobic bacteria predominate in the oral flora and it is not
surprising when they are isolated in AP. The actual frequency of
Figure 16.4  Orbital cellulitis. anaerobes may be obscured by inefficiency in anaerobic recovery
196 HEAD–NECK INFECTIONS

Table 16.1 Bacteria commonly isolated in acute suppurative parotitis. Occasionally, medical therapy fails or AP may progress to an
Aerobic and facultative bacteria Anaerobic bacteria abscess in the gland or adjacent lymph node. Patients with diabetes
Staphylococcus aureus Peptostreptococci are at increased risk of abscess formation. In some cases facial nerve
palsy has been associated with parotid abscess (Tan and Goh 2007).
Hemophilus influenzae Actinomyces israelii
Once an abscess has formed surgical incision and drainage are usually
a-Hemolytic streptococci Propionibacterium acnes indicated. Surgical drainage should also be considered if the patient
Streptococcus pneumoniae Eubacterium lentum fails to improve after 3–5 days of antibiotic therapy, the facial nerve
Streptococcus pyogenes Fusobacterium ssp. is involved, or adjacent structures such as the deep fascial planes
become involved.
Escherichia coli Bacteroides fragilis
Repeated episodes of AP may lead to damage of the duct and acini
Klebsiella pneumoniae Bacteroides melaninogenica of the gland. This can result in chronic parotitis, which is characterized
Pseudomonas aeruginosa Prevotella intermedia by recurrent, painful swelling of the gland. Initially, management of
this condition should be conservative but may ultimately require surgi-
Porphyromonas assacharolytica
cal intervention including injection of sclerosing agents, ductoplasty,
tympanic neuronectomy, or partotidectomy (Motamed et al. 2003).
of these organisms (Brook 2003a). Bacteria commonly isolated in
AP are listed in Table 16.1. S. aureus is the most common pathogen.
Any ICU-associated pathogen can colonize the oral cavity and can
■■MIDFACIAL CELLULITIS
be identified in AP. Viruses have been reported to cause parotid Midfacial cellulitis encompasses a spectrum of disease including
inflammation and include enteroviruses, Epstein–Barr virus, cyto- both primary and secondary infections of the skin and underlying
megalovirus, parainfluenza, and influenza (Brill and Gilfillan 1977). soft tissues. The midface is uniquely prone to the development of
dangerous complications due to venous communication with the
■■Diagnosis cavernous sinuses. Several important etiologies of midfacial cellulitis
are highlighted, followed by a brief discussion of its treatment, risk
AP will typically present with a unilateral, sudden-onset, indurated, factors, and complications.
warm, and erythematous swelling of the cheek that extends to the
angle of the jaw. The gland will be extremely tender to palpation. In
up to 20% of cases of infection may be bilateral. Patients may also have
■■Primary cellulitic infections
fever, delirium, and other non-specific signs of infection. Primary cellulitis of the midface includes infections that arise in
The opening of the parotid duct may also appear inflamed. Pus can otherwise healthy and intact skin. Such infections generally involve
often be expressed from the duct with gentle pressure applied to the a single microbial species, and the exact entry point of the pathogen
gland. Expression of purulent material from the orifice of the Stensen’s is often uncertain. The usual risk factors of immunosuppression,
duct is diagnostic of AP parotitis. Rarely, occlusion of the duct may uncontrolled diabetes, corticosteroid therapy, and others (Figtree et
prevent pus expression. Fine-needle aspiration of the gland may be al. 2010) are associated with all of the cellulitis conditions discussed.
performed with Gram stain, culture, and sensitivities of the specimens. Erysipelas refers to an acute, superficially spreading infection with
Imaging studies can be useful to determine if a sialolith or stricture 90% of cases occurring on the extremities and 10% on the face (Buck-
is causing ductal obstruction. They can also rule out other unusual land et al. 2007). Facial erysipelas presents with an erythematous,
causes of acute parotid swelling such as neoplastic processes. CT indurated, and painful lesion with raised borders extending over the
or ultrasonography can also be used to determine if an abscess has nasal dorsum and malar areas, with irregularly advancing margins.
formed that may require surgical drainage. Sialography is generally Systemic symptoms include fever, chills, and malaise. Extensive
contraindicated in acute infection due to increased risk of rupture of an lymphatic involvement may lead to lymphedema and tender cervical
ectatic duct from the pressure of the injected dye (Graham et al. 1998). lymphadenopathy. The most common bacterial isolate is group A b-
hemolytic streptococci, although several others including groups B, C,
■■Treatment and G streptococci and S. aureus have been observed. Most cases occur
in very young, elderly, or immunocompromised patients. Infections in
The first line of treatment consists of adequate hydration, systemic immunocompromised patients may involve atypical pathogens such
antibiotics, and pain control. Sialogogues and parotid massage are also as Strep. pneumoniae, K. pneumoniae, Yersinia enterocolitica, and H.
useful adjuncts. Good oral hygiene should be practiced, and in many influenzae and have a recurrence rate of up to 20%. When instituted
cases will help prevent infection. When started early, medical therapy early, antibiotics are generally curative with a mortality rate of <1%.
alone may be sufficient. Most patients will improve significantly within Steroids or anti-inflammatory therapies have been shown to hasten
the first 24–48 h of treatment. the resolution of symptoms and decrease the duration of hospital stay
Empirical antibiotics should be tailored to treat suspected organ- (Celestin et al. 2007). Bacteremia has been noted in up to 5% of cases,
isms. Initially, broad-spectrum antibiotics are indicated to cover S. au- and potential complications include sepsis, meningitis, endocarditis,
reus, hemolytic streptococci, and other anaerobic and Gram-negative necrotizing fasciitis, toxic shock syndrome, and chronic lymphedema
bacteria (see Table 16.1). Sensitivities will allow tailoring of antibiotic (Buckland et al. 2007, Celestin et al. 2007).
choices. A semisynthetic penicillin (e.g., nafcillin) or first-generation Impetigo refers to a superficial infection of the epidermis resulting
cephalosporin may be sufficient for meticillin-sensitive S. aureus. in non-follicular pustules with honey-colored crusting. It is the most
However, in patients with penicillin allergy or MRSA, vancomycin is common skin infection affecting children. The incidence is highest at
appropriate. Clindamycin, cefoxitin, imipenem, meropenem, amoxicil- age <5 years, and decreases to become rare in adulthood. S. aureus
lin clavulanate, or a combination of macrolide and metronidazole may has surpassed streptococci as the most common microbial etiology of
be necessary for other anaerobic and aerobic bacteria (Brook 2003a). impetigo. Bullous impetigo is nearly always caused by S. aureus, and is
 Midfacial cellulitis 197

characterized by blistering of the epidermis from exfoliative toxins as- furunculosis involves the evacuation of purulent debris and application
sociated with staphylococci (Bernard 2008). Initial treatment consists of topical antimicrobial therapy to prevent recurrence. Oral antibiot-
of cleansing regularly with soap and water, and application of topical ics should be considered for refractory or severe infections. Epidemic
antibiotic ointment effective against S. aureus, such as mupirocin. furunculosis should be controlled using aggressive nasal hygiene with
Widespread infections and those not responding to topical therapy disinfecting washes, along with application of mupirocin ointment
require oral or parenteral antibiotic therapy. twice daily for 5 days for patients and their close contacts (El-Gilany
Buccal cellulitis resulting from H. influenzae type b (Hib) infection and Fathy 2009). Complications such as alar stenosis and MRSA en-
is a disappearing disease that immunization has virtually eliminated. docarditis have been reported (Bernard 2008).
Before immunization, it represented the second most common eti- Ethmoid sinusitis is classically associated with the potential for
ology of facial cellulitis among children. Buccal cellulitis typically orbital complications, including preseptal or periorbital cellulitis.
presented between the ages of 3 and 24 months with a history of mild In addition, acute maxillary sinusitis in the absence of odontogenic
upper respiratory infection followed by the development of high fever, disease has been reported as a cause of midfacial bullous cellulitis in
irritability, and facial swelling. Bacteremia was frequently noted, with an otherwise healthy patient. Successful treatment included functional
blood cultures positive in nearly 75% of cases. Complications resulted endoscopic sinus surgery with maxillary antrostomy and removal of
from hematogenous spread, and included meningitis. One study failed purulent material from the affected sinuses along with parenteral
to identify a single case of buccal cellulitis over a 10-year period fol- antibiotic therapy (Yemison et al. 2009).
lowing the institution of Hib immunization. Surgical site infection of the well-vascularized facial skin is uncom-
Another primary cellulitis infection is group B streptococcal (GBS) mon when appropriate perioperative antiseptic and prophylactic
infection after the first week of life. The infection typically presents in practices are employed. Postoperative infection is more common
the buccal, submental, and submandibular areas of the face, and is after procedures involving the nose (6.5%) and ears (5%) than the
complicated by GBS sepsis and meningitis in up to 25% of affected face (1.5%). In addition, oncological surgery and complex procedures
infants. Lumbar puncture is an essential component to the initial involving grafts and local flaps increase the risk of postoperative infec-
workup when GBS infection is suspected in the neonate, and broad- tion significantly when compared with non-oncological interventions
spectrum parenteral antibiotic therapy should be administered with primary wound closure (Sylaidis et al. 1997).
(Pickett and Gallaher 2004). Traumatic abrasions and lacerations of the facial skin are low
risk for infectious complications, and local wound care is usually
■■Secondary cellulitic infections sufficient. Inoculation of debris such as soil into a deeper wound is,
however, rarely associated with invasive soft tissue infection involv-
Secondary cellulitis of the midface arises from direct spread from ing environmental pathogens such as the Zygomycetes class of fungi.
an adjacent infectious entity or from inoculation of a pathogen with Aggressive angioinvasion with hematogenous dissemination and
breach of the cutaneous barrier. The microbiology of secondary infec- rapidly progressing necrosis make early recognition of zygomycosis,
tions is variable, and polymicrobial infections are frequently observed. treatment with surgical debridement, and parenteral amphotericin
Successful treatment may require identification and resolution of the essential management (Kindo et al. 2007). Blunt trauma often results
inciting factors. in facial fractures that allow for direct communication between the
Secondary bacterial infections may occur during viral illnesses paranasal sinuses and the adjacent orbit. Once identified, the patient
such as chickenpox or shingles in otherwise healthy individuals. As in should be advised against nose blowing or straining. Treatment
most skin infections, group A b-hemolytic streptococci and S aureus includes decongestants, humidification, and antibiotic therapy for
are the most frequent microbial isolates. The potential complications clinical infection. Periorbital edema, ophthalmoplegia, and proptosis
of pediatric chickenpox reportedly include impetigo, skin abscess, should prompt urgent CT evaluation to guide further management of
cellulitis, necrotizing fasciitis, myositis, osteomyelitis, and severe orbital complications.
systemic processes such as sepsis and toxic shock-like syndrome
(Santos-Juanes et al. 2001).
Odontogenic infection is one of the most common etiologies of
■■Treatment
facial cellulitis and deep cervical space infections. A history suggesting b-Lactam or broad-spectrum quinolone antibiotics covering both
frequent toothache before the onset of facial edema and tenderness streptococcal and staphylococcal infections are the mainstay of treat-
often identifies the source of infection. Fever and trismus arise as the ment for superficial infections of the midface. Community-associated
infection progresses. Treatment includes antibiotic therapy followed MRSA infections are commonly treated with trimethoprim–sulfa-
by dental or surgical intervention to address the odontogenic source methoxazole, doxycycline, or clindamycin. Inpatient MRSA infection
of infection. Potential complications vary according to the location is treated with vancomycin. Linezolid provides a costly yet effective
of the infection. Maxillary infections spread to the paranasal sinuses means of either single-agent oral or parenteral therapy. Appropri-
and the upper face, and potential complications arise from orbital ate antibiotic therapy results in symptomatic improvement within
involvement, cavernous sinus thrombosis, and intracranial spread. 24–48 h. Continued advancement of the margins of erythema and
In contrast, mandibular infections spread to the lower face and the induration suggests microbial resistance to therapy (O’Connor and
deep cervical spaces with the potential for deep cervical abscess or Paauw 2010).
Ludwig’s angina with airway compromise.
Furuncles of the nasal vestibule result from the spread of S. aureus
along hair follicles into the deep dermis where an abscess subsequently
■■Complications
develops. Chronic carriers of S. aureus in the anterior nares have higher Sepsis is a potential complication of midface cellulitis regardless of
recurrence rates. In addition, MRSA and the presence of virulence fac- the etiology, and should be suspected in the presence of the systemic
tor Panton–Valentine leukocidin have been associated with epidemic inflammatory response, and treated accordingly with broad-spectrum
outbreaks of more severe furunculosis (Bernard 2008). Treatment of parenteral antibiotic therapy, and surgical drainage and debridement
198 HEAD–NECK INFECTIONS

when appropriate. Blood cultures should be obtained before initiating dental enamel allows for entry of bacteria into the pulp chamber and
antibiotic therapy to validate the putative pathogen. subsequent endodontal spread to the root apex, where continued
Necrotizing fasciitis involves the spread of infection along fascial erosion and bone resorption accompany the formation of an api-
planes with progressive thrombosis and necrosis of the dermis, sub- cal abscess. Gingivitis is another route of bacterial spread along the
cutaneous fat, fascia, and underlying soft tissues (see Chapter 5). The periodontal ligaments resulting in bone resorption and subsequent
clinical presentation may initially mimic cellulitis with unrelenting periodontal pocket formation (Rana and Moonis 2011). Regardless of
pain disproportionate to exam findings, bullae and discoloration of the pathway, the end result is infection within the mandibular or max-
the overlying skin, subcutaneous emphysema, cutaneous anesthesia, illary bone surrounding the diseased tooth. The infection progresses
woody induration of the subcutaneous tissue extending beyond the along the pathways of least resistance until the inner or outer cortex
margins of erythema, rapid spread, and systemic toxicity (fever, leuko- is penetrated and invasion of soft tissue ensues.
cytosis, mental status changes, and renal failure). Imaging studies may Maxillary odontogenic infections involving the incisors, premolars,
suggest edema extending along fascial planes. Surgical exploration is and first molars are most likely to spread to the buccal space. Maxil-
required to define the extent and to provide early, aggressive surgical lary canine infections spread to the canine space resulting in blunting
debridement with parenteral antibiotic therapy. of the nasolabial fold. Second maxillary molar infections more often
Meningitis presents clinically with rapid onset of fever, headache, spread to the masticator space, and third maxillary molar infections
mental status changes, photophobia, and meningismus. MRI is the usually spread to the parapharyngeal space.
imaging study of choice to evaluate intracranial pathology, because Mandibular odontogenic infections involving the incisors occa-
meningitis may have a normal appearance on CT scan. Treatment sionally spread to the submental space, whereas infected mandibular
consists of broad-spectrum parenteral antibiotic coverage. Long-term canines and first premolars are most likely to spread to the sublingual
neurological sequelae may include seizures and sensorineural deficits space above the mylohyoid muscle. Mandibular infections arising in
such as hearing loss in up to 25% of cases (Epstein and Kern 2008). the second and third molars exit the cortex below the attachment of
Cavernous sinus thrombosis is the feared complication of midfacial the mylohyoid muscle and into the submandibular space (Christian
cellulitis. Venous outflow from the midface communicates directly 2010).
with the cavernous sinuses through the valveless ophthalmic veins. Odontogenic infections have the potential to invade the deep
Subsequent thrombosis and intracranial spread of infection results in cervical spaces discussed above. Involvement of the deep cervical
headache, fever, altered consciousness, ophthalmoplegia secondary space increases the life-threatening potential of complications such
to deficits of cranial nerves III, IV, and VI, and paraesthesiae of the as mediastinitis.
ophthalmic and maxillary branches of the trigeminal nerve. Involve-
ment of the superior ophthalmic vein may lead to complications such
as visual disturbances, orbital pain, and orbital cellulitis or abscess
■■Risk factors
(Dhariwal et al. 2003). Contrast-enhanced CT of the skull base and CT Odontogenic infection is primarily associated with dental caries and
venography are useful to detect cavernous sinus thrombus or filling poor oral hygiene. Systemic diseases, particularly the hyperglycemia of
defects, whereas MRI of the brain with contrast may demonstrate dural diabetes, have been shown to increase the risk for cervical space infec-
enhancement adjacent to the cavernous sinuses (Rana and Moonis tion and its associated complications. One prospective study recently
2011). Treatment consists of long-term, culture-directed, parenteral found that spreading odontogenic infections were associated with
antibiotic therapy (up to 8 weeks) with or without the use of antico- tobacco smoking in 80% and social deprivation in 72% of their study
agulation. The use of steroid therapy is not recommended (Epstein and population. Other comorbidities associated with odontogenic infection
Kern 2008). The mortality rate approaches 30–40% despite aggressive include alcohol abuse, intravenous drug abuse, immunosuppression,
treatment (Oliver and Gillespie 2010). and other medical illnesses such as hypertension, asthma, malnutri-
tion, and iron-deficiency anemia (Wang et al. 2005, Bakathir et al. 2009).
■■ODONTOGENIC INFECTIONS
Odontogenic infections are widespread and represent the most com-
■■Microbiology
mon cause of deep cervical space abscesses in adults. Appropriate The mouth is colonized by at least 350 distinct bacterial species, many
management requires a thorough understanding of the cervical spaces of which have the potential to cause odontogenic infection. Infections
of head and neck anatomy, as well as the potentially severe complica- are polymicrobial. Cultures from odontogenic abscesses typically
tions that may accompany these infections. Dental expertise is also reveal four to seven separate bacterial isolates (Robertson and Smith
needed to address the source and prevent recurrence of the infection. 2009). Obligate anaerobes outnumber aerobic or facultative flora, and
Hospitalizations for acute dental infections have an incidence of ap- are essentially universal in odontogenic infections. Peptostreptococci,
proximately 1 in 2600 annually in the USA, and last an average of 8 days and Fusobacterium, Prevotella, Bacteroides, and Porphyromonas
(Wang et al. 2005). Most severe or spreading odontogenic infections spp. comprise the strict anaerobes (Kuriyama et al. 2000, Robertson
affect patients in their 20s and 30s (Boffano et al. 2011). Children have and Smith 2009). Facultative anaerobes are also present in more than
a much higher rate of maxillary odontogenic infection with associated 50% of cases (Kuriyama et al. 2000). Viridans group streptococci and
buccal space infections, whereas adults are more prone to infections b-hemolytic streptococci represent the most common facultatives
arising from the posterior mandible (Wang et al. 2005). observed, followed by Fusobacterium and Prevotella spp. in frequency
(Robertson and Smith 2009).
■■Pathogenesis
Odontogenic infection initially requires a compromise in the natural
■■Diagnosis
barriers that protect the dentoalveolar structures. The pathogenesis History and physical examination usually identify the source of
of these infections occurs in several different patterns. Breach of the infection, and special attention is given to evaluation of the airway.
 Odontogenic infections 199

Rapid airway compromise may develop in the setting of Ludwig’s an-

gina or an enlarging posterior deep cervical space abscess. Depending
■■Complications
on the degree of airway compromise, either awake fiberoptic naso- Cervical space infection (CSI) represents a complex spectrum of
tracheal intubation or emergency tracheostomy or cricothyroidotomy disease governed by the spread of infection along pathways of least
may be necessary. Once the airway has been stabilized, appropriate resistance. Tonsillitis is the most frequent etiology of CSI in children,
antibiotic therapy should be initiated as described below. Any suspi- but odontogenic disease represents the most common cause in adults.
cion for deep cervical space involvement is an indication for CT of the Treatment consists of broad-spectrum antibiotic administration, and
neck to accurately identify the extent of infection before any surgical surgical interventions aimed at draining the involved cervical spaces
intervention. Ultrasonography has been found to accurately assess and removing the odontogenic source of infection. Airway compro-
the more superficial cervical spaces (buccal, submandibular, canine, mise, descending infection, and vascular sequelae may complicate
submasseteric, submental, and infraorbital spaces), but should not be severe cases of CSI.
relied on for assessment of the deeper spaces (masticator, parapha- Cervical necrotizing fasciitis (see above and Chapter 5), mediasti-
ryngeal, and sublingual spaces) (Bassiony et al. 2009). nitis (Kinzer et al. 2009), and Lemierre syndrome (see above) are addi-
tional complications of invasive odontogenic infection. Lemierre cases
■■Treatment with Fusobacterium spp. have been reported in the past decade, arising
from pharyngeal and odontogenic infections that breach the retro-
Dental care, incision, and drainage, and appropriate antibiotic styloid compartment of the parapharyngeal space or spread directly
therapy, comprise the approach to managing odontogenic infections. from thrombophlebitis of the adjacent facial venous plexus. Septic
The dentition responsible for inciting the odontogenic infection must emboli potentially give rise to microabscesses within the lungs, liver,
be extracted at the time of surgical drainage. Any cervical space that kidneys, and central nervous system, and may lead to septic shock.
appears to be involved with infection on CT should be incised, cleared Intracranial infections from odontogenic bacterial infection can
of any purulent or necrotic debris, and a drain or irrigation catheter occur either by direct extension through the cribriform plate, hematog-
left in place. Needle drainage is not recommended in the setting of enous seeding, or retrograde thrombosis in the setting of odontogenic
anaerobic infection with the potential for significant tissue destruc- sinusitis. Intracranial pathology may include cavernous sinus throm-
tion. Most of the spaces should be approached extraorally; however, bosis, abscess, or meningitis. Polymicrobial (primarily anaerobic)
the retropharyngeal, canine, and some isolated buccal and sublingual flora mirror those observed in odontogenic infections (Brook 2006).
space infections can be safely incised and drained using a transoral As many as 86% of refractory maxillary sinusitis cases may actually
approach. Appropriate empirical antibiotic therapy must take into be related to odontogenic infections, especially in the setting of radio-
account the susceptibilities of the common odontogenic pathogens. graphic evidence of oroantral fistula, periapical abscess, periodontal
Anaerobes with significant b-lactamase activity, such as Prevotella and disease, projecting tooth root, and dental caries. Empirical antibiotic
Bacteroides spp., often necessitate the use of b-lactamase-resistant coverage in the setting of odontogenic origin (anaerobic infection)
therapies. Polymicrobial odontogenic abscesses require broad-spec- differs from that of non-odontogenic sinusitis. Dental pathology is
trum coverage. Culture results have not been found to alter antibiotic addressed before consideration of functional endoscopic sinus surgery
management in the setting of adequate coverage; rather, changes in (Bomeli et al. 2009).
therapy are indicated when clinical indicators such as persistent fever Oroantral fistula refers to an osteomucosal communication
or leukocytosis suggest therapeutic failure (Wang et al. 2005). between the oral cavity and either the nose or one of the maxillary
First-line treatment of uncomplicated odontogenic infections sinuses. It usually represents an iatrogenic complication of dental
should consist of penicillin in combination with metronidazole, or extraction, maxillary cyst removal, or the Caldwell–Luc approach to
monotherapy consisting of a formulation that includes a b-lactamase maxillary sinus surgery; however, it has been linked to odontogenic
inhibitor such as amoxicillin–clavulanate (co-amoxiclav) or ampicil- infection as well. Fistulas <5 mm in diameter can be expected to resolve
lin–sulbactam. The addition of metronidazole provides coverage for with antibiotic therapy. Fistulas >5 mm require primary closure using
most of the clinically important anaerobes, with the notable exception local advancement or pedicle flaps. Closure should be deferred until
of Actinomyces spp. It should not, however, be used as monotherapy any signs of ongoing maxillary sinusitis have responded to antibiotic
because it lacks aerobic activity. Clindamycin is an effective alternative or surgical therapy (Hajiioanou et al. 2010).
to penicillin with adequate coverage of streptococci, most penicillin- An orocutaneous fistula forms when periapical infection causes
resistant staphylococci, and clinically significant anaerobes. It is the gradual erosion through alveolar bone with subsequent development
recommended treatment for patients allergic to penicillin (Levi and of a sinus tract to the overlying skin. The resulting lesion can be mis-
Eusterman 2011). taken for local trauma, furuncle, carcinoma, and several other entities,
Cephalosporins generally provide adequate microbial coverage with which may lead to >50% of patients undergoing unnecessary rounds
fewer potential side effects than clindamycin, but should be avoided of antibiotic therapy and dermatological procedures. Mandibular
in penicillin-allergic patients. b-Lactamase-resistant cephalosporins dentition is involved in 80% of cases. Radiographs reveal bone loss
are particularly useful in severe infections (Kuriyama et al. 2000). at the apex of the affected dentition. Orocutaneous fistulas generally
Carbapenems possess excellent activity against most Gram-positive, resolve within 5–14 days of root canal or dental extraction as indicated
Gram-negative, and anaerobic bacteria, and should be considered (Pasternak-Junior et al. 2009).
when other treatments fail (Levi and Eusterman 2011). Moxifloxacin Osteomyelitis related to odontogenic infection can lead to bony
provides adequate coverage for most odontogenic infections and was erosion of the mandible or maxilla. Dental implants, in particular,
found to be superior to clindamycin with more rapid clinical resolution carry up to a 15% risk of localized osteomyelitis (Pigrau et al. 2009).
and fewer side effects (Cachovan et al. 2011). Finally, macrolides have Alveolar osteitis refers to focal osteomyelitis within a tooth socket
been recommended in the past for treatment of odontogenic infection; after dental extraction, and occurs in about 3% of cases (Younis and
however, emerging microbial resistance now limits their usefulness in Hantash 2011). These are often chronic polymicrobial infections,
moderate-to-severe infections (Kuriyama et al. 2000). and are frequently resistant to clindamycin but remain sensitive
200 HEAD–NECK INFECTIONS

to penicillin and fluoroquinolones. Prolonged antibiotic therapy further divided into intra- versus extraconal disease by the extraocular
in addition to surgical interventions, including debridement, mar- muscles. Signs of an orbital abscess include pain, swelling, chemosis,
ginal resection, and sequestrectomy, may be necessary. Hyperbaric limitation of eye movements, proptosis, and decreased visual acu-
oxygen therapy has also been used as adjunctive therapy (Pigrau ity. Optic neuritis, atrophy, and blindness may result from elevated
et al. 2009). intraorbital pressure in severe infections. Posterior infectious spread
Orbital complications are rare in association with odontogenic may lead to intracranial abscess, meningitis, and death. Treatment
infection, whereas 80% of orbital infections are believed to arise from involves aggressive parenteral antibiotic therapy and surgical drainage
paranasal sinus disease. Infection anterior to the orbital septum pres- for any suspected abscess, as well as emergency lateral canthotomy
ents as preseptal cellulitis with periorbital edema in the absence of or- when necessary to relieve intraorbital pressure and prevent vascular
bital involvement. Infectious spread posterior to the orbital septum is insult to the orbital contents (Kim et al. 2007).

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Chapter 17 Vascular surgical site infection
Kelley D. Hodgkiss-Harlow, Dennis F. Bandyk

Surgical site infection (SSI) after vascular intervention, an important wound facilitates colonization by bacterial strains with the virulence
cause of postoperative morbidity, requires patient-specific treatment factor of biofilm formation, and if not addressed can progress to an
and an accurate microbiological diagnosis. Based on the clinical SSI with predictable increased morbidity. Healthcare costs are then
presentation, microbiology of the infectious process, and extent of increased from an extended hospitalization, return to the operating
graft involvement, multiple surgical options are appropriate, includ- room for wound debridement/closure procedures, and necessary
ing graft excision alone, graft preservation, in situ graft replacement, home healthcare and outpatient visits for wound management.
or graft excision proceeded by ex situ bypass via uninvolved tissue Prevention of SSI should be of paramount concern but reducing the
planes. As most patients present with low virulence infection, the incidence requires knowledge of its changing epidemiology and the
preferred approach is in situ revascularization, using autologous use of effective patient-care strategies. An implanted vascular graft
conduit (femoral or saphenous vein), cryopreserved allograft, or an or endovascular stent graft is most susceptible to colonization during
antibiotic (rifampin)-impregnated prosthesis. Antibiotic therapy is the early (<1 month) postoperative period from either bacteremia or,
essential and should utilize bactericidal drugs that penetrate bacteria more commonly, the adherence of pathogenic strains to the device
biofilms. Antibiotic delivery to the infected surgical site is convention- with the development of a bacterial biofilm – an organism-produced
ally done with parenteral drugs, but antibiotic-impregnated beads microenvironment protective against host defenses and antibiotics.
may be used for local administration. Prevention of vascular infection Understanding the implications of a biofilm infection, especially the
requires the surgeon to be cognizant of its changing epidemiology, concept of selective antibiotic resistance, is essential for clinical suc-
the known patient risk factors, and application of effective measures cess in treatment of vascular SSIs (Frei et al. 2011).
to reduce its incidence. The majority of vascular SSIs are caused by
Gram-positive bacteria. Meticillin-resistant Staphylococcus aureus
(MRSA) is the most common pathogen and is identified in more than
■■EPIDEMIOLOGY OF
a third of cases. Nasal colonization by S. aureus, recent hospitalization, VASCULAR SITE INFECTION
a failed arterial reconstruction, and the presence of a groin incision are
major risk factors for developing a vascular SSI. Preoperative measures Infection involving a vascular wound may be superficial, i.e., cellulitis,
to decolonize the nares and surgical site of S. aureus, together with deep incisional involving the subcutaneous tissue/fascia, or involving
appropriate, bactericidal antibiotic prophylaxis, meticulous wound other areas than the incision itself, i.e., organ/space, such as along the
closure, and postoperative care to optimize patient host defense length of an implanted vascular prosthesis or as an intracavitary aortic
regulation mechanisms (temperature, oxygenation, blood sugar), can graft infection. For autogenous arterial revascularizations, only infec-
minimize vascular infection occurrence. tions occurring within 30 days should be classified as an SSI, but when
Vascular infection occurs as a result of perioperative events leading a prosthetic graft or endovascular device is implanted the incidence
to bacterial colonization of the wound and frequently the underlying of SSIs is calculated for 1 year. The diagnostic criteria for SSIs should
prosthetic graft when present. The vascular patient requiring arterial include signs/symptoms of infection (pain, tenderness, erythema,
reconstruction has an increased SSI risk with an overall incidence in swelling), purulent drainage for the wound, and organisms isolated
the range of 5–10%. This rate of infection is significantly higher than from aseptically obtained cultures of fluid or tissue.
the 1.5–5% rate predicted by the Centers for Disease National Noso- Although virtually any microorganism can produce an SSI or infect
comial Infections Surveillance System for “clean” procedures in risk a vascular prosthesis, Gram-positive bacteria, especially S. aureus, are
index categories 1 and 2 (Culver et al. 1991, Vogel et al. 2008, 2010). the prevalent pathogens involved in approximately 80% of all cases
The increased likelihood of SSI is due to both procedure- and patient- (Reifsnyder et al. 1992, Cowie et al. 2005, Armstong et al. 2007, Vogel
specific risk factors – highest after lower limb bypass for critical limb et al. 2010, Frei et al. 2011). As in other surgical disciplines, the mi-
ischemia, lowest after carotid endarterectomy or endovascular aortic crobiology of vascular SSIs has changed since 2000 with an increased
aneurysm repair. Implantation of a vascular prosthesis increases SSI prevalence of antibiotic-resistant organisms, including staphylococcal
risk by producing a microenvironment conducive to bacterial attach- strains. An audit of prosthetic arterial graft infections treated by our
ment and biofilm formation which sustains bacterial colonization and vascular surgery group demonstrated a fourfold increase in MRSA
protects encased organisms from host defenses and antimicrobial infection from 10% in the 1990s to 40% since 2000 (Perl et al. 2002,
therapy. Injured skin/skin structures and soft-tissue edema are com- Pounds et al. 2005). In a series of complex vascular SSIs treated by
mon sequelae after femoral and lower limb arterial revascularizations aggressively staged surgical debridement, antibiotic bead therapy,
and impede wound healing. In addition to intraoperative contamina- and selective sartorius muscle flap coverage, MRSA accounted for 20%
tion, postoperative skin separation of the incision with underlying of all infections and 50% of reinfections (Frei et al. 2011). This trend
hematoma and serous wound drainage extend the time available for has been verified from other vascular centers in the USA and Europe,
bacterial invasion from external sources. including a 2005 report from the University of Texas Galveston docu-
Bacteremia from remote sources or bacterial transport via lym- menting a SSI rate of 11% after lower bypass grafting with S. aureus
phatic channels in the reconstructed extremity can be sources of sec- involved in 64% of cases of which half were caused by MRSA (Cowie et
ondary infection of the surgical site and arterial graft. The non-healing al. 2005). MRSA should be suspected in any vascular patient presenting
204 VASCULAR SURGICAL SITE INFECTION

with an SSI, including patients with a non-healing lower limb ampu-

tation performed for ischemia. The changing microbiology of SSIs, Box 17.1 Patient, procedure, and environmental risk factors for
especially the increase in MRSA infection, has implications for initial surgical site infection.
treatment of SSIs, as well as antibiotic prophylaxis in vascular patients
with multiple risk factors for postoperative infection, especially MRSA Patient-related risk factors
nasal and skin colonization (Armstrong et al. 2007). Patient outcomes Nasal carriage of Staphylococcus aureus
are less favorable with an MRSA versus meticillin-sensitive S. aureus Prolonged preoperative length of stay
(MSSA) SSIs with an increase in both 30-day mortality (odds ratio Postoperative bacteremia
of 3.4) and morbidity (median of 5 days additional hospitalization) End-stage renal disease
(Armstrong et al. 2007). Obesity
The appearance time for vascular SSIs depends on procedure Malnutrition/low serum albumin
type and whether a prosthetic graft has been implanted. Although Older age
wound infections typically are clinically demonstrated within 30 Smoking/Nicotine use
days of surgery, infection involving a lower limb prosthetic arterial Diabetes mellitus
bypass usually presents beyond 4 months (mean of 7 months), and Prior incision site irradiation
after aortic grafting, clinical signs of infection may appear years later Malnutrition/low serum albumin
(mean of 3.5 years) (Bandyk 2002, Perl et al. 2002, Pounds et al. 2005). Autoimmune disease/corticosteriod therapy
The late presentation of vascular graft infection is attributed to the Malignancy/chemotherapy
bacteria biofilm nature of the infectious process caused by low viru-
lence S. epidermidis strains. Once the graft is colonized by bacterial Procedure-related risk factors
biofilm, the infection can evolve to a more virulent, invasive process Femoral/groin incision
by superinfection with other bacterial species, such as MSSA, MRSA, Remote infection
or Gram-negative bacteria. The likelihood of this is increased if graft Biomaterial implant
erosion progresses through the skin (graft cutaneous sinus tract) or Emergency/reoperative procedure
into the gastrointestinal (GI) tract (graft enteric erosion). When the American Society of Anesthesiology (ASA) score >2
presentation of aortic graft infection includes Gram-negative bacteria, Extended operative time
graft enteric erosion should be suspected. Overall, Gram-negative Hypothermia
bacteria account for approximately 20–25% of vascular SSIs with the Shock
most common strains being Escherichia coli, Pseudomonas aerugi- Hyperglycemia
nosa, Proteus spp., and Klebsiella pneumoniae. When confronted with
a vascular SSI, initial antibiotic therapy should be guided by Gram stain Environmental risk factors
of wound or aspirated perigraft fluid. Identification of Gram-positive Operating suite ventilation – environmental surface cleaning
organisms should prompt antibiotic therapy with bactericidal killing Instrument and vascular implant sterility
properties to MRSA (Perl et al. 2002). Surgical attire and sterile operative technique

■■RISK FACTORS FOR vascular patient, the most significant risk factors are: nasal coloniza-
VASCULAR INFECTION tion with MSSA/MRSA, presence of a groin incision, prosthetic grafting
or patch angioplasty, lower limb arterial bypass grafting, postopera-
Most arterial surgery procedures are classified as “clean” class I by tive bacteremia, and end-stage renal disease (ESRD). Characteristics
the National Research Council because the surgical exposure and such as obesity, advanced age, smoking, and diabetes are known
revascularization are performed in uninfected tissues without inflam- risk factors for SSIs in all surgical patients and are present in most
mation. Furthermore, the respiratory, alimentary, or infected urinary vascular patients.
tract is not entered. These wounds are closed primarily with suction Numerous studies have confirmed increased SSI rates in people
drainage if necessary (Culver et al. 1991). Although diseased arter- with S. aureus nasal carriage. Approximately 6–35% of vascular pa-
ies may harbor bacteria, most commonly S. epidermidis strains that tients harbor S. aureus in their nares with the prevalence highest in
are within atherosclerotic plaque or mural thrombus, the inoculum patients with ESRD, active skin infection, immunodeficiency states
and virulence are considered low. This observation is an important such as infection with HIV, or residence in a long-term care facility.
rationale for routine antibiotic prophylaxis. Arterial revascularization Preoperative S. aureus carriage has been shown to the risk of SSI by
is not recommended in patients with invasive remote infection or bac- four- to eightfold in patients undergoing cardiothoracic, neurosur-
teremia except when the intervention is judged life saving. In patients gical, and orthopedic procedures. The “cause–effect” mechanism
with critical limb ischemia and a clinical presentation of foot sepsis is felt to be patient transmission of bacteria from the nares to the
or wet gangrene, initial management should be surgical debridement surgical site(s) via their hands. Nasal colonization with MRSA ver-
of infected tissues together with antibiotic therapy. Debridement and sus MSSA further increases the likelihood of SSI to approximately
antibiotic therapy are followed by open or endovascular revasculariza- eight- to tenfold compared with an S. aureus carrier, and has been
tion when the invasive infectious process has been controlled. linked to MRSA SSI outbreaks in hospital wards (Cowie et al. 2005).
Vascular SSI involves a complex interaction of the bacterial in- In vascular patients, MRSA colonization has been shown to increase
oculum, host defense mechanisms, and surgical site healing. Audits the frequency (odds ratio of 4.5) of any nosocomial (wound, blood,
performed in US hospitals of SSIs have identified patient, procedure, urine, lung) infection (44% incidence). MRSA infection increases
and environmental risk factors that increase the risk for postoperative hospital stay when compared with similar MSSA infections. These
infection for the vascular reconstruction patient (Box 17.1). For the epidemiological observations prompted a randomized clinical trial
 Treatment of vascular graft infections 205

of decolonizing therapy with application of intranasal antibiotic 8–10%. These rates are significantly higher after infrainguinal prosthetic
ointment (mupirocin calcium) before and after surgical procedures. (10–29%) or in situ saphenous vein (18–22%) bypass grafting proce-
Mupirocin, a topical anti-staphylococcal agent that inhibits RNA and dures (Perl et al. 2002, Vogel et al. 2008, Frei et al. 2011). The increased
protein synthesis, eliminated S. aureus carriage in 83% of colonized rates of SSIs in lower limb arterial procedures is related to tissue in-
patients (23% of study population) compared with no effect in the jury/ischemia of critical ischemia, secondary lymphedema produced
placebo group. However, no decrease in SSI rates was observed (7.9% by surgical trauma and revascularization edema, and failure of the
vs 8.5%) (Cowie et al. 2005). femoral/groin incision to heal. The development of wound hematoma
Of note, this study demonstrated that the odds of a S. aureus carrier or incision separation caused by dermal or fat necrosis reduces the
developing SSI was 4.5 times that of a non-carrier (p <0.001). There was bacteria inoculum required to produce an invasive infection. These
a trend to reduced S. aureus SSIs (38% reduction) but the differences wound problems occur more frequently in the groin incision, especially
between the treatment and placebo groups were not significant. These in the clinical setting of a repeat arterial construction or in patients
data confirm the increased SSI risk in MSSA and MRSA nasal carriers, who are obese or diabetic. Extensive utilization of electrocautery and
but reduction in postoperative infection rate requires a treatment extended application of wound retractors can produce skin and soft
strategy beyond intranasal decolonization alone. Of note, prolonged tissue trauma, which results in large volumes of necrotic tissue that
use of topical mupirocin has been associated with the development become evident in the early postoperative period by cyanotic incision
of resistant strains. Audits of patients admitted for elective arterial skin margins.
revascularization procedures or abdominal aortic aneurysm (AAA)
repair have documented an 4–8% incidence of MRSA nasal coloniza-
tion; but much higher rates of nasal colonization (30–40%) in dialysis-
■■TREATMENT OF VASCULAR
dependent patients (Bandyk 2008). GRAFT INFECTIONS
Procedure-specific risk factors for vascular SSIs include ‘open’
versus endovascular intervention, the presence of a femoral groin The management of vascular SSIs, especially abdominal aorta graft
incision, and prosthetic graft/patch usage. If a procedure lasts >3 h, enteric erosions, fistulas, or mycotic aneurysms, require adherence
is associated with shock or hypothermia, or requires blood transfu- to the guidelines based on clinical presentation, and microbiology
sion, then the likelihood of postoperative infection is increased. that are presented in Table 17.1 and Figure 17.1 (Bandyk et al. 2001,
Intraoperative hypothermia of 1–1.5°C increases the relative risk of Oderich et al. 2001, 2006, Armstrong et al. 2005, Stone et al. 2006,
postoperative infection twofold. SSI risk is lowest after AAA repair with Bandyk 2008, Vogel et al. 2008, Reifsnyder et al. 1992). The diagnostic
a similar incidence after open (0.2%) and stent-graft (0.16%) repair. process begins with computed tomography (CT) to assess extent of
There is an increased incidence of SSIs in patients who developed graft/artery involvement (presence of perigraft fluid–air). This is
any nosocomial infection during hospitalization (Cowie et al. 2005). followed by surgical exploration in selected patients to confirm the
Similarly, carotid endarterectomy and endovascular interventions infectious process and its microbiology. In most patients, steriliza-
involving stent angioplasty (carotid, visceral, iliac, femoropopliteal) tion of the surgical site with parenteral antibiotics and antibiotic bead
are also associated with low (<1%) SSI rates. placement is possible leading to “staged” in situ graft replacement
By contrast, open arterial reconstructions for peripheral arterial using either autologous vein or an antibiotic-impregnated vascular
disease are associated with overall wound and graft infection rates of prosthesis (Bandyk et al. 2001, Oderich et al. 2001, 2006, Stone et al.

Table 17.1 Reported outcome for treatment of aortic and peripheral graft infections (Bandyk et al 2001, Oderich et al 2001, 2006, Armstrong et al 2005,
Stone et al 2006, Bandyk 2008, Vogel et al 2008, Frei et al 2011).
Aortic graft infection
Procedure Operative Amputation Reinfection Survival rate >1 Comments
mortality rate rate (%) rate (%) year (%)
(%)
Ex-situ bypass and total graft excision 11–24 5–25 3–13 73–86 Previously considered the “gold standard”
treatment
In situ replacement and total graft excision
Deep vein 7–10 5 0–1 82–85 Complicated procedure, some patients are
not candidates
Allograft 12–24 5 10–15 70–80 Graft deterioration can occur
Rifampin–PTFE graft 0–15 <5 10–20 80–90 Bridge graft or in situ reconstruction or
biofilm infection

Peripheral graft infections

Graft site Operative mortality rate (%) Amputation or stroke Comments
rate (%)
Infrainguinal bypass 0– 9 5–33 Low (<5%) infection rate with autogenous bypass
Thoracic aorta 10–12 0 Life-long antibiotic suppression
Carotid–subclavian 10–20 10 High morbidity associated with carotid ligation
Carotid patch 5 5–10 Autogenous vein reconstruction recommended
206 VASCULAR SURGICAL SITE INFECTION

Figure 17.1  Algorithm for

Aortic graft evaluation and surgical
infection management of arterial graft
infections.

Body and Aortofemoral CT scan

limbs involved limb involved graft imaging

Virulent bacterial
Total graft infection proximal Biofilm
excision to groin infection
Surgical
exploration
In-situ Extra-anatomic Explore intra- Explore
replacement bypass cavitary segment groin sgment

Antibiotic Infection Intra-cavitary

impregnated Proximal limb No infection localized to graft limb
graft infected idedentified groin infected

Graft excision
Aortic-iliac Excise distal In-situ Excise infected
and in situ vein
allograft graft limb prosthetic graft graft limb
replacement

Lower limb In-situ vein In-situ vein or

deep veins replacement prosthetic graft

2006, Bandyk 2008). Accurate anatomic assessment of the infection aminoglycoside or a fluoroquinolone is recommended for extended
extent is critical because in situ prosthetic replacement should be Gram-negative bacteria coverage. Once the infecting organism has
considered only in the presence of bacterial biofilm infection with been isolated (e.g., by needle aspiration of perigraft fluid or surgi-
no signs of mycotic aneurysm formation. CT, magnetic resonance cal exploration), antibiotic coverage should be modified based on
imaging (MRI), and indium-111-labeled white blood cell scans are antibiotic susceptibility testing of the recovered strains. Antibiotic
helpful in assessment of graft involvement, but surgical exploration therapy, including both parenteral administration and local delivery
remains the most reliable method of confirming or excluding infection. via antibiotic-impregnated beads, is an adjunct to surgical manage-
The presence of hydronephrosis after aortofemoral bypass indicates ment which includes drainage of perigraft abscesses, debridement of
advanced perigraft inflammation and denotes diffuse graft involve- infected tissues, and excision of the infected graft (Stone et al. 2006,
ment by a biofilm infection. Armstrong et al. 2007).

■■Antibiotic therapy ■■Patient selection for in situ

Broad-spectrum bactericidal, parenteral antibiotic therapy should graft replacement
be started on clinical suspicion of a vascular SSI. The most com- The option of in situ replacement therapy depends on the clinical
mon infecting organisms (in decreasing order of prevalence) are presentation, extent of graft infection, and clinical microbiology as
staphylococcal strains (S. aureus, S. epidermidis), streptococci, determined by surgical exploration of the involved graft segment (see
E. coli, Klebsiella and Pseudomonas spp., and Candida albicans. Figure 17.1) (Bandyk et al. 2001, Oderich et al. 2001, 2006). The intent
MRSA now accounts for 50% of early and 25% of late aortofemo- of the evaluation process is to accurately establish whether the infec-
ral graft infections. If S. aureus or S. epidermidis is the proven or tion involves the entire aortic graft or is localized to a graft segment.
suspected pathogen, parenteral antibiotic therapy with a first- or This initial assessment is followed by a determination of whether a
second-generation cephalosporin is employed for MSSA. A preferred graft biofilm is present (amenable to in situ prosthetic grafting) or
antibiotic for Gram-positive infection where MRSA is suspected or there is a more virulent infectious process. If surgical exploration
documented is daptomycin (6 mg//kg with dosing based in renal demonstrates an invasive, virulent graft infection (organisms pres-
function) because of rapid, concentration-dependent bactericidal ent on intraoperative Gram stain, positive perigraft tissue cultures),
activity to all Gram-positive bacteria, including MRSA. Daptomycin an autogenous vein in situ reconstruction should be considered.
has also been demonstrated to penetrate bacteria biofilms and kill Preliminary implantation of antibiotic-impregnated beads in the
bacteria in stationary phase growth. Vancomycin and linezolid are perigraft space is recommended to aid in surgical site sterilization
also be used to treat MRSA infections but these antibiotics have (Stone et al. 2006). For Gram-positive infection, implantation of dap-
time-dependent bacteriostatic activity and do not penetrate bacte- tomycin (1.5 g/40 g bone cement powder) beads is recommended;
ria biofilms. In patients allergic to penicillin, administration of an for Gram-negative infections, tobramycin bone cement should be
 Preventive measures 207

used. When possible, autogenous vein reconstruction of the excised through the skin and attached to a button for extraction at the bedside.
graft segment should be performed in all cases except when a “local- Parenteral antibiotic therapy administration is modified based
ized” biofilm infection is present. When an aortic graft infection is on the explanted graft cultures with the intent to maintain bacte-
associated with a graft–enteric fistula, extra-anatomic (axillofemoral) ricidal serum levels for 4–6 weeks after the in situ grafting proce-
reconstruction together with graft excision and aortic stump closure dure. Before discharge from the hospital a baseline CT scan of the
is still considered the “safest” option when an adequate length of in- abdomen and femoral regions is obtained. This scan is repeated at
frarenal aorta is present for ligation. Infection involving the pararenal 3 months and then every 6–12 months depending on the type of in
aorta should be managed by in situ replacement therapy combined situ reconstruction. In general, prolonged oral antibiotic therapy is
with adjunctive antibiotic bead implantation. not prescribed after femoropopliteal vein (FPV) reconstruction, but
If the infectious process is isolated to an aortofemoral graft limb used for at least 3 months after in situ prosthetic reconstruction.
or peripheral bypass, a staged surgical approach is recommended. The oral antibiotic prescribed is selected based on graft culture
In the presence of extensive inguinal inflammation or abscess, a results and antibiotic susceptibility testing. Reported outcomes
combined inguinal and lower abdominal oblique (“transplanta- for treating aortic and peripheral graft infections are shown in
tion”) retroperitoneal incision can be used for surgical exposure. Table 17.2.
At the initial operation, the perigraft abscess is drained, necrotic
tissue excised, and the cavity is locally irrigated with a solution
composed of half strength hydrogen peroxide and 10 ml Betadine
■■PREVENTIVE MEASURES
(povidone–iodine)/500  ml. This solution disrupts bacterial bio- A multipronged approach is required to minimize the occurrence of
films, and aids in surgical site debridement and tissue steriliza- vascular SSI, including attention to pre-, intra-, and postoperative
tion. Antibiotic beads fabricated within a plastic bead mold are preventive measures published by the Centers for Disease Control
then placed adjacent to the infected graft and the wound closed. in 1999 (Mangram et al. 1999). The guidelines address aspects
The second stage is performed 3–5 days later after culture results of patient preparation, sterile surgical technique, surgical team
are available (Stone et al. 2006). Exploration of the proximal aor- antisepsis, hand disinfection, incision care, and antimicrobial
tofemoral graft limb is performed to assess for the presence of prophylaxis. Surveillance of patients for nasal carriage of S. aureus,
graft incorporation. If found to be uninvolved with infection (i.e., especially MRSA, as well as review in each patient of the inventory
no perigraft fluid), with graft incorporated with surrounding tis- of SSI risk factors, can identify the “high-risk” cases and prompt
sue, the proximal graft limb is clamped and transected. The distal an individualized prevention strategy. The increasing incidence of
graft is then excised to the femoral anastomosis and the graft bed drug-resistant Gram-positive infections after arterial surgery is a
irrigated with an antibacterial solution (clorpactin 3 g/l) using a concern and serves to re-emphasize the importance of preventive
pulsed wound irrigation system. Depending on the prior culture strategies. Surgeon should recognize that expanding the coverage
results, either deep vein or a rifampin-bonded PTFE (polytetra- of antibiotic prophylaxis is not a primary solution. Instead preven-
fluoroethylene) graft is implanted. tion strategies to decolonize the S. aureus carrier in combination
Before wound closure, all surgical fields are pulse lavaged again with meticulous wound care and thoughtful antibiotic prophylaxis
with the clorpactin solution and, if a rifampin graft is used, the ex- is recommended. There is accumulating evidence that regulation
ternal graft surface re-soaked with the rifampin (60 mg/ml) solution of host defense factors – body temperature, oxygenation, and blood
(Oderich et al. 2011). If The Gram stain indicates a Gram-negative sugar – are important in determining the SSI risk in an individual
infection or presence of a graft–enteric erosion, tobramycin powder patient. Care measures to maintain normal temperature during
is spread along the arterial reconstruction and at anastomotic sites. and after surgical procedures, use of insulin therapy to keep blood
Perigraft fluid cavities and empty grafts tunnels are drained using flat, sugar levels <180 mg/dl, and pulse oximetry monitoring to ensure
closed-suction drain systems. Closed-suction drains are also placed 100% hemoglobin saturation are associated with reductions in SSI
in beds of the excised femoral vein and the sartorius muscle is used rates. Supplemental oxygen in the immediate postoperative period
to cover the extracavitary segment of the in situ graft reconstruction. improves incisional oxygen tension and decreases wound-healing
Antibiotic-impregnated beads are placed in the superficial portion complications (Greif et al. 2000).
of the groin wound for 7–10 days to prevent bacterial biofilm forma- Antimicrobial prophylaxis in vascular patients should include
tion. The beads are attached to a 2/0 polypropylene suture brought therapy directed at S. aureus nasal colonization, parenteral anti-

Table 17.2 Patient selection criteria for treatment of a prosthetic graft infection by excision alone, in situ replacement, or ex situ bypass and graft excision.
Treatment option Clinical presentation Microbiology
Excision alone Thrombosed graft and adequate collateral flow + cultures
In situ replacement
  Autogenous vein Invasive graft infection + cultures
 Allograft Invasive graft infection and no suitable autogenous conduit + cultures
  Rifampin-bonded graft Bacterial biofilm graft infection S. epidermidis/S. aureus
Salmonella sp.
Excision and ex situ bypass
  Simultanous procedure Unstable patient with GEE or GEF No exclusion criteria
  Staged procedure Stable patient +/- GEE or GEF No exclusion criteria
GEE, graft enteric erosion; GEF, graft enteric fistula
208 VASCULAR SURGICAL SITE INFECTION

biotic therapy to ensure that adequate tissue levels are achieved

before the procedure is begun and throughout the procedure, Box 17.2 Preventive strategies to prevent vascular surgical site
and surgical site care to impend bacteria colonization of injured infection.
skin and soft tissue is provided (Box 17.2). For effective antibi-
otic prophylaxis, a first- or second-generation cephalosporin is Patient screening for nasal carriage of S. aureus, including MRSA
administered 30–60 min before the procedure. Daptomycin has Preoperative intranasal mupirocin (applied to both nares for 3 days
been used when MRSA is suspected but this is not a Food and before and 2 days after surgery)
Drug Administration (FDA)-approved indication. Daptomycin Hibiclens wipes to decolonize skin surface at planned incision
cannot be used alone for vascular procedure prophylaxis because site(s)
it does not have activity against Gram-negative bacteria known to Antibiotic prophylaxis
produce vascular SSIs. If vancomycin is used for prevention then Cefazolin, weight based, intravenous (IV) 1–3 g slowly 60 min before
the infusion should be initiated 120 min before incision to reduce procedure, and repeated 1–2 g if procedure >3 h or blood loss >1.5 l.
complications of drug administration. The author recommends Dosing repeated every 8 h for 24 h, or IV cefuroxime 1.5 g 60 min
cephalosporin antibiotics should be re-dosed if the procedure takes before surgery and every 12 h for total of 6 g
longer than 3 h or if blood loss exceeds 1.5 l. Preventive antibiotics For “high-risk” patient based on surgical site infection (SSI) risk
are administered for 24 h. factors, including MRSA nasal carriage or history of MRSA infec-
tion – add IV daptomycin 6 mg/kg (single dose) over 2 min before
■■CONCLUSION procedure, or IV vancomycin 15 mg/kg slowly over 1 h, 120 min
before the procedure.
Antimicrobial-resistant pathogens are an increasing threat in preven- If patient has a cephalosporin allergy, give IV aztreonam 1 g 60 min
tion and treatment of vascular SSIs. A program of patient surveillance before procedure and every 8 h for 24 h
for nasal carriage for MRSA, decolonization, preventing transmission If patient has vancomycin allergy, give IV daptomycin 6  mg/kg
to other patients, and thoughtful antibiotic prophylaxis usage, com- (single dose) before procedure
bined with local antiseptic measures (preoperative skin cleansing, an- Soaking vascular prosthesis in a rifampin (30-60 mg/ml) solution
timicrobial sutures, silver eluting dressings), is an effective strategy to for 15 min
reduce SSIs. The entire surgical team must participate in institutional Use of silver-impregnated wound dressing for 24–48 h, followed
efforts to control nosocomial infections, antimicrobial resistance in by topical mupirocin ointment to incision if wound drainage or
bacteria, and SSI rates. injured skin edges present

■■REFERENCES
Armstrong PA, Back MR, Wilson JF, et al. Improved outcomes in the recent
Oderich DS, Panneton JM, Bower TC, et al. Infected aortic aneurysms:
management of secondary aortoenteric fistula. J Vasc Surg 2005;42:660–6.
aggressive presentation, complicated early outcome, but durable results. J
Armstrong PA, Back MR, Bandyk DF, et al. Selective application of sartorius
Vasc Surg 2001;34:900–8.
muscle flap and aggressive staged surgical debridement can influence long-
Oderich GS, Bower TC, Cherry KJ, et al. Evolution from axillofemoral to in situ
term outcomes of complex graft infections. J Vasc Surg 2007;46:71–8.
prosthetic reconstruction of the treatment of aortic graft infection at a single
Bandyk DF. Antibiotics – Why so many and when should we use them? Semin
center. J Vasc Surg 2006;43:1166–74.
Vasc Surg 2002;15:268–274.
Oderich GS, Bower TC, Hofer J, et al. In situ rifampin-soaked grafts with omental
Bandyk DF. Vascular surgical site infection – risk factors and preventive
coverage and antibiotic suppression are durable with low infection rates in
measures. Semin Vasc Surg 2008;21:119–123.
patients with aortic graft enteric erosion or fistula. J Vasc Surg 2011;53:99–
Bandyk DF, Novotney M, Johnson BL, Back, MR, et al. Expanded application of in
107.
situ replacement for infected vascular grafts. J Vasc Surg 2001;34:411–20.
Perl TM, Cullen JJ, Wenzel RP, et al. The mupirocin and the risk of Staphylococcus
Cowie SE, Ma I, Lee SK, et al. Nosocomial MRSA infection in vascular patients:
aureus study team: intranasal mupirocin to prevent postoperative
Impact on patient outcome. Vasc Endovasc Surg 2005;39:327–34.
Staphylococcus aureus infections. N Engl J Med 2002;346:1987–90.
Culver DH, Horan TC, Gaynes RP, et al. Surgical wound infection rates by wound
Pounds LL, Montes-Walters M, Mayhall CG, et al. A changing pattern of infection
class, operative procedure, and patient risk index. Am J Med 1991;91:S152–7.
after major vascular reconstructions. Vasc Endovasc Surg 2005;39:511–15.
Frei E, Hodgkiss-Harlow KD, Rossi PJ, et al. Microbial pathogenesis of bacterial
Reifsnyder TR, Bandyk DF, Seabrook G, et al. Wound complications of the in situ
biofilms: A causative factor of vascular surgical site infection. Vasc Endovasc
saphenous vein bypass technique. J Vasc Surg 1992;15:843–50.
Surg 2011;45:688–96.
Stone PA, Armstrong PA, Bandyk DF, et al. Use of antibiotic-loaded
Grief R, Akca O, Horn EP, et al. for the Outcomes Research Group. Supplemental
polymethylmethacrylate beads for the treatment of extracavitary prosthetic
perioperative oxygen to reduce of surgical-wound infection. N Eng J Med
graft infections. J Vasc Surg 2006;44:757–61.
2000;342:161–7.
Vogel TR, Symons R, Flum DR. The incidence and factors associated with graft
Mangram AJ, Horan TC, Pearson ML, et al. Hospital Infection Control Practices
infection after aortic aneurysm repair. J Vasc Surg 2008;47:264–9.
Advisory Committee. Guideline for prevention of surgical site infection, 1999.
Vogel TR, Dombrovsky VY, Carson JL, et al. Infectious complications after
Infect Control Hosp Epidemiol 1999;20:250–61.
elective vascular surgical procedures. J Vasc Surg 2010;51:122–30.
Chapter 18 Urological infections
Mathew C. Raynor, Ian Udell, Raj Kurpad, Culley C. Carson

Urological infections are one of the most common reasons people to rule out the presence of hydronephrosis. CT can be performed with
seek medical attention and the urinary tract is the most common entry or without intravenous contrast agents to assess for hydronephrosis or
point for bacteria causing nosocomial infections, bacteremia, and calculus disease. There are no specific radiological findings on CT to
sepsis. Over half of women will have at least one urinary tract infec- diagnose pyelonephritis. Some subtle findings to suggest the diagnosis
tion during their lifetime and most of these will require a physician include renal enlargement and perinephric fat stranding. In reality, if
visit and antibiotic treatment. The high prevalence continues to the a patient presents with acute fever and flank or abdominal pain, most
inpatient setting where genitourinary infections are the most common patients will undergo cross-sectional abdominal imaging to evaluate
nosocomial infection. The efficient diagnosis and effective treatment for other causes, such as appendicitis, diverticulitis, or urolithiasis.
of urological infections is a major healthcare concern. Factors such Imaging should be strongly considered in a patient with clinical signs
as economic efficiency and emerging resistance are increasingly and symptoms of pyelonephritis and risk factors for a complicated
becoming more important considerations in providing patient care. UTI. These include known functional or anatomic abnormalities in
Urological infections are among the most likely to be multi-antibiotic the urinary tract, recent instrumentation, recent antibiotic use, im-
resistant and are often difficult to treat without combined medical munosuppression, pregnancy, or history of diabetes.
and surgical approaches. Escherichia coli accounts for about 80% of cases of pyelonephritis.
Special virulence, including P pili, K antigens, and endotoxins contrib-
■■PYELONEPHRITIS ute to the pathogenesis of infection. Patients with P blood group anti-
gen receptors may be susceptible to recurrent bouts of pyelonephritis
Pyelonephritis refers to inflammation of the kidney and renal pel- due to the ability of the bacteria to adhere to the receptor through P
vis and is considered an upper urinary tract infection (UTI). Acute pili, and lead to repeated episodes of infection (Roberts 1991). Patients
pyelonephritis is a clinical diagnosis based on the classic presenta- with a history of recurrent UTIs or those with recent hospitaliza-
tion of fever (>100°F), chills, and flank or costovertebral angle pain. tion, instrumentation, or indwelling catheter may be prone to more
These signs and symptoms may be associated with urinary urgency, resistant species of bacteria, including Proteus, Klebsiella, Serratia,
frequency, and dysuria. However, patients do not always present with Enterobacter, or Citrobacter spp. Enterococcus faecalis, Staphylococ-
classic symptoms. Gastrointestinal symptoms, such as nausea and em- cus epidermidis, and S. aureus are the most common Gram-positive
esis may be present. Patients usually have a history of a previous UTI. organisms to cause pyelonephritis.
Diagnosis of acute pyelonephritis is based mainly on clinical Management of acute pyelonephritis depends on properly clas-
symptoms. Laboratory diagnosis consists of urinalysis, urine culture, sifying patients into uncomplicated and complicated groups. Any
complete blood count (CBC), and serum chemistries. Urinalysis patient with presumed acute pyelonephritis without complicating
usually demonstrates evidence of inflammation and infection with factors and minimal symptoms without significant nausea or emesis
hematuria, pyuria, and bacteriuria. Leukocytosis is usually present can be treated as an outpatient. Empirical oral antimicrobial therapy
with a predominance of neutrophils. Serum creatinine is usually should be initiated until results of urine cultures are finalized. In
normal. However, an elevated creatinine could indicate the presence the vast majority of cases, E. coli is the causative bacterium. A much
of obstruction or severe infection. Blood cultures are not routinely smaller percentage of Gram-positive bacteria can cause pyelonephritis
drawn, unless the patient exhibits signs of significant illness (sepsis) (S. epidermidis, S. aureus, and E. faecalis). Therefore, antimicrobial
or has risk factors for a complicated UTI, including previous urological therapy can be chosen based on the presumed causative bacteria.
instrumentation, indwelling catheter, urinary tract anatomic abnor- Typically, a fluoroquinolone for 10–14 days is sufficient in an oth-
mality, or pregnancy. Blood cultures have been shown to be positive erwise healthy non-pregnant patient with a normal urinary tract.
in about a quarter of patients, with uncomplicated pyelonephritis Alternatively, trimethoprim–sulfamethoxazole can be used for 10–14
in women (Velasco et al. 2003). However, this finding does not alter days. If a Gram-positive organism is suspected, then amoxicillin or
management decisions about therapy, so blood cultures can be omit- amoxicillin–clavulanic acid can be used.
ted in cases of uncomplicated pyelonephritis. Patients who are severely ill or have complicating factors require
The use of imaging studies in the diagnosis of acute pyelonephritis hospital admission. These patients should undergo abdominal
is a difficult clinical decision. The presence of a urinary tract obstruc- imaging to evaluate for obstruction or other causes of illness. Broad-
tion or stone in the setting of acute infection would certainly alter treat- spectrum parenteral antibiotics should be instituted, including a
ment strategies. However, most cases of uncomplicated pyelonephritis fluoroquinolone, aminoglycoside with or without ampicillin, or
do not result from a stone or obstruction. Imaging options include extended-spectrum cephalosporin with or without an aminoglycoside
plain radiograph, intravenous urogram (IVU), renal ultrasonography, (Warren et al. 1999). If there is any evidence of urinary tract abnormal-
or computed tomography (CT). The use of plain radiographs has a very ity or obstruction, urgent urological consultation is needed because
limited role in the management of the urinary tract. It may be useful to drainage of the urinary tract may be required with either a ureteral
investigate other causes of abdominal pain. Likewise, IVU has fallen stent or percutaneous nephrostomy. Parenteral antibiotic therapy
out of favor, given the routine availability and better anatomic detail should be continued until susceptibilities are returned and the patient
with other modalities. Renal ultrasonography is a useful screening tool demonstrates clinical improvement. Once improved and afebrile for
210 UROLOGICAL INFECTIONS

more than 24 h, oral antibiotics can be started and continued for a imaging procedure of choice, given its excellent anatomic delinea-
total of 14 days. If a patient remains febrile with or without persistent tion (Figure 18.1).
leukocytosis after 72 h of therapy, then repeat abdominal imaging is Management involves broad-spectrum antibiotics. In cases of small
warranted to evaluate for possible renal or perinephric abscess. In (<3 cm) renal abscesses, these can be managed similar to complicated
addition, repeat cultures from urine and blood should be obtained. pyelonephritis, with parenteral antibiotics and conversion to oral an-
Follow-up urine culture should be obtained before completion of tibiotics. Follow-up imaging is needed to document improvement or
therapy and again several weeks after completion of therapy to ensure resolution of the abscess. In cases of larger renal abscesses (>3–5 cm),
sterility. Relapse of infection can occur and usually requires a repeat smaller abscesses that do not respond to antimicrobial therapy, pa-
14-day course of culture-specific therapy. tients with diabetes, or in immunosuppressed patients, percutane-
ous aspiration and drainage of the abscess are indicated. Antibiotic
■■RENAL ABSCESS/PERINEPHRIC regimens can be tailored to culture results. Urological consultation
is recommended in these cases, because follow-up imaging will be
ABSCESS necessary. With today’s improvements in imaging and image-guided
therapy, surgical drainage is rarely necessary (Shu et al. 2004).
Renal abscess refers to an abscess confined to the renal parenchyma, Management of perinephric abscesses requires drainage. These
whereas a perinephric abscess refers to an abscess cavity extending abscesses do not respond to antimicrobial therapy alone. Most of these
into or involving the perinephric space. Perinephric abscesses can cases can be aspirated and drained percutaneously. Surgical drain-
result from extension of a renal abscess into the perinephric space or age is, again, usually not required. However, in cases of large abscess
extension from another source, such as a psoas abscess, perforated cavities or poorly functioning kidneys, open drainage or nephrectomy
appendicitis, or diverticulititis. Renal abscesses usually arise from may be necessitated. In addition, the presence of a perinephric ab-
ascending urinary tract infections and can often be associated with ob- scess usually indicates an underlying problem. This could include an
struction or calculus disease. Gram-negative bacteria account for most obstructed and infected kidney or a possible enteric communication.
renal abscesses. Gram-positive organisms can spread hematogenously Further treatment directed at the underlying cause is needed once the
and should be suspected in patients with symptoms of pyelonephritis abscess has been appropriately managed.
and coexisting skin infections, endocarditis, or intravenous drug use.
On the other hand, perinephric abscesses can often be polymicrobial.
Diagnosis of a renal or perinephric abscess is suspected in patients
■■EMPHYSEMATOUS
with fever and abdominal or flank pain. In addition, renal or perineph- PYELONEPHRITIS/PYELITIS
ric abscess should be suspected in patients with clinical pyelonephritis
who have remained febrile for >72 h despite appropriate antimicrobial Emphysematous pyelonephritis is a rare and very serious infection
therapy. A marked leukocytosis is usually present. Urinalysis and involving gas-forming bacteria, which results in renal parenchymal
urine culture can be misleading. These tests can often be negative in necrosis. This condition usually occurs in patients with diabetes and
a patient in whom the abscess cavity does not communicate with the has a high mortality rate, ranging from 19% to 60% (Somani et al. 2008).
collecting system. This situation most commonly occurs where there In addition to diabetes, many patients may have underlying poor renal
has been hematogenous spread of an infection. Blood cultures are function, urolithiasis, or urinary tract obstruction.
usually positive in these cases. Diagnosis is made on the basis of clinical findings and, primarily,
Unlike cases of uncomplicated pyelonephritis, imaging is diag- on imaging studies. Most patients have diabetes and present with high
nostic for renal or perinephric abscess. Ultrasonography is a very fever, flank pain, and vomiting. Laboratory studies show a significant
reliable and inexpensive method of diagnosis. However, CT is the leukocytosis and may demonstrate elevated serum creatinine, resulting

a b

Figure 18.1  Renal abscess. (a) Hypoattenuating fluid collection with enhancing rim confined to the renal parenchyma. (b) Imaging after antibiotics and
percutaneous drainage demonstrates resolution.
 Management of urinary infection with obstruction 211

from parenchymal necrosis and destruction. Urinalysis and urine culture

usually demonstrate bacteriuria. The most common causative organism
■■MANAGEMENT OF URINARY
is E. coli, followed by Proteus and Klebsiella spp. These patients are gener- INFECTION WITH OBSTRUCTION
ally severely ill, with sepsis and hypotension common.
Imaging is diagnostic of emphysematous pyelonephritis. Plain In patients with evidence of UTI and imaging demonstrating ob-
radiograph or IVU is rarely used, but can demonstrate a collection struction of the urinary tract, urological consultation is warranted.
of gas around the location of the kidney. This can be confused with Obstruction causing hydronephrosis in the setting of an infection can
bowel gas. CT is the imaging modality of choice, and demonstrates lead to serious complications, including sepsis and death. The causes
significant loculated gas throughout the renal parenchyma, even of obstruction include urolithiasis, ureteral stricture or scar, extrinsic
extending into the perinephric space. In severe cases, there can be compression, or significant bladder outlet obstruction resulting in uri-
complete destruction of the renal parenchyma. Emphysematous nary retention (Figure 18.2). In the setting of obstruction and infection,
pyelonephritis must be differentiated from emphysematous pyelitis. pyonephrosis can occur. This term refers to a collection of purulent
This entity refers to the finding of gas within the collecting system of material in the collecting system proximal to the site of obstruction. This
the kidney and not in the renal parenchyma. This condition is usually is essentially equivalent to an abscess in the urinary tract. Prompt inter-
caused by a gas-forming bacterial UTI and does not require any spe- vention and drainage of the urinary tract are needed, usually including
cial intervention unless urinary tract obstruction is present. In cases Foley catheter placement, ureteral stent placement, or nephrostomy
of emphysematous pyelonephritis, a renal scan is recommended to drainage. Culture-specific antibiotics should be continued for at least
assess split renal function. 14 days and management of the underlying cause will be needed. In
Emphysematous pyelonephritis should be treated as an emergency. general, in cases of urinary tract obstruction and coexisting infection,
Patients are generally severely ill and require aggressive hydration, antibiotics and urinary tract drainage are necessitated.
broad-spectrum antimicrobial therapy, and management of sepsis. Xanthogranulomatous pyelonephritis (XGP) represents a rare
Urological consultation should be promptly obtained. Historically, and severe form of renal deterioration secondary to obstruction and
emphysematous pyelonephritis was considered a surgical emergency infection. Most patients present with flank pain, fever, and recurrent
and usually resulted in emergent nephrectomy. However, recent UTI with persistent bacteriuria. CT is the imaging modality of choice
evidence suggests that medical management may actually improve and usually demonstrates an enlarged, poorly functioning kidney with
outcomes and renal salvage (Pontin and Barnes 2009). In a recent dilated calyces and thinning of the renal parenchyma. In most cases,
systematic review, mortality rates were 50% with medical management the condition affects the entire kidney. The classic radiological finding
alone, 25% with medical management and emergent nephrectomy, is a severely enlarged, hydronephrotic kidney with a thin rim of paren-
and 13.5% with medical management and percutaneous nephrostomy chyma and a centrally obstructing stone in the renal pelvis. Multiple
drainage (Somani et al. 2008). renal or perinephric abscesses can occur (Figure 18.3). Proteus spp.
In general, management usually involves emergent percutaneous and E. coli are the most common causative bacteria (Korkes et al.
drainage of the affected kidney with a percutaneous nephrostomy. If 2008). Nuclear medicine renal function studies usually demonstrate
conservative management fails, surgical therapy may be considered, severely diminished or no function in the affected kidney.
but mortality rates after failure of conservative therapy are extremely Management of XGP depends on the initial presentation and
high. Risk factors for mortality with emphysematous pyelonephritis renal function of the affected kidney. Patients presenting acutely ill
include altered mental status, thrombocytopenia, hyponatremia, and need medical stabilization and imaging to investigate for abscess
bilateral renal involvement. Surgical therapy after successful conserva- and/or obstruction. Acute management of these patients usually
tive management may still be required if significant renal parenchymal involves broad-spectrum antibiotics and percutaneous drainage of
destruction has occurred. the kidney. Once stabilized and treated with appropriate antibiotics,

a b

Figure 18.2  Ureteral obstruction and infection. (a) Cross-sectional imaging demonstrates hydronephrosis and perinephric fat stranding. (b) A mid-ureteral
obstructing stone was identified with proximal hydroureter.
212 UROLOGICAL INFECTIONS

for testicular torsion. Further evaluation usually involves urinalysis

and urine culture, especially in patients with indwelling urinary
catheters or recent urinary instrumentation. In men at risk for a sexu-
ally transmitted infection, urethral swabs should also be obtained. In
young boys with epididymo-orchitis, evaluation should also include
abdominal ultrasonography and voiding cystourethrography, because
these patients may have an underlying urinary tract anatomic abnor-
mality (Tracy et al. 2008).
In most cases of postoperative epididymo-orchitis, the underlying
cause is urinary tract instrumentation or urinary catheterization, and
subsequent UTI. Indwelling urinary catheters are commonly left in
critically ill patients for volume monitoring, after urological procedures
for healing, secondary to mobility issues after surgery or injury, in
spinal cord injury patients, or in patients with urinary retention. These
patients are at higher risk of developing a catheter-associated UTI and
are at risk for development of acute epidiymo-orchitis.
Treatment is usually directed at the underlying cause, if identified.
Scrotal elevation and anti-inflammatory medications are helpful in
Figure 18.3  Xanthogranulomatous pyelonephritis. Imaging shows a large managing discomfort. Antibiotics are tailored to the specific pathogen
centrally obstructing stone with complete obliteration of renal parenchyma
and are usually continued for 14 days. However, urine cultures are
and perinephric abscesses.
frequently non-diagnostic and treatment is started empirically. The
Centers for Disease Control recommends that men aged <35 receive
treatment then depends on renal function. If the kidney still main- ceftriaxone or doxycycline and men >35 receive a fluoroquinolone
tains decent function, management of the obstructing stone and UTI (Workowski and Berman 2011).
can be pursued. Segmental involvement of XGP may be amenable to
partial nephrectomy. If the kidney has little or no function, delayed
nephrectomy is usually recommended.
■■PROSTATITIS/PROSTATE ABSCESS
Prostatitis represents one of the most common urological complaints
■■EPIDIDYMO-ORCHITIS among men, affecting up to 16% of men in their lifetime (Sharp et
al. 2010). Prostatitis can be subdivided into several classifications,
Epididymitis and orchitis refer to inflammation of the epididymis and ranging from acute bacterial prostatitis to chronic pelvic pain syn-
testis, respectively. These conditions manifest clinically with pain, drome and asymptomatic prostatitis. This section focuses only on
swelling, and inflammation. Epididymo-orchitis can be divided into infectious causes because as these would be most prevalent in the
several classifications, including acute bacterial, non-bacterial infec- surgical patient.
tious, non-infectious, and chronic epididymo-orchitis. This section Acute bacterial prostatitis refers to acute infection of the prostate
focuses on the acute infectious and non-infectious causes, because and usually requires urgent treatment. Often, these patients are acutely
these types would be most common in the surgical patient. ill with symptoms of a UTI. High fever, significant suprapubic pain,
Acute infectious epididymo-orchitis is most commonly caused by dysuria, urinary urgency, and even urinary retention from prostate
urinary pathogens reaching the epididymis and testis from the urethra, inflammation can be present. Patients may exhibit signs of sepsis in
prostate, or bladder through the ejaculatory ducts and vasa deferen- advanced cases. Physical examination usually demonstrates lower
tia. In boys and elderly men, coliform organisms that are common abdominal tenderness to palpation. Examination of the scrotum may
causes of bacteriuria are the most frequent causative agents (E. coli). demonstrate epididymal or testicular pain on palpation, if concomi-
In young, sexually active men, sexually transmitted infections are the tant epididymo-orchitis is present. Digital rectal examination can
most common cause (Neisseria gonorrheae, Chlamydia trachomatis) confirm the suspected diagnosis because the prostate is exquisitely
(Berger et al. 1979). tender to gentle touch, although prostate massage must be avoided
Acute non-bacterial causes of infection include viral, fungal, and as this may cause florid bacteremia or sepsis. Imaging is usually not
parasitic organisms. Mycobacterial organisms have also been im- necessary in the initial diagnostic evaluation. Bladder ultrasonography
plicated, including granulomatous inflammation seen after bacillus may be useful to evaluate for urinary retention. Indwelling urethral
Calmette–Guérin (BCG) bladder instillations for the treatment of catheters are also a significant risk factor for acute prostatitis and UTI.
bladder cancer. In rare cases of isolated orchitis without epididymitis, Laboratory studies likely show a leukocytosis. Urinalysis and mid-
a viral cause is found, most commonly mumps and mononucleosis. stream urine culture should be obtained and identify a causative
Clinical presentation of acute epididymo-orchitis is usually acute- pathogen in most cases. E. coli is the most common bacterial cause
onset scrotal pain and swelling. Patients may experience fever and of acute prostatitis. Other causative organisms include Klebsiella and
other symptoms suggestive of a coexisting UTI, along with abdomi- Pseudomonas spp., and enterococci. Younger sexually active men
nal pain, nausea, and emesis. Sexually active men may complain of should also be screened for N. gonorrhea and C. trachomatis with a
concomitant urethral discharge, suggestive of a sexually transmitted urethral swab.
infection. Physical examination typically demonstrates a tender, Treatment of acute prostatitis involves antibiotics. Typically,
erythematous, and/or edematous scrotum. The affected testis and acutely ill patients require admission and parenteral broad-spectrum
epididymis are usually exquisitely tender to palpation. Pain may be antibiotics, usually with a penicillin derivative and an aminoglycoside
improved with scrotal elevation. (ampicillin and gentamicin). For patients with acute urinary retention,
Diagnostic evaluation of any acute onset scrotal pain should in- urinary catheter drainage may be needed. Treatment is continued
clude scrotal ultrasonography with Doppler flow studies to evaluate until the patient is afebrile and then antibiotics are tailored to urine
 Necrotizing fasciitis (Fournier gangrene) 213

culture sensitivities. Antibiotics should be continued for 4–6 weeks. abscess can be performed via transrectal or transperineal ultrasound-
If no clinical improvement is seen or if fever persists, pelvic imaging guided aspiration and drainage or via transurethral unroofing and
should be obtained to evaluate for prostatic abscess (pelvic CT with/ drainage. Transurethral drainage is considered the gold standard
without intravenous contrast). Mildly ill patients may be treated as procedure but requires general or spinal anesthesia. Worsening of
an outpatient with oral antibiotics for 4–6 weeks (trimethoprim–sul- sepsis is possible with drainage. Suprapubic catheter placement may
famethoxazole or a fluoroquinolone). be necessary in cases of large prostate abscesses, but urethral cath-
Chronic bacterial prostatitis refers to a persistent bacterial infection eterization usually suffices. Catheter drainage should continue for
of the prostate. Chronic bacterial prostatitis is the most common cause 1–2 weeks and antibiotic therapy should be continued for 4–6 weeks.
of recurrent UTI in men. E. coli and enterococci are the most com- Repeat imaging is recommended to ensure resolution.
mon causes. Etiologies as to the cause of chronic bacterial prostatitis
range from persistent untreated bacteria after acute prostatitis, BPH
with urinary obstruction, urethral stricture, to urinary catheterization
■■NECROTIZING FASCIITIS
or instrumentation. (FOURNIER GANGRENE)
Diagnosis is usually made on history and physical examination.
In contrast to acute bacterial prostatitis, men with chronic bacterial Necrotizing fasciitis of the male genitalia represents a urological
prostatitis do not usually appear ill. Urinary urgency, frequency, and emergency. It is a life-threatening infection with a mortality rate of
dysuria are common, suggestive of an underlying UTI. Perineal and up to 40% (Morpurgo and Galandiuk 2002). Immunocompromised
scrotal pain may also be present. Fevers are uncommon. Physical ex- patients, including patients with diabetes or alcohol dependence,
amination findings often vary and may demonstrate a tender prostate, may be at higher risk due to atypical presentation or delayed diag-
but this is not a universal finding. nosis. In the vast majority of cases, mixed bacterial flora are isolated,
Diagnosis involves examination of the urine. A modified two-glass including Gram-positive, Gram-negative, and anaerobic bacteria.
voiding test can be used to identify bacterial prostatitis. This test Group A streptococcal infections of the soft tissue can also occur,
involves a mid-stream urine specimen collected and examined for even in healthy immunocompetent patients. The source of infection
WBCs and bacteria and an additional urine specimen obtained after can arise from the skin, urethra or rectum. Local skin infections, such
vigorous prostate massage via digital rectal examination. In addition, as balanitis (cellulitis of glans penis), posthitis (cellulitis of prepucial
expressed prostatic secretions (EPSs) obtained at the time of prostate skin), or scrotal/perineal abscess can lead to necrotizing infections.
massage may be examined and sent for culture. Theoretically, the Perirectal abscesses and urethritis, especially associated with urethral
initial urine specimen represents bladder flora. The post-prostate stricture disease, can lead to perineal spread of infection. Necrotizing
massage specimen represents a mixture of prostatic and bladder flora. fasciitis can also be seen postoperatively after circumcision, hernia
An increase in WBCs or bacteria of the post-prostate massage or EPSs repair, orchiectomy, or any other inguinal, perineal, or scrotal surgery.
is indicative of bacterial prostatitis. Serum prostate-specific antigen Necrotizing fasciitis can spread rapidly along fascial planes and extend
(PSA) is rarely indicated in the diagnosis of prostatitis and is likely to along the abdominal wall to the chest in advanced cases.
be markedly elevated. Patients usually present acutely ill with fevers and significant pain
Treatment for chronic bacterial prostatitis involves antibiotics. out of proportion to the visible extent of infection. Physical examina-
Fluoroquinolones are the preferred treatment, due to their ability tion usually reveals significant erythema suggestive of cellulitis. Ne-
to concentrate in the prostate. Doxycycline or trimethoprim–sulfa- crotic appearing skin may be visible as the subcutaneous infection
methoxazole is considered a second-line treatment alternative. Treat- progresses, leading to vascular congestion, thrombosis, and ischemia
ment should be continued for a minimum of 4 weeks. Recurrence is of small vessels to the skin. Crepitus (“popping” or cracking sound
relatively common (Benway and Moon 2008). with palpation) may be present and represents collection of gas in the
Prostate abscess represents a rare infectious condition, although subcutaneous tissues (Figure 18.4). The penis should be examined for
it is more prevalent in immunocompromised patients and should be extent of disease and potential causative infectious sources. Likewise,
considered (Lebovitch and Mydlo 2008). Prostate abscesses may arise rectal examination should be performed to evaluate for abscess.
from a concomitant UTI or acute prostatitis, hematogenous spread Laboratory evaluation usually demonstrates leukocytosis and
(especially Gram-positive bacteria), or iatrogenic (prostate biopsy). anemia. Elevated serum creatinine, hyponatremia, and hypercalcemia
E. coli is the most common cause, followed by enterococci. are common. Imaging can be obtained in cases where the diagnosis
Diagnosis of prostate abscess is suspected based on history and is in doubt. However, imaging should not delay surgical exploration
physical examination. Urine culture should be obtained and is usually when the index of suspicion is high. CT is the imaging modality of
positive. Patients may present similar to acute prostatitis, appearing choice and can demonstrate subcutaneous air and/or abscess. Plain
quite ill with fever and suprapubic pain. Dysuria is common. Urethral radiography may also show pockets of subcutaneous gas (Figure 18.5)
discharge may be present if the abscess cavity communicates with the (Levenson et al. 2008).
urethra. Digital rectal examination should be performed gently and The mainstay of treatment is surgical intervention. Broad-spectrum
usually demonstrates an exquisitely tender prostate with possible fluc- parenteral antibiotics are started but removal of the involved soft tis-
tuance. Urinary retention is common. Imaging should be performed sue is paramount to patient survival. Aggressive wide debridement
in patients where prostate abscess is suspected. A pelvic CT with and of involved skin and soft tissue is undertaken. Removal of all visibly
without intravenous contrast is the procedure of choice. Transrectal necrotic skin with debridement back to healthy bleeding tissue is
ultrasonography may also be useful. necessitated. Usually, the testes are not involved and can be spared.
Treatment is usually multimodal. Small abscesses (<1 cm) in pa- In cases where scrotal skin is excised, the testes can be wrapped with
tients who are not severely ill or immunocompromised may be treated saline gauze and preserved. Historically, thigh pouches were created to
with bladder drainage and parenteral antibiotics. Repeat imaging is protect the testes, but this practice is rarely performed today. Urinary
necessary to ensure response to treatment. However, most patients diversion with suprapubic catheter drainage and bowel diversion
require intervention to drain the abscess. Broad-spectrum parenteral with diverting colostomy may be required in advanced cases. After
antibiotics are initiated and tailored to culture results. Drainage of the debridement, a large tissue defect is usually present. Wound packing
214 UROLOGICAL INFECTIONS

Figure 18.4  Fournier

gangrene.
Examination reveals
necrotic tissue at
the base of scrotum
extending inferiorly to
perineum.

Figure 18.5  Fournier

gangrene. (a) Cross-
sectional and (b)
coronal imaging
demonstrate massive
or a negative-pressure wound device (wound vac) is usually required. subcutaneous gas
Patients routinely return to the operating room in 24–48 h after initial present within the
debridement for re-evaluation and excision of unhealthy tissue. In perineum, scrotum,
most cases, multiple debridement procedures are required. Hyper- and anterior
abdominal wall.
baric oxygen therapy has been shown in some studies to be beneficial
Surgical exploration
in improving wound healing after excision. identified the source
After debridement, most patients require extensive skin grafting as a ruptured sigmoid
to cover large tissue defects. Primary closure of scrotal defects can be diverticulum.
performed even when up to 50% of scrotal skin has been removed.
Otherwise, meshed split-thickness skin grafts are used. The testes are
sewn together in approximation before grafting to prevent formation
of a bifid neoscrotum. Non-meshed skin grafts are used to cover penile
skin defects (Chen et al. 2010).
Necrotizing fasciitis is a true surgical emergency and requires
a team approach. These patients are usually acutely ill and require
critical care expertise in addition to urologists, general surgeons, b
and plastic surgeons to appropriately treat this potentially rapidly
progressive condition.

■■REFERENCES
Benway BM, Moon TD. Bacterial prostatitis. Urol Clin North Am 2008;35:23–32, v. Sharp VJ, Takacs EB, Powell CR. Prostatitis: diagnosis and treatment. Am Fam
Berger RE, Alexander ER, Harnisch JP, et al. Etiology, manifestations and Physician 2010;82:397–406.
therapy of acute epididymitis: prospective study of 50 cases. J Urol Shu T, Green JM, Orihuela E. Renal and perirenal abscesses in patients with
1979;121:750–4. otherwise anatomically normal urinary tracts. J Urol 2004;172:148–50.
Chen SY, Fu JP, Wang CH, et al. Reconstruction of scrotal and perineal defects in Somani BK, Nabi G, Thorpe P, et al. Is percutaneous drainage the new gold
Fournier’s gangrene. J Plast Reconstr Aesthet Surg 2010;64:528–34. standard in the management of emphysematous pyelonephritis? Evidence
Korkes F, Favoretto RL, Broglio M, et al. Xanthogranulomatous pyelonephritis: from a systematic review. J Urol 2008;179:1844–9.
clinical experience with 41 cases. Urology 2008;71:178–80. Tracy CR, Steers WD, Costabile R. Diagnosis and management of epididymitis.
Lebovitch S, Mydlo JH. HIV-AIDS: urologic considerations. Urol Clin North Am Urol Clin North Am 2008;35:101–8; vii.
2008;35:59–68; vi. Velasco M, Martinez JA, Moreno-Martinez A, et al. Blood cultures for women
Levenson RB, Singh AK, Novelline RA. Fournier gangrene: role of imaging. with uncomplicated acute pyelonephritis: are they necessary? Clin Infect Dis
Radiographics 2008;28:519–28. 2003;37:1127–30.
Morpurgo E, Galandiuk S. Fournier’s gangrene. Surg Clin North Am Warren JW, Abrutyn E, Hebel JR, et al. Guidelines for antimicrobial treatment of
2002;82:1213–24. uncomplicated acute bacterial cystitis and acute pyelonephritis in women.
Pontin AR, Barnes RD. Current management of emphysematous pyelonephritis. Infectious Diseases Society of America (IDSA). Clin Infect Dis 1999;29:745–58.
Nat Rev Urol 2009;6:272–9. Workowski KA, Berman SM. Centers for Disease Control and Prevention Sexually
Roberts JA. Etiology and pathophysiology of pyelonephritis. Am J Kidney Dis Transmitted Disease Treatment Guidelines. Clin Infect Dis 2011;53(suppl
1991;17:1–9. 3):S59–63.
Chapter 19 Bone and joint infections
Charalampos G. Zalavras, Michael J. Patzakis

■■INTRODUCTION bind molecules such as fibronectin and facilitate adhesion of the

organism on host tissues as well as prosthetic devices. The organism
Bone and joint infections are challenging to treat, lead to morbidity evades host defenses by several strategies: Protein A inactivates im-
and even mortality, and have a considerable socioeconomic impact. munoglobulins, chemotaxis inhibitory protein interferes with leuko-
Infections after orthopedic procedures prolong hospitalization, in- cyte chemotaxis, capsular polysaccharide reduces opsonization and
crease healthcare costs, create physical limitations, and reduce quality phagocytosis of the organism, and leukocidins damage leukocytes.
of life for patients (Whitehouse et al. 2002, Lee et al. 2006, Poultsides Staph. aureus releases enzymes that destroy host tissues and produces
et al. 2010). Orthopedic surgical site infections significantly increase toxins that lead to a systemic inflammatory reaction.
the median duration of hospitalization (19 days with infection versus Infections with Staph. aureus may persist because of slow growing
5 days without) and median direct cost of hospitalization ($24 344 vs subpopulations that may persist intracellularly (small colony vari-
$6636 in 1997 and 1998 prices) (Whitehouse et al. 2002). Infection after ants) and/or biofilm formation. Biofilm formation is a key pathogenic
orthopedic surgery in elderly patients is an independent risk factor mechanism of chronic musculoskeletal infections (Costerton et al.
for mortality (Lee et al. 2006). 1999, Costerton 2005, Zalavras and Costerton 2009). A biofilm is a
Therefore, the importance of prevention, prompt diagnosis, and highly structured multicellular community of microorganisms that
effective treatment cannot be overemphasized. The treatment goals adhere to an inert or living surface, and are embedded within a self-
are control of infection and restoration of function. Pathogen resis- produced polymeric matrix mainly composed by polysaccharides.
tance and tissue loss resulting from infection or surgical debridement Biofilm microorganisms demonstrate decreased susceptibility to
often complicate achievement of these goals. The treatment principles antibiotics and host immune responses compared with individual
include aggressive surgical debridement, appropriate antibiotic ad- or planktonic organisms. Protective mechanisms include incomplete
ministration, and, if needed, bone stabilization, soft-tissue coverage, biofilm penetration by antibiotics and antibodies, altered chemical
and bone defect reconstruction (Patzakis and Zalavras 2005). This microenvironment, slow-growing or starved state of biofilm cells,
chapter discusses the pathogenesis, diagnosis, and management of and development of resistant phenotypes as an adaptive response
the common bone and joint infections. to stress. As a result, formation of biofilm leads to persistence and
chronicity of infection (Costerton et al. 1999, Costerton 2005). Radical
■■PATHOGENESIS debridement with removal of foreign bodies and nonviable bone and
soft tissue is essential for control of infection (Patzakis and Zalavras
The pathogenesis of musculoskeletal infections involves, first, inocu- 2005, Zalavras and Costerton 2009).
lation of microorganisms into musculoskeletal tissues and, second,
interaction of these microorganisms with the host. When the host is
unable to eradicate or control the inoculated microorganisms, they
■■Local and systemic host factors
proliferate and result in an inflammatory response and host tissue Local host factors that facilitate infection include compromised
damage, with the resultant clinical picture of infection. vascularity (resulting from arterial disease, venous stasis, irradiation,
Microorganisms may gain access to musculoskeletal tissues scarring, and smoking) and trauma. Trauma reduces tissue perfu-
through three principal mechanisms: hematogenous spread after sion, devitalizes tissues, creates a dead space filled by hematoma,
bacteremia (e.g., acute pediatric osteomyelitis), spread from a con- and results in exposure and contamination of the underlying bone.
tiguous source of infection (e.g., adjacent osteomyelitis in cases of Systemic host factors that reduce the ability of the host’s immune
septic arthritis), or direct inoculation during trauma (e.g., infections system to respond to the pathogen include systemic diseases (such
after open fractures) or surgical procedures (e.g., periprosthetic as diabetes mellitus, renal and liver disease, malignancy, rheumato-
joint infections) (Lazzarini et al. 2004). The interaction of inoculated logical disease, acquired immune deficiency syndrome, alcoholism,
microorganisms with the host will determine the occurrence and malnutrition) and medications (e.g., anti-rheumatic drugs, glucocor-
severity of infection. ticoids, and others).
Host status is a key part of the Cierny–Mader classification of osteo-
■■Microorganism factors myelitis and refers to the patient’s physiological capacity to overcome
infection and withstand treatment (Cierny et al. 1985). An otherwise
Virulence is the ability of a microorganism to overcome the host healthy patient is classified as an A host, a B host has comorbidities
defenses and cause infection. Virulence varies among and within with a detrimental effect on immune response and wound healing,
organism species. Staphylococcus aureus is the most common and a C host is so compromised that surgical intervention poses a
pathogen in musculoskeletal infections and employs distinct greater risk than the infection itself, and qualifies for only palliative
mechanisms in order to cause infection (Gordon and Lowry 2008, treatment. Host status has important management and prognostic
Fry and Barie 2011). implications. Compromised hosts demonstrate increased infection
Staph. aureus initially expresses surface proteins, called “microbial rates after open fractures and increased recurrence rates after surgical
surface components recognizing adhesive matrix molecules,” which management of osteomyelitis.
216 BONE AND JOINT INFECTIONS

■■DIAGNOSIS OF BONE AND JOINT frozen sections of tissue for polymorphonuclear leukocytes can help
establish the diagnosis of infection intraoperatively.
INFECTIONS: AN OVERVIEW
Diagnosis of bone and joint infections is based on clinical findings,
■■Microbiological methods
laboratory tests, imaging modalities, histopathology, and microbio- Cultures have been considered the gold standard for the diagnosis of
logical methods. New molecular diagnostic methods appear to be infection; however, there are clinical problems with their use. False-
promising. positive results may occur due to contamination, so culture swabs
should be opened immediately before use and each tissue sample
■■Clinical findings should be taken with separate, sterile instruments. False-negative
results may be due to prior administration of antibiotics, inadequate
Local clinical findings of inflammation (pain, edema, erythema, specimen sampling, improper specimen handling and transporta-
increased temperature) as well as systemic findings (fever, chills) tion, or short incubation time. Biofilm formation is another reason
may be present in acute infections but are usually absent in chronic for negative cultures in chronic bone and joint infections.
musculoskeletal infections. Drainage from a sinus tract may be pres-
ent in chronic infections. ■■Molecular methods
■■Laboratory tests Molecular diagnostic methods may improve diagnostic efficacy. Poly-
merase chain reaction (PCR) can amplify and detect bacterial DNA,
An elevated peripheral blood white blood cell (WBC) count with in- leading to increased sensitivity but concerns exist about false-positive
creased polymorphonuclear cells is indicative of infection, but has low results secondary to contamination (Costerton et al. 2011). A novel
sensitivity. The erythrocyte sedimentation rate (ESR) and C-reactive method with mass spectrometric technology appears promising for
protein (CRP) are markers of the acute phase response secondary detection of musculoskeletal infection in the presence of negative
to inflammatory processes of infectious or noninfectious etiology. cultures (Gallo et al. 2011).
Although these inflammatory markers have high sensitivity, their
specificity is relatively low and false positives may occur in patients
with systemic inflammatory diseases or neoplasms. Also they may be
■■PEDIATRIC SEPTIC ARTHRITIS
elevated in the postoperative period as a response to surgery. Interleu- AND OSTEOMYELITIS
kin-6 is another inflammatory marker that appears to be promising in
the diagnosis of infection. Analysis of joint fluid is discussed below. ■■Epidemiology and pathogenesis
■■Imaging modalities Septic arthritis and osteomyelitis are more common in children aged
<5 years, usually involve the larges joints of the lower extremity, and are
Radiographs should be evaluated for bone changes (presence of most commonly caused by Staph. aureus (Ross 2005). Other organisms
sequestrum, resorption, periosteal new bone formation). In post- include coagulase-negative staphylococci, group A β-hemolytic strep-
traumatic infections the status of bone healing and the integrity of any tococci, Streptococcus pneumoniae, group B streptococci, and Kingella
implants should be assessed. In infections following fracture fixation, kingae. Children with sickle cell disease are more prone to infections
radiographs may show lucency around the implants; however, this from Salmonella spp. Hemophilus influenzae type b used to be a com-
may also result from aseptic loosening. mon pathogen in children aged between 1 and 3 years, but routine
Computed tomography (CT) demonstrates subtle changes of corti- immunization has almost eliminated its role in pediatric infections.
cal bone, such as erosion and periosteal reaction, but is not helpful Septic arthritis and osteomyelitis are usually hematogenous in
for evaluation of surrounding soft tissue. origin. Septic arthritis may also result from contiguous spread of ad-
Magnetic resonance imaging (MRI) can detect early changes jacent infection or from direct inoculation of microorganisms after a
secondary to infection. Increased water content secondary to edema penetrating injury. Pediatric acute hematogenous osteomyelitis has a
and hyperemia results in decreased marrow signal in T1-weighted predilection for the metaphysis of long bones. The sluggish circulation
images and increased signal in T2-weighted images. MRI has 98% and relative absence of tissue macrophages in the metaphyseal bone
sensitivity for detecting osteomyelitis with a specificity of 75% (Erd- allow bacterial proliferation. Purulent exudate may spread through
man et al. 1991). MRI provides details of the extent of involvement of the metaphyseal bone to the subperiosteal region, resulting in a
the medullary canal and adjacent soft tissues. subperiosteal abscess. Elevation of the periosteum by the abscess
Bone scintigraphy using technetium-99m evaluates perfusion and may devitalize cortical bone, which then becomes a sequestrum.
osteoblastic activity of the skeleton and helps identify multiple ana- The periosteum forms new bone, called the involucrum, which sur-
tomic areas of infection, but has low specificity. Indium-111-labeled rounds the sequestrum. Infants have a distinct vascular pattern with
leukocyte scintigraphy has 83% sensitivity and 86% specificity for metaphyseal vessels traversing into the epiphyseal area, which allows
musculoskeletal infection but is labor intensive and produces low- osteomyelitis to spread to the epiphysis.
resolution images (Merkel et al. 1985). Positron emission tomography It should be noted that septic involvement of the adjacent joint
(PET) with [18F]fluorodeoxyglucose is a new and promising modality. occurs in 33% of patients with metaphyseal osteomyelitis (Perlman
et al. 2000). Joint involvement is facilitated if the metaphysis is intra-
■■Histopathology articular. Therefore, careful evaluation of the adjacent joint should be
an important part of the evaluation of any child with osteomyelitis.
Identification of organisms after a Gram stain of specimens from the The infectious process may also spread to the surrounding soft tissues
involved area has low sensitivity but is very specific. Evaluation of and rarely to the medullary canal. Acute hematogenous osteomyelitis
 Pediatric septic arthritis and osteomyelitis 217

in older children usually involves a single site but in neonates may percentage >75% suggest septic arthritis but lower values may be seen.
involve multiple bones. Bone cultures and blood cultures are essential in the management of
osteomyelitis. Bone cultures can be obtained by needle aspiration or
■■Diagnosis intraoperatively.
The differential diagnosis of septic arthritis includes transient
The clinical picture of musculoskeletal infection in children usually synovitis of the hip, juvenile rheumatoid arthritis, poststreptococcal
consists of pain and inability to use the extremity. In septic arthritis reactive arthritis, and rheumatic fever. Trauma and neoplasms may
the range of motion of the involved joint is markedly decreased and present with a clinical picture resembling osteomyelitis. Distinguishing
painful. Fever may not always be present. A history of local trauma septic arthritis from transient synovitis of the hip in a young child with
is often reported and the treating physician needs to consider both an acutely irritable hip may be difficult. Fever, inability to weight bear,
infection and trauma in the differential diagnosis. Diagnosis can be ESR >40 mm/h, and peripheral WBC count >12 000 cells/mm3 are in-
challenging in neonates because the clinical picture is often subtle dependent variables that can help differentiate the two conditions. The
and a high index of suspicion is needed. probability of septic arthritis was found to be 99.6% for children with
The ESR and CRP are elevated in 90% and 95% of children with all four factors, 93.1% for those with three factors, 40% for those with
septic arthritis, respectively, and reach a peak in 5 and 2 days, re- two factors, and 3% for those with one factor only (Kocher et al. 1999).
spectively (Kallio et al. 1997). The ESR and CRP are elevated in 92% However, a subsequent study reported a 59% predicted probability of
and 98% of children with osteomyelitis, respectively. The ESR rises septic arthritis in a child with all four factors (Luhmann et al. 2004).
within 2 days from the onset of infection, reaches a peak in 3–5 days
and returns to normal after approximately 3 weeks, whereas the CRP
begins rising within 6 h, reaches a peak in 2 days, and returns to normal
■■Treatment
approximately 1 week after successful therapy (Unkila-Kallio et al. Treatment modalities include antibiotics and surgery. Empirical
1994). Combining these two markers results in increased sensitivity antibiotic therapy should be started immediately after appropriate
in pediatric osteoarticular infections. Surgical treatment prolongs the cultures have been collected and should always target Staph. aureus.
peak and normalization times of both markers (Khachatourians et al. Coverage for other pathogens should be provided based on the child’s
2003). The CRP demonstrates a closer temporal relationship to the age and the clinical setting (Table 19.1). Septic arthritis and/or os-
course of infection and is preferable for monitoring recovery. Only teomyelitis in neonates may also be caused by group B streptococci
35% of children with acute hematogenous osteomyelitis had a WBC and Gram-negative organisms. Children younger than 3 years of age
count >12 000/mm3 at the time of admission (Unkila-Kallio et al. 1994), may have Kingella kingae or Hemophilus influenzae type b infections
so values within normal limits should be interpreted with caution. if non-immunized. Children older than 3 years may have Streptococ-
Radiographs show soft-tissue swelling during the early stages of cus pneumoniae or group A S. pyogenes infections. In sexually active
acute hematogenous osteomyelitis but do not demonstrate osseous adolescents with septic arthritis Neisseria gonorrhoeae should be
changes until 7–14 days later. MRI shows joint effusion in septic arthri- considered as a pathogen. Children with sickle cell disease may have
tis, evaluates adjacent bone for osteomyelitis, and identifies soft-tissue salmonella infections. Systemic administration of antibiotics can be
abscesses. Bone scanning is helpful when the pathology location is converted to oral therapy if the patient is afebrile with considerable
uncertain or involvement of multiple locations is suspected. clinical improvement and considerably decreased CRP levels. The
In septic arthritis aspiration of the involved joint should be per- optimal duration of antibiotic therapy has not been defined. For
formed to establish the diagnosis and identify the pathogen. The joint uncomplicated cases that respond rapidly to treatment, 3 weeks of
aspirate should be sent for Gram stain, cultures and sensitivity testing, antibiotic therapy may be sufficient in septic arthritis and 4 weeks in
WBC count, and differential. WBC count >50 000/mm3 and neutrophil acute osteomyelitis.

Table 19.1 Common pathogens and empirical antibiotic therapy in pediatric bone and joint infections.
Clinical setting Common pathogens Empirical antibiotic therapy
Neonate Staphylococcus aureus Penicillinase-resistant penicillin (oxacillin) and
Streptococcus pyogenes group B aminoglycoside (gentamicin)
Gram-negative organisms or
Third-generation cephalosporin (ceftriaxone)
Child <3 years Staph. aureus Third-generation cephalosporin (ceftriaxone)
Hemophilus influenzae (if nonimmunized)
Kingella kingae
Older child Staph. aureus Penicillinase-resistant penicillin (oxacillin)
Strep. pneumoniae
Strep. pyogenes group B
Child with sickle cell disease Staph. aureus Third-generation cephalosporin (ceftriaxone)
Salmonella species
Risk factors for MRSA Meticillin-resistant Staph. aureus (MRSA) Vancomycin or clindamycin
Immunocompromised patient Gram-positive organisms Penicillinase-resistant penicillin (oxacillin) and
Gram-negative organisms aminoglycoside (gentamicin)
Sexually active patient Staph. aureus Third-generation cephalosporin (ceftriaxone)
Neisseria gonorrhoeae
218 BONE AND JOINT INFECTIONS

Surgical intervention in septic arthritis consists of decompression healthy adults, antibiotic therapy should cover both N. gonorrhoeae
and irrigation by open arthrotomy or arthroscopy. Joint aspiration may and Staph. aureus. Immunocompromised hosts and intravenous
be an alternative in easily accessible joints but careful monitoring is drug users should receive coverage for both Staph. aureus and Gram-
necessary. If there is no improvement within 24 h, then surgical de- negative organisms including Pseudomonas aeruginosa. The duration
compression is warranted. Prompt intervention is especially important of antibiotic therapy for an uncomplicated case septic arthritis that
in septic arthritis of the hip because delayed or incomplete decom- responds well to treatment is 3 weeks. In gonococcal arthritis 1 week
pression impairs perfusion of the femoral head and may result in of antibiotic therapy is sufficient.
osteonecrosis, hip dislocation, and osteomyelitis. Surgical intervention Surgical decompression and irrigation of the septic joint by ar-
in acute hematogenous osteomyelitis is warranted when an abscess is throtomy or arthroscopy relieve pressure and evacuate enzymes,
present. However, early antibiotic therapy may contain the infectious toxins, inflammatory mediators, and bacteria from the joint, thereby
process and prevent abscess formation. Surgery is also indicated when preventing further cartilage damage. Repeated joint aspirations may be
septic arthritis of an adjacent joint is present. sufficient in an easily accessible joint such as the knee. Synovial biopsy
for culture and histology may be useful in recurrent cases or when the
■■SEPTIC ARTHRITIS IN ADULTS diagnosis is uncertain. Persistence of clinical signs of infection after
surgical management of septic arthritis should raise the suspicion of
■■Epidemiology and pathogenesis adjacent osteomyelitis, especially in patients with comorbidities, and
MRI helps detect residual infection (Zalavras et al. 2006b).
In adults the knee joint is most often involved by septic arthritis.
Staphylococcus aureus is the most common pathogen (Ross 2005).
Immunocompromised patients may also have infections with Gram-
■■ADULT OSTEOMYELITIS
negative organisms or unusual pathogens, such as mycobacteria Osteomyelitis in adults usually results from either trauma (infections
or fungi (Zalavras et al. 2006a). Intravenous drug users and elderly after open fractures) or surgical procedures (postoperative infections).
patients in addition to Staph. aureus may have infections with Gram- Postoperative infections may develop after joint arthroplasty proce-
negative organisms. Young, otherwise healthy, sexually active adults dures (periprosthetic joint infections) or fixation of closed fractures.
may have infections with Neisseria gonorrhoeae. Contiguous spread from adjacent infections and hematogenous
The portals of pathogen entry in septic arthritis include hematog- spread are uncommon pathogenic mechanisms. The most common
enous inoculation, spread from adjacent infection, or inoculation organisms causing adult osteomyelitis are Staph. aureus and other
by a penetrating or surgical wound. Immunocompromised patient Gram-positive cocci. P. aeruginosa or other Gram-negative organisms,
status, pre-existing joint pathology such as rheumatoid arthritis, and mycobacteria, or fungi may cause infection in immunocompromised
loss of skin integrity or skin infections are important risk factors for patients.
development of septic arthritis. Microorganisms in the joint cavity
trigger an inflammatory response that recruits polymorphonuclear
cells to the involved area. Both the bacterial invasion and the inflam-
■■PREVENTION OF INFECTION
matory response contribute to cartilage damage. Enzymes and toxins IN OPEN FRACTURES
released by bacteria, as well as enzymes and cytokines released by
inflammatory cells, result in loss of glycosaminoglycans and collagen. Open fractures are complex injuries that involve not only the bone but
also the surrounding soft tissue envelope, and may lead to consider-
■■Diagnosis able morbidity or amputation of the extremity (Zalavras and Patzakis
2003). The soft-tissue injury results in communication of the open frac-
Septic arthritis usually presents as monoarthritis. The involved joint is ture with the outside environment and contamination of the wound
painful, swollen, with limited range of motion, and may be erythema- with microorganisms, which increases the risk of infection. Infection
tous. Fever is present in approximately half the patients and other complicates management and leads to further morbidity. Therefore,
systemic symptoms and signs may be absent. Gonococcal arthritis prevention is an important management principle.
may present as monoarthritis or migratory polyarthritis with rash and The risk of clinical infection depends on the severity of the in-
tenosynovitis of the dorsal aspect of the wrist and hand. jury, host status, and treatment factors. The severity of the injury is
CRP and ESR are elevated in >90% of cases (Mehta et al. 2006). described by the Gustilo and Anderson classification system, subse-
Ultrasonography is useful in detecting a joint effusion. MRI shows
intra-articular fluid and detects potential spread of infection into
adjacent bone or soft tissues. Table 19.2 Open fracture classification by Gustilo and Anderson, modified
Aspiration of the involved joint helps establish the diagnosis and by Gustilo, Mendoza, and Williams.
identify the pathogen. The joint aspirate should be sent for Gram Type I Puncture wound of ≥1 cm, with minimal contamination or
stain, cultures, and sensitivity testing, WBC count and differential, muscle crushing
and polarizing microscopy to detect crystals. WBC count >50  000/ Type II Laceration >1 cm long with moderate soft-tissue damage
mm3 and neutrophil percentage >75% indicate but do not confirm the and crushing; bone coverage is adequate and comminution
diagnosis of septic arthritis. Blood cultures also detect the pathogen. minimal
Type IIIA Extensive soft-tissue damage, often due to a high-energy
■■Treatment injury, with severe comminution and/or contamination
Type IIIB Extensive soft-tissue damage with periosteal stripping and
Empirical antibiotic therapy should be started immediately after bone exposure requiring flap coverage
aspiration and collection of joint fluid for culture. It should cover
Type IIIC Associated arterial injury requiring repair
the most likely pathogens based on the clinical setting. In otherwise
 Adult osteomyelitis 219

quently modified by Gustilo et al. (1984) (Table 19.2). Classification Gram-positive organisms, combined with an aminoglycoside (e.g.,
of the open fracture should be done only in the operating room after gentamicin or tobramycin), which is active against Gram-negative
wound exploration and debridement. Infection rates are in the range organisms. Antibiotics should be effective against both Gram-positive
0–2% for type I, 2–10% for type II, and 10–50% for type III (Zalavras and Gram-negative organisms, because contamination with both
and Patzakis 2003). types of pathogens occurs in open fractures. Anaerobic coverage (e.g.,
Host status, such as presence of medical comorbidities and smok- ampicillin or penicillin) is needed in farm injuries and vascular injuries
ing, are important. Presence of one or two comorbidities is associated to prevent clostridial myonecrosis (gas gangrene). Antibiotics should
with an approximately threefold increased risk of infection, and three be started upon patient presentation because a delay >3 h has been
or more comorbidities with an approximately sixfold increased risk shown to increase the risk of infection (Patzakis and Wilkins 1989).
(Bowen and Widmaier 2005). The recommended duration of therapy is 3 days with an additional 3
Treatment factors that help prevent infection after open frac- days for subsequent surgical procedures (Patzakis and Wilkins 1989,
tures include early administration of appropriate antibiotic therapy, Zalavras and Patzakis 2003).
wound debridement, soft-tissue coverage, and fracture stabilization Local antibiotic delivery with the antibiotic-impregnated polymeth-
(Patzakis and Wilkins 1989). The length of antibiotic therapy, elapsed ylmethacrylate cement bead pouch technique has been used in open
time from injury to surgery, and type of wound closure do not have fractures to achieve high local concentration of antibiotics, minimal
a significant association with infection (Patzakis and Wilkins 1989, systemic toxicity, and prevention of secondary contamination (Figures
Skaggs et al. 2005). 19.1–19.4) (Zalavras et al. 2004). Aminoglycosides are common choices
because of their broad spectrum of activity and heat stability. Vanco-
■■Antibiotic therapy in open fractures mycin is not recommended as an initial agent because of potential
development of resistance. The antibiotic bead pouch technique has
Antibiotic therapy plays an important role in prevention of infection been shown to significantly reduce the overall infection rate from 12%
in open fractures. This was established in a study by Patzakis et al. when only intravenous (IV )antibiotics were used to 3.7% when IV an-
(1974), which demonstrated that administration of a cephalosporin tibiotics were combined with antibiotic beads (Ostermann et al. 1995).
decreased the infection rate (2/84 fractures, 2%) compared with no Wound cultures in open fractures often fail to identify the organism,
antibiotics (11/79 fractures, 14%). subsequently causing an infection. Pre-debridement wound cultures
A commonly used antibiotic therapy protocol consists of a first- are not recommended. Post-debridement cultures are controversial
generation cephalosporin (e.g., cefazolin), which is active against but help select empirical antibiotic therapy if an early infection occurs.

Figure 19.1  Open fracture of the distal humerus. Figure 19.2  Open fracture of the distal radius and ulna.
220 BONE AND JOINT INFECTIONS

Figure 19.3  Application of antibiotic cement beads to achieve high local Figure 19.4  Coverage of the open fracture wound with a semipermeable
concentration of antibiotics. membrane to prevent secondary contamination.

■■Debridement The wound should also be copiously irrigated. The optimal volume,
delivery method, and irrigation solution remain controversial. High-
Surgical debridement is an important management principle. Retained pressure pulsatile irrigation may create bone damage and propagate
nonviable tissue and foreign material facilitate biofilm formation and bacteria into soft tissue and low-pressure pulsatile or gravity flow
development of a persistent infection. All nonviable bone and soft may be preferable (Petrisor et al. 2011). No significant differences in
tissue should be resected. Bone fragments without any soft tissue at- infection rates were reported when irrigation was performed with
tachments should not be retained unless they contain a considerable soap solution versus saline (Petrisor et al. 2011).
articular fragment. The injury wound should be surgically extended
to allow assessment of tissue viability and execution of debridement.
Debridement performed within or after 6 h from the injury does not ap-
■■Wound management
pear to be associated with the infection rate. Open fractures in children Primary wound closure, after a thorough debridement, does not in-
treated within 6 h from the injury had an infection rate of 3% (12/344) crease the infection rate and may prevent secondary contamination.
compared with 2% (4/210) for those treated 6 h after the injury (Skaggs However, it may lead to gas gangrene if debridement is inadequate.
et al. 2005). If necessary, a repeat debridement may be performed after The partial closure technique, in which the surgical extension of the
48 h based on the degree of contamination and soft-tissue damage. wound is closed but the traumatic wound is left open, is recommended
 Post-traumatic osteomyelitis 221

for type I and type II open fractures. Type III open fracture wounds (medullary, superficial, localized, diffuse) and the physiological class
should be left open. of the host (A: normal; B: compromised, systemic, local, or both; C:
Reconstruction of the soft-tissue envelope is necessary in type IIIB treatment is worse than disease) (Cierny et al. 1985) (Table 19.3).
open fractures to cover the wound, prevent secondary contamination, Diagnosis is based on clinical findings (pain, erythema, draining
and improve local vascularity, thereby enhancing local host defenses sinuses, systemic symptoms), laboratory tests (elevated CRP, ESR),
and delivery of antibiotics at the fracture site. Soft-tissue coverage is and imaging modalities (radiographs, MRI, scintigraphy). Cultures
of particular concern in open fractures of the tibia, and may be ac- and sensitivity testing help identify the responsible organism and
complished by local or free muscle flaps depending on the location determine antibiotic therapy. The clinical picture may be subtle and
and size of the defect. The muscle gastrocnemius is useful for coverage laboratory tests may be normal in chronic infections, so a high index of
of proximal third defects of the tibia, and the soleus for middle third suspicion is necessary in nonunions after an open fracture or internal
defects. Local muscle that has been compromised by the injury (direct fixation of a closed fracture.
trauma, ischemia, compartment syndrome) should not be transferred. Management of the patient with post-traumatic osteomyelitis is
A free muscle flap is necessary in these cases as well as in defects in- usually complex and prolonged. Amputation is an option in some
volving the distal third of the tibia. Soft-tissue reconstruction should cases and should be discussed with the patient. Management of adult
be performed early, within the first 3–7 days. post-traumatic osteomyelitis with limb salvage is based on a staged
protocol that includes debridement, systemic and local antibiotic
■■Fracture stabilization treatment, skeletal stabilization, soft-tissue coverage, and manage-
ment of bone defects and ununited fractures (Patzakis and Zalavras
Stabilization of the open fracture prevents further soft-tissue injury and 2005). Management is optimized by the presence of a multidisciplinary
helps reduce the infection rate. Fixation can be definitive or provisional team consisting of an orthopedic surgeon, an infectious disease spe-
and techniques include intramedullary nailing, external fixation, and cialist, and a microvascular surgeon.
plate fixation. The selection of technique for a specific injury depends Debridement needs to be radical and achieve resection of all nonvi-
on the fractured bone, the location of the fracture (intra-articular, able tissues (including skin, other soft tissues, and bone) and removal
metaphyseal, diaphyseal), the extent of soft-tissue injury, degree of of implants. Specimens of purulent fluid, soft tissue, and bone are sent
contamination, and patient’s physiological status. for aerobic, anaerobic, mycobacterial, and fungal cultures. The goal
of debridement is to have only bleeding, viable tissue present at the
■■Specialized procedures wound. Inadequate debridement fails to remove the biofilm that has
formed on local tissues and implants, thereby leading to recurrence
Bone defects >6  cm require specialized reconstructive procedures, of infection. However, fracture fixation implants may be retained in
such as vascularized bone grafts (fibula, iliac crest) or distraction the early postoperative period if they are intact and providing stabil-
osteogenesis. The free vascularized fibular graft provides structural ity to a healing fracture. In this case, the goal is not eradication but
support and new blood supply to the defect site can be used in defects suppression of infection until the fracture heals.
up to 26 cm, and is a versatile graft that can include bone, muscle, Local antibiotic delivery via methylmethacrylate beads or spacers
skin, and fascia (Malizos et al. 2004). The Ilizarov technique, based on impregnated with antibiotics results in high local concentration and
the principle of distraction osteogenesis, can reconstruct large bone low systemic side effects of antibiotics, and eliminates dead space
defects and correct malalignment (Paley and Maar 2000). after debridement (Zalavras et al. 2004). The area is sealed with a
semipermeable membrane to keep eluted antibiotics at the involved
■■POST-TRAUMATIC area. A potential disadvantage of nonabsorbable antibiotic delivery
vehicles is the need for reoperation and removal, so that the vehicle
OSTEOMYELITIS does not act as a foreign body. However, reoperation is usually planned
to manage the dead space and reconstruct the existing bone or soft-
The tibia is the most common site of adult post-traumatic osteomy- tissue defect. Biodegradable delivery systems appear promising
elitis. Adult osteomyelitis is staged with the Cierny–Mader classifica- (McKee et al. 2010). Systemic antibiotic administration is based on
tion system, which evaluates the anatomic type of bone involvement culture and sensitivity results and the recommended duration is 4–6

Table 19.3 Cierny–Mader classification system.

Anatomic type of bone involvement (increasing order of complexity)
Medullary Infection involves the endosteal bone and the medullary canal. Association with intramedullary implants in healed fractures
without presence of a sequestrum
Hematogenous mechanism rare in adults
Superficial Infection involves the superficial part of an otherwise healthy bone. Association with soft-tissue defects
Localized Infection involves the full thickness of the cortex but bone is stable
Association with healed fractures in the presence of a cortical sequestrum
Diffuse Infection involves the full thickness of the cortex but bone is unstable or will become unstable after debridement
Association with infected acute healing fractures and infected nonunions
Physiological class of the host (increasing order of compromised physiology)
A: Normal Otherwise healthy patient with normal response to infection, wound healing, and treatment
B: Compromised Patient with comorbidities (local, systemic, or both) that compromise response to infection, wound healing, and treatment
C: Treatment worse than disease Morbidity associated with treatment exceeds the impact of infection on the patient
222 BONE AND JOINT INFECTIONS

weeks in localized or diffuse osteomyelitis. Antibiotic therapy is not neutrophil percentage >73% has a sensitivity and specificity of 93%
a substitute for inadequate debridement. and 95%, respectively (Parvizi et al. 2006). In PJI developing within 6
Skeletal stabilization is necessary for infection control in the pres- weeks of surgery, a synovial leukocyte count >27 800 cells/mm3 has
ence of anatomic type IV osteomyelitis, as in infected healing fractures 84% sensitivity and 99% specificity for the diagnosis and a neutrophil
or infected nonunions. Different techniques may be applicable for percentage >89% has a sensitivity and specificity of 84% and 69%,
each anatomic location but our preference is to stabilize the tibia respectively (Bedair et al. 2011).
with an external fixator, the femur with an intramedullary rod, and Plain radiographs may reveal loosening of the implant, osteolysis,
the humerus and forearm with plates and screws. or periosteal reaction but cannot differentiate septic from aseptic loos-
Wound management and soft-tissue coverage are performed, if ening. Technetium-99m bone scan has low sensitivity for detection of
needed, at a second stage usually 3–7 days after the initial debride- PJI and may be positive up to 2 years postoperatively in a well-fixed
ment. Muscle flaps eliminate dead space, prevent secondary contami- prosthesis. 111In-labeled leukocyte scan has 77% sensitivity and 86%
nation, enhance vascularity, improve local host defenses, and facilitate specificity in the diagnosis of PJI (Scher et al. 2000). PET with [18F]
the healing process. Soft-tissue coverage is of particular concern in fluorodeoxyglucose is a promising new modality with 95% sensitivity
osteomyelitis of the tibia and may be accomplished by local or free and 93% specificity for PJI (Parvizi et al. 2006).
muscle flaps, depending on the location and size of the defect. Intraoperative tests can be helpful in equivocal cases. Gram stain
Management of bone defects and ununited fractures by bone graft- has 19% sensitivity and 98% specificity, whereas frozen sections with
ing is performed at a third stage, usually 6–8 weeks after the muscle more than five stromal polymorphonuclear leukocytes per high power
transfer to ensure viability of the flap and initial control of infection. field have 80% sensitivity and 94% specificity (Spangehl et al. 1999).
Autogenous iliac crest bone graft is the gold standard for management Cultures obtained intraoperatively have 94% sensitivity and 97% speci-
of bone defects and can be harvested from the anterior or posterior ficity (Spangehl et al. 1999). Another study reported that the culture
iliac crest (Ahlmann et al. 2002). In nonunions of the tibia, bone graft sensitivity decreases from 77% with an antibiotic-free interval >14
can be placed either directly at the nonunion site or posterolaterally days to 48% with an interval of 4–14 days (Trampuz et al. 2007). Soni-
to achieve tibiofibular synostosis. Bone defects >6 cm require special- cation of explanted prosthesis has been shown to improve sensitivity
ized reconstructive procedures, such as vascularized bone grafts or of cultures. In hip and knee PJs the sensitivity of tissue cultures was
distraction osteogenesis. 61% whereas that of sonicate fluid cultures was 78% (Trampuz et al.
The described limb salvage protocol can achieve a satisfactory 2007). Recently, a definition of PJI was proposed by the Workgroup of
outcome. An outcomes study of 46 patients with chronic osteomyelitis the Musculoskeletal Infection Society (Box 19.1) (Parvizi et al. 2011).
of the tibia with a mean follow-up of 5 years showed that limb salvage
was accomplished in all patients, infection control in 98% (45/46), and
union in 95% (44/46) (Siegel et al. 2000). In this study 85% (39/46) were Box 19.1 Definition of periprosthetic joint infection proposed by
able to ambulate independently without pain. the workgroup of the Musculoskeletal Infection Society.

■■PERIPROSTHETIC JOINT Major criteria

1 Sinus tract communicating with the prosthesis
INFECTIONS 2 Pathogen isolated by culture from at least two separate tissue
or fluid samples obtained from the affected prosthetic joint
■■Epidemiology and pathogenesis Minor criteria
1 Presence of purulence in the affected joint
Periprosthetic joint infection (PJI) is a challenging complication that 2 Elevated erythrocyte sedimentation rate (ESR) and C-reactive
occurs in approximately 1–2% of primary arthroplasty cases. The most protein (CRP) concentration
common pathogens are Staph. aureus and Staph. epidermidis. The 3 Elevated synovial leukocyte count
pathogenesis of infection involves direct inoculation of microorgan- 4 Elevated synovial neutrophil percentage
isms (contamination during the procedure), hematogenous spread 5 More than five neutrophils per high-power field in five high-
(at any point postoperatively as a result of infection at a remote loca- power fields observed from histological analysis of peripros-
tion and bacteremia), or contiguous spread from adjacent infection. thetic tissue at × 400 magnification
6 Isolation of a microorganism in one culture of periprosthetic
■■Diagnosis tissue or fluid
Definite periprosthetic joint infection exists in the presence of one
The clinical picture of PJI is often subtle and pain may be the only of the two major criteria or in the presence of four of the six minor
symptom. Decreased range of motion, drainage, and systemic symp- criteria. Periprosthetic joint infection may be present even if fewer
toms may be present. than four of the six minor criteria are met.
Inflammatory markers are helpful. In patients without connec-
tive tissue disorders, elevated ESR (>30  mm/h) has 82% sensitivity
and 85% specificity, elevated CRP (>10 mg/l) has 96% sensitivity and
92% specificity, and elevated WBC count has 20% sensitivity and 96%
■■Treatment
specificity (Spangehl et al. 1999). Interleukin-6 has 97% sensitivity, Management of PJI depends on the timing and duration of infection,
91% specificity, and the advantage of returning to normal values a the medical condition of the patient, the susceptibility of the pathogen
few days after surgery (Berbari et al. 2010). to antibiotics, and the status of the surrounding soft-tissue envelope
Aspiration at the site of a prosthetic hip or knee joint provides useful and the implant. Surgical management options for PJI include debride-
information. In chronic PJIs a synovial leukocyte count >1760 cells/ ment with retention of components, exchange arthroplasty (one-stage
mm3 has 90% sensitivity and 99% specificity for the diagnosis and a vs two-stage), arthrodesis, permanent resection arthroplasty, and
 References 223

amputation (McPherson et al. 1999). Surgical management is comple- plantation at a subsequent procedure with an interval of 6–12 weeks).
mented by systemic antibiotic administration for a period of usually 6 One-stage exchange arthroplasty avoids an additional procedure and
weeks. Nonsurgical management with chronic antibiotic suppression expedites patient management, if successful. Optimal indications for
may be considered in selected patients. one-stage exchange arthroplasty include an otherwise healthy patient
Debridement with exchange of the polyethylene liner and reten- with good soft-tissue envelope and infection by a susceptible pathogen.
tion of the components is an option in early infections (<3 weeks Two-stage exchange arthroplasty requires an additional procedure
postoperatively) or acute hematogenous infections (acute onset with but allows for repeat debridement and local antibiotic delivery dur-
symptom duration <3 weeks in a previously well-functioning patient) ing the reimplantation interval via antibiotic-impregnated spacers.
by the presence of well-fixed implants (Zimmerli et al. 1998). Exchange arthroplasty may not be feasible due to patient comor-
Exchange arthroplasty is the preferred option in late chronic infec- bidities, poor soft-tissue envelope, deficient bone stock, or presence of
tions (developing more than 3 weeks postoperatively with indolent resistant organisms. Other management options include arthrodesis,
course and duration >3 weeks) and when loosening of the implants is resection arthroplasty (in patients with limited functional demands),
present. Flap coverage may be necessary if the soft-tissue envelope is chronic antibiotic suppression (in severely compromised patients
compromised. Exchange arthroplasty can be performed with either a with low-grade infections by organisms sensitive to oral antibiotics),
one-stage protocol (reimplantation at the same surgical procedure as or amputation (in severely compromised patients with severe or
debridement and component removal) or a two-stage protocol (reim- uncontrollable infections).

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Chapter 20 Obstetric and gynecological
infections
Sebastian Faro, Jonathan Faro, Constance Faro

Infection associated with the obstetric and gynecological patients has highly contagious infection. It is caused by Staph. aureus, meticillin-
a long history. This chapter deals with the current available informa- resistant Staph. aureus (MRSA), and Strep. pyogenes. Impetigo is
tion and foregoes the historical information pertaining to this subject. typically treated with antibiotics.
Suffice it to state that the first real association among healthcare givers, Cellulitis can present as a blanching erythematous cutaneous
bacteriology, and nosocomial infection was brought to light by the infection, or may be associated with other conditions such as the
publications of Semmelweis and Holmes describing the transmis- Bartholin or Skene gland abscess, surgical site abscess, furuncles,
sion of Streptococcus pyogenes from infected patients to non-infected and carbuncles. Cellulitis is an infection of the deeper dermis and
patients via healthcare providers. may extend to the subcutaneous tissues (King et al. 2006, Sachdeva
Infectious diseases in obstetrics and gynecology slowly gained and Tomecki 2008). Cellulitis usually presents with the four cardinal
interest before 1980 and reached a zenith from 1980 to the early 1990s. signs of inflammation: Rubor (erythema), calor (heat), dolor (pain),
Interest has since waned but has not dissipated. Modern technology and tumor (swelling). Cellulitis commonly follows cutaneous trauma
has resurrected interest and is leading to a better understanding of but can occur from folliculitis or even from remote hematogenous
the infectious diseases associated with obstetric and gynecological seeding of the skin.
patients. This treatment of the subject will be limited to those infections Cellulitis associated with an abscess (e.g., Bartholin or Skene gland
requiring not only antimicrobial therapy but also surgical interven- abscess or surgical site infection) requires both antibiotic therapy and
tion. The key to applying both therapies is recognizing the opportune surgical intervention. Antibiotics alone will not suffice in the treat-
time for surgical intervention. Delaying surgical intervention results ment of these conditions, in contrast to cellulitis without abscess. If
in increased morbidity and mortality. the treatment requires the administration of antibiotics and surgical
intervention, the antibiotics should be administered before making
■■VULVAL INFECTIONS the incision. Preferably the antibiotics should be administered 1 hour
before making the incision and continued until the clinical cellulitis
Although there are many infections that afflict the vulva, those that has resolved, the patient’s white blood cell count (WBC) has returned
may require surgical intervention are mainly of a bacterial etiology. to normal, and the fever has resolved.
They can be divided into the following categories: (1) Cellulitis, (2) The principles involved for treating cellulitis associated with an
furuncle, (3) carbuncle, (4) abscess, (5) hidradenitis suppurativa, and abscess are based on a logical approach to evaluating the etiology,
(5) Fournier gangrene (necrotizing fasciitis). These infections can all diagnosis, and management of any abscess. The first step is to identify
involve Staphylococcus aureus but can also involve the microflora its location, the second step is having a strong inclination as to which
commonly found in the vagina and rectum. Therefore, although fu- bacteria are likely to be involved, the third step is to obtain a specimen
runcles and carbuncles are most commonly caused by Staph. aureus for Gram stain, culture, and antibiotic sensitivities, and the fourth
the others listed above may indeed involve Staph. aureus but can also step is management.
be polymicrobial. Location of the infection, characteristic changes Individuals who have pure cellulitis seldom have culture informa-
in the skin at the point of infection, presence of fever, and pain are tion. Therefore, antibiotic selection is based on knowledge gained from
all important clinical findings, but not pathognomonic of bacterial the literature and realizing that the bacteria involved are most likely
infections and must be differentiated from viral and fungal infections. from the patient’s own endogenous vaginal microflora.

■■Cellulitis ■■Furuncles
Cellulitis is a condition that is not uncommon, occurring mainly in A furuncle is an acute inflammatory infection involving a hair follicle.
the labia majora. However, cellulitis must be differentiated from other Initially, it appears as a round, firm, or nodular, erythematous lesion.
skin conditions such as erysipelas and impetigo. Erysipelas is a super- These perifollicular lesions are most commonly caused by Staph.
ficial skin and soft-tissue infection involving the dermal lymphatic aureus. The evolution of the lesion is characterized by it becoming
system. Erysipelas presents as a tender, well-demarcated, bright-red firm and painful, with the development of central suppuration. The
edematous area with raised borders. The borders are indurated and furuncle will frequently drain spontaneously and resolve. However,
progressive (Bisno and Stevens 1996, Rogers and Perkins 2006). it can become quite large and have a significant amount of surround-
Erysipelas is most commonly caused by Strep. pyogenes but other ing cellulitis.
species of Streptococcus can also cause it. The infection is treated by Furuncles and carbuncles should be viewed as potentially seri-
antibiotics. Other bacteria can cause an erysipelas-like picture but this ous infections. Initially these infections start as a folliculitis and can
is very uncommon. Erysipelas is managed by medical therapy only. proceed to abscess, bacteremia, and necrotizing fasciitis. Infections
Impetigo is a superficial infection involving the epidermis and is a such as folliculitis, furuncles and carbuncles have become significant
226 OBSTETRIC AND GYNECOLOGICAL INFECTIONS

infections because they are commonly caused by community-

acquired MRSA (King et al. 2006, Moran et al. 2006).
■■Abscesses
Vulval abscesses, aside from pyodermatous lesions such as folliculitis,
■■Carbuncles furuncles, and carbuncles, can occur in the labia majora, Bartholin
glands, Skene glands, and urethral diverticulum. The most common
A carbuncle is made up of two or more confluent furuncles in close vulva abscesses are the Bartholin gland abscess and a true labial ab-
proximity, with invasion of the subcutaneous tissue. Multiple ab- scess. A labial abscess must be distinguished from a Bartholin gland
scesses are separated by connective tissue septations. A carbuncle is abscess because the two are treated very differently. The goal of treating
a more serious infection, accompanied by pain, fever, and malaise. In a Bartholin gland abscess is to maintain a functioning draining gland.
common with furuncles, patients often attempt to express the contents The approach to treating a labial abscess is to first establish that
of a furuncle and carbuncle, which often leads to deeper invasion of the mass is an abscess (Table 20.2). This holds true for a true labial
the infection and the potential for bacteremia. mass, a mass in the area of the Bartholin gland, or a mass in the area
Treatment of furuncles and carbuncles includes antibiotics, ap- of the vaginal introitus.
plication of hot compresses to encourage spontaneous drainage, Before initiating an invasive procedure, ultrasonography of the
and, ultimately, incision and drainage. Frequently, the pus within the mass and surrounding area could be performed. This will allow the
furuncle or carbuncle becomes very viscous and is not easily removed. determination of whether the mass is cystic or solid, and whether it
The purulent content forms an almost solid core and requires surgi- contains septations or is uniloculated. Ultrasonography will also allow
cal intervention to remove the contents of the abscess. As the most the examiner to determine the distance from the epithelial surface to
likely cause is community-acquired MRSA and, therefore, b-lactam the inner aspect of the cyst. This information will help in determining
antibiotics, e.g., cephalosporin, and broad-spectrum penicillins the depth of penetration that is needed to enter the cyst or abscess to
(piperacillin/tazobactam, ampicillin/sulbactam) are not effective. obtain a specimen via aspiration, as well as for incision and drainage.
Recommended antibiotics are listed in Table 20.1 (Stevens et al. 2005). This approach can also be used in the management of a Bartholin cyst,
Patients requiring incision and drainage should be given intra- although the tissue depth in the true labia majora is thicker than that
venous (IV) antibiotics. A blood urea nitrogen (BUN) and creatinine of a Bartholin abscess or cyst.
should be obtained because if the patient has renal impairment adjust-
ment in the antibiotic dose may be necessary. Incision of a carbuncle Labial abscess
will require the disruption of septa because the lesion is made up of The involved labia should be prepped with an antiseptic solution and
closely oppressed or coalesced abscesses or furuncles. As these infec- local anesthetic (e.g., 1% xylocaine) is injected into the skin overlying
tions are extremely inflamed and very painful, incision and drainage the mass where the incision is to be made. Large masses may require
will require anesthesia. the operating room and either general anesthesia or IV sedation plus
Surgical management begins with providing anesthesia, thus local anesthetic. A 20-gauge needle is used to obtain an aspirate of
allowing cleansing of the area with an antiseptic, draping the area 2–5 ml fluid. Part of the specimen should be used for a Gram stain
with sterile towels, and obtaining a specimen for Gram stain, culture and the remainder processed for the isolation, identification, and
of bacteria, and identification of the infecting organism, as well as antibiotic sensitivities of facultative and obligate anaerobic bacteria.
determining the antibiotics to which the isolate is sensitive and resistant. The incision should be made in either the lateral fold or the medial
An incision is made that is long enough to allow for good exploration aspect of the labial majora, but not on the anterior surface. Incising
to disrupt any septa that may be present. The wound should be well the anterior surface of the labia majora typically results in penetrating
irrigated with sterile 0.9% saline. The abscess cavity that remains a thicker layer of tissue and the healing often results in a depression of
should be packed with iodoform gauze, which is removed within 24–48 the healed incised area. The incision should be large enough to allow
h. The area should be bandaged until the lesion has healed. for adequate drainage, disruption of any septations, and packing the
area with iodoform gauze.
Table 20.1 Antibiotic choices for cellulitis, furuncles, and carbuncles.
Bartholin gland abscess
Oral therapy Dosage
The initial approach is much the same as in the initial approach in a
Doxycycline 100 mg twice daily for 10 days labial abscess. The incision is made extending from the superior to the
Minocycline 100 mg twice daily day for 10 days
Clindamycin 300–450 mg three times per day for Table 20.2 Differential diagnosis of a labial mass.
10 days
Vulval mass Vaginal mass
Trimethoprim–sulfamethoxazole One tablet (400 mg
trimethoprim/80 mg sulfa) twice daily Sebaceous cyst Inclusion cyst
for 10 days Dysontogenetic cyst Endometriosis
Dicloxacillin 250 mg four times daily for 10 days (not Hematoma Adenosis
for MRSA)
Syringoma Gartner duct cyst
Intravenous therapy Dosage (continued until switch to
oral treatment) Endometriosis Leiomyoma

Vancomycin 30 mg/kg every 12 h Myoblastoma Inguinal hernia

Linezolid 600 mg every 12 h Accessory breast tissue

Daptomycin 4 mg/kg every 24 h Von Recklinghausen tumor

Clindamycin 600 mg every 8 h Adenocarcinoma

 Vulval infections 227

inferior border of the abscess. Typically, if this is the first episode in would suggest anaerobic bacteria, peptococci, or if in chains pepto-
a woman of reproductive age, a simple incision is made through the streptococci to be present. The presence of intracellular Gram-negative
epithelium and the abscess capsule. If this is a recurrent abscess or diplococci indicates the presence of N. gonorrhoeae. C. trachomatis
the first episode in a postmenopausal woman elliptically shaped tis- lacks a cell wall and therefore does not stain with Gram reagents; if
sue is excised, including the epithelium and the abscess wall, and this present it will be undetected by the Gram stain.
tissue is sent to pathology for histological examination. Carcinomas The abscess cavity should be explored with a hemostat to disrupt
of Bartholin gland are rare tumors and account for approximately 1% any septations present and copiously irrigate the cavity with sterile
of all gynecological cancers (Barclay et al. 1964, Copeland et al. 1986, saline until the contents issuing forth are clear. The abscess wall is
Felix et al. 1993, Lelle et al. 1994, DiSaia and Creasman 1997). The ma- sutured to the epithelium with interrupted suture (marsupialization).
jority, 80–90%, are squamous cell carcinomas and adenocarcinomas The cavity is packed with half-inch (1.25–cm) iodoform gauze and left
(Felix et al. 1993). Most of these carcinomas occur in postmenopausal in place for 24–48 h. Repacking is not necessary; the cavity will fairly
women aged >65 years. rapidly collapse and the diameter of the opening will be reduced to a
Before aspirating or incising the abscess, antibiotics should be small opening and leave the gland functioning.
administered. The microbiology of a Bartholin gland abscess is varied An alternative to marsupialization is placement of a Word catheter
and can involve sexually transmitted bacteria and bacteria from the into the abscess cavity, which is indicated in patients experiencing
lower genital tract or rectum. Therefore, empirical therapy is initially their first Bartholin cyst or a simple abscess. The patient treated with
with a combination of antibiotics until bacteria have been isolated, a Word catheter should not have signs or symptoms of a systemic
identified, and the antibiotic sensitivities are known. Chlamydia tra- response to infection. In treatment of a Bartholin abscess with a Word
chomatis, Neisseria gonorrhoeae, Gram-negative and Gram-positive catheter, if septations are present within the abscess are and are not
facultative, and obligate anaerobic bacteria are common causes of disrupted, the patient will likely experience a recurrence.
Bartholin gland abscess and a combination of antibiotics is neces- A Word catheter is approximately 6 cm long, diameter is equal to
sary (Box 20.1). 10 French (Fr), and there is a 1-ml inflatable balloon at the tip (Word
1968). The Word catheter is typically used to drain a Bartholin cyst
Box 20.1 Antibiotic choices for treatment of a Bartholin gland or abscess in an office setting or emergency room. The procedure is
abscess (intravenous therapy). performed by cleansing the surface epithelium overlying the enlarged
Bartholin gland with an antiseptic, such as povidone iodine. Insert a
Combination antibiotic choices and dosing sterile 20-G needle into the abscess and withdraw approximately 2 ml
Clindamycin 900 mg every 8 h + ampicillin 2 g every 6 h + genta- purulent fluid. Send the fluid in a capped syringe or instill the fluid
micin 5 mg/kg body weight every 24 h into an appropriate transport system for Gram stain, and culture of C.
Metronidazole 500 mg every 8 h + ampicillin 2 g every 6 h + genta- trachomatis, N. gonorrhoeae, and facultative and obligate anaerobic
micin 5 mg/kg body weight every 24 h bacteria. A stab incision is then made into the Bartholin gland abscess.
Metronidazole 500 mg every 8 h or clindamycin 900 mg every 8 h Aspirate all fluid, and insert a hemostat into the cavity to disrupt any
+ levofloxacin 500 mg every 24 h adhesions or septations that may be present. Irrigate the abscess cavity
Metronidazole 500 mg every 8 h or clindamycin 900 mg every 8 h with copious amounts of sterile saline. Insert the Word catheter and
+ doxycyline 100 mg every 12 h inflate the balloon with sterile saline; do not use air because this will
not permit the balloon to remain inflated. The catheter should be left
in place for 4–6 weeks, at which time it can be removed. Patients who
Broad-spectrum antibiotic administration is indicated because develop a recurrent Bartholin abscess should undergo marsupializa-
there is usually a significant inflammatory response surrounding the tion of the abscess and this procedure should also be used for such
Bartholin gland abscess and this may indicate an associated cellulitis. patients. Individuals who develop recurrent Bartholin abscesses or
In addition, the surgical procedure may cause bacteremia. Once the cysts should have the gland removed.
Gram stain results are known adjustment in antibiotic therapy can Empirical antibiotic administration should include antimicrobial
be made (Table 20.3). Although the identity of the bacteria present activity against C. trachomatis, N. gonorrhoeae, and facultative and
cannot be determined from the Gram stain, it is possible to choose obligate anaerobic bacteria. A combination of metronidazole 500 mg
appropriate antibiotic coverage. every 8 h and levofloxacin 500 mg daily will provide such coverage.
If the contents of the Bartholin gland abscess had a foul odor and When collecting specimens, a specimen for culture of N. gonorrhoeae
the Gram stain revealed large Gram-positive cocci in clusters, this should be obtained in case the polymerase chain reaction (PCR)
test for gonorrhea is positive. An alternative antibiotic regimen is a
single dose of metronidazole and ceftriaxone followed by doxycyline
Table 20.3  Interpretation of the Gram stain based on microbial (100 mg) twice daily for 7 days.
morphology.
Bacterial species Microscopic morphology Hidradenitis suppurativa
Staphylococci Gram-positive cocci in clusters Hidradenitis suppurativa, also known as acne inversa or acne
tetrad, is a skin disorder of unknown etiology. The current theory
Streptococci Gram-positive cocci in chains
is that hyperkeratosis of the follicular epithelium results in occlu-
Enterobacteriaceae Gram-negative rods, morphological sion of the follicle and associated apocrine gland with subsequent
similar follicular rupture (Slade et al. 2003, Wiseman 2004). Once the fol-
Bacteroides or Prevotella spp. Pleomorphic Gram-negative rods licular canal and apocrine gland become obstructed, the bacterial
Fusobacterium spp. Fusiform Gram-negative rods infection leads to abscess formation. It occurs two to five times more
often in women, and in 1–4% of the population (Von der Werth and
Clostridium spp. Gram-positive rods with endospores
Jemec 2001).
228 OBSTETRIC AND GYNECOLOGICAL INFECTIONS

The disease has multiple components: first there is the obstructive Simple incision and drainage could result in the gland developing an
phase in which the follicular canal becomes blocked; second is the adhesion between oppressing walls and render the gland relatively
infection phase in which bacteria trapped below the obstruction initi- non-functional, depending on how much of the gland becomes oblit-
ate the infection, eventually forming abscesses; third is development erated. An alternative treatment, marsupialization, would leave the
of fistulae or sinus tracts emanating from the abscess and granulating gland open with a small duct and, thus, leave a functioning gland.
inflammation – these sinus tracts extend into the dermis in a leaf-like In 1880 Skene published a report describing two ducts that drain
pattern – and fourth is progression to new lesions (Kurzen et al. 1999). the distal apart of the gland through two openings which are adjacent
The disease can invade the subcutaneous tissue and this is usually to the urethral meatus (Skene 1880, Gittes and Nakamura 1996).
seen in patients with long-standing chronic disease. Hydradenitis Huffman in two publications (1948, 1951) described Skene glands as
suppurativa may appear similar to many other perineal conditions branching paraurethral structures originating from the urethral lumen
(Box 20.2). It requires a careful history, detailed inspection, and may into the adjacent soft tissues, traveling along the distal two-thirds of
even require biopsy to differentiate it from other conditions. the urethra. Clinical symptoms characteristic of Skene gland abscess
is vulvar pain, dysuria, urinary obstruction, and dyspareunia.
Box 20.2 Differential diagnosis for anogenital hidradenitis sup- Therefore, the first step in managing an abscess in this region is to
purativa (acne inversa). determine if the abscess is in a urethral diverticulum or in the Skene
gland. A Skene gland abscess usually appears as a fluctuant mass lat-
Furuncle eral or inferolateral to the urethral meatus. Typically, unlike a urethral
Carbuncle diverticulum, a Skene gland abscess does not communicate with the
Labial abscess urethra. However, during the evaluation of the patient with a suspected
Bartholin abscess Skene gland abscess, it should be documented that the abscess does
Lymphadenitis not communicate with the urethra.
Infected sebaceous cyst
Epidermoid or dermoid cyst
Granuloma inguinale
■■POSTOPERATIVE INFECTIONS
Lymphogranuloma venereum Postoperative infections occurring in the obstetric and gynecologi-
Crohn disease cal patient are typically due to the patient’s own endogenous vaginal
Cryptoglandular fistula bacteriology. Interestingly, the bacteriology of the vagina impacts not
Steatocytoma multiplex only the patient’s potential risk of developing a postoperative infec-
Pilonidal cyst tion but also the effectiveness of antibiotic prophylaxis. Staph. aureus,
Actinomycosis including MRSA, is a common cause of abdominal SSI.
Scrofuloderma The number of surgical sites varies depending on the operation
being performed. Patients undergoing an abdominal hysterectomy
will have at least two surgical sites that are at risk for infection: The
Treatment of hidradenitis suppurativa consists of medical and abdominal incision and the vaginal apical incision. Patients under-
surgical therapy. Although medical therapy has been and continues going a vaginal hysterectomy with anterior and posterior repair will
to be used it has met with limited success. Various medical treatments have at least three surgical incisions. Therefore, the gynecological
have been administered, including antibiotic regimens, monoclonal surgeon must be aware of the potential of each surgical site to be
antibody therapy directed against tumor necrosis factor (TNF)-α (inf- contaminated by the bacteria of the vagina. Once the vagina has been
liximab, etanercept, adalimonab), and antiandrogens (Van der Zee et opened the operation is classified as a clean-contaminated case and
al. 2011). Isotretinoin has also been used, but is of questionable value the pelvic floor is potentially contaminated. Bringing instruments
and is known to be teratogenic. and the gloved hands of the surgeon and assistants, repeatedly, from
Decisions to pursue surgical management of hidradenitis suppura- the pelvic floor through the abdominal incision can contaminate the
tive are commonly made by using the Hurley (1989) staging system. abdominal incision. Care must be taken to minimize this potential
Stage 1 disease is single or multiple abscesses but without sinus tracts for contamination.
and scarring. Stage 2 represents recurrent abscesses with sinus tract A vaginal hysterectomy is conducted through this contaminated
formation and scarring. There may be a single or multiple lesions. field from start to finish. If reconstructive procedures are performed
Stage 3 is multiple areas of involvement with multiple interconnected vaginally and the rectum is not covered adequately, in addition to the
sinus tracts, abscesses, and scarring. vaginal bacteriology, the rectal microflora can also contaminate the
Disease that has advanced to stages 2 and 3 usually requires surgical surgical field. The use of synthetic and biologic adjuncts in vaginal
intervention. The surgical approaches that have been used have been reconstructive surgery adds a potential risk for infection. These ad-
incision and drainage, excision of the lesion with a narrow margin, juncts are foreign bodies and as such can become colonized by these
excision of the lesion with a wide margin, and wide excision with bacteria and thus add another dimension to postoperative infection.
excision of the sinus tracts (Matuziak et al. 2009). The patient undergoing a cesarean delivery poses a significant
risk for developing an abdominal SSI as well as a the potential for
Skene gland abscess developing postpartum endometritis. The patient who labors with
Skene glands are the homolog to the male prostate and are subject to ruptured amniotic membranes for >6 h is at significant risk for de-
the same diseases although their occurrence is much rarer. However, veloping a postoperative infection. Labor in the presence of ruptured
Skene glands are subject to infection by C. trachomatis, N. gonor- amniotic membranes provides time for bacteria to ascend into the
rhoeae, and Trichomonas vaginalis, as well as facultative and obligate uterine cavity, colonize the decidual layer of the uterus, and invade
anaerobic bacteria. Skene glands can abscess and the approach to the myometrium, allowing for infection to begin during labor. During
management can be either incision and drainage or marsupialization. manual delivery of the fetal head, copious amounts of vaginal fluid
 Postoperative infections 229

are brought up into the uterine cavity as well as over the uterine and mately 1000 lactobacilli:1 pathogen. Therefore, patients undergoing
abdominal incisions. an obstetric or gynecological operation where the vagina is entered
Thus in both the obstetric and the gynecological patient, the risk have their pelvic cavity and pelvic organs exposed to potential bacte-
for infection is considerable because most surgical procedures are rial contamination. This places the patient at significant risk for the
clean-contaminated operations, and the potential sources of infection development of a postoperative infection.
are numerous (Table 20.4). Therefore, preventive measures begin well However, when the vaginal pH is between 4.5 and 5, lactobacilli
before the operations by assessing the endogenous vaginal microflora. are in danger of losing dominance and one or more of the pathogenic
One it has been decided that the patient is in need of surgery, evalu- bacteria will gain dominance. Which bacterium or bacteria gain domi-
ation of the vaginal microflora should be performed and corrected nance depends on several factors that are not well understood. The
if it is altered. events that initiate a change in pH are not always known. However,
once the vaginal pH ≥5 lactobacilli do not grow well and cannot com-
■■Vaginal microflora pete with the pathogenic bacteria. The inhibition of lactobacilli result
in a significant decrease in the concentration of lactobacilli in the
Managing both the obstetric and the gynecological patient who de- vagina. The concentration of lactobacilli declines from ≥106 bacteria/
velops an SSI requires an understanding of the endogenous bacteri- ml to ≤103 bacteria/ml vaginal fluid.
ology of the lower genital tract. The lower genital tract is a complex The administration of antibiotics for surgical prophylaxis is not
ecologic niche consisting of metabolic products from both the host sufficient to overcome this concentration of pathogenic bacteria and
and microbes, breakdown products of cellular components from the failure to prevent postoperative infection is likely to result. Lin et al.
host and the microbes, and introduced compounds via douching, (1999) found that women with bacterial vaginosis undergoing hyster-
feminine hygiene products, or foreign bodies (e.g., sexual toys) and ectomy were statistically more likely to develop a postoperative pelvic
sexual practices. Any exogenous factor as well as endogenous fac- infection than women with a Lactobacillus or group B streptococcus-
tors that can alter the pH of the vagina will result in a change in the dominant vaginal microflora. Therefore, two preventive measures that
microbial composition of the vagina. can be taken to reduce the risk of the patient developing a postopera-
Thus, this environment exists in a dynamic and fragile state, and tive pelvic infection are: (1) Evaluation of the vaginal microflora and (2)
is constantly challenged. The status of the bacteriology of the lower the administration of antibiotic for surgical prophylaxis. The vaginal
genital tract depends on which bacteria are dominant. A healthy en- pH should be determined at least 1 week before the surgery date,
dogenous vaginal ecosystem is characterized by having a pH of 3.8–4.5, and if the pH ≥5 it should be corrected. This can be achieved, in most
the dominant bacterium is Lactobacillus spp., squamous epithelial cases, by the intravaginal administration of boric acid, 600 mg twice
cells that are well estrogenized, and the number of white blood cells a day for 7 days. Patients not evaluated the week before surgery can
(WBCs) is ≥5 per field at 40 × magnification (Lin et al. 1999, Burrows be evaluated in the operating room by determining the vaginal pH. If
et al. 2004). The species of Lactobacillus that are present in the vagina the pH ≥5 and there is a fish-like odor associated with the discharge,
are important, because they must produce sufficient quantities of then metronidazole can be administered in addition to cefazolin or
organic acids, hydrogen peroxide (H2O2), and bacteriocin. The endog- other antibiotic that is routinely administered for surgical prophylaxis.
enous vaginal bacteriology is complex and consists of Gram-positive This combination will provide antimicrobial activity against obligate
and Gram-negative facultative and obligate anaerobic bacteria. It is anaerobes (metronidazole) and Gram-positive and Gram-negative
through the ability of Lactobacillus spp., e.g., L. crispatus, to produce facultative bacteria (cefazolin).
lactic acid keeping the pH of the vagina <4.5, and the production
of H2O2 and bacteriocin (lactocin) that the pathogenic bacteria are
suppressed to low numbers. In a healthy state the concentration of
■■Surgical site infection
lactobacilli is ≥106 bacteria/ml vaginal fluid and the pathogenic bac- There are multiple surgical incision sites in obstetric and gynecological
teria numbers are ≤103 bacteria/ml vaginal fluid or a ratio of approxi- patients. The most visible surgical incision sites are those made in the
abdominal wall and the perineum. Infections occurring in either of
Table 20.4  Postoperative infections in the obstetric and gynecological these sites that require surgical intervention are abscess, necrotizing
patient. cellulitis, and necrotizing fasciitis. Most SSIs are uncomplicated and
Obstetrics Gynecology respond to antibiotic therapy; however, some may require incision
and drainage.
Abdominal incision Abdominal incisions
Indication that an SSI is developing typically begins with a slight
Postpartum endometritis Endometritis increase in the patient’s temperature, e.g., in the late afternoon or early
Myometrial microabscesses Pelvic cellulitis evening a temperature >38°C but <38.5°C may be noted on one or two
occasions. In addition there may be a slight rise in the patient’s pulse
Myometrial necrosis Tubo-ovarian abscess
rate (>90) and erythema that extends >1 cm around the incision. There
Episiotomy Pelvic abscess may be an associated induration of the erythematous area. These can
Infected pelvic hematoma Infected pelvic hematoma all be very early findings of a surgical site that is developing an infec-
Necrotizing fasciitis Necrotizing fasciitis tion. The wound may begin to drain within the next day or two. Once
these conditions have developed the infection may progress in one
Bacteremia Bacteremia
of three directions (Figure 20.1).
Pneumonia Pneumonia A logical approach to evaluating the surgical incision and to
Pyelonephritis Pyelonephritis determining if there is a fluid collection (seroma, infected seroma,
Cystitis Cystitis hematoma, infected hematoma, or abscess), cellulitis, or necrotizing
infection is to perform imaging studies, either ultrasonography or
Sepsis/septic shock Sepsis/septic shock
computed tomography (CT) of the area. The appearance of cellulitis
230 OBSTETRIC AND GYNECOLOGICAL INFECTIONS

Figure 20.1  Progression of surgical site

Clinical surgical site infection infections.

Cellulitis Abscess Necrotizing infection

Medical management Medical + surgical management

does not preclude presence of infection in the deeper tissues. There- common bacteria isolated from blood in the immediate postpartum
fore, a thorough evaluation of the suspicious site must be undertaken period (Monif and Baer 1976, Ledger et al. 1975, Monif 1982). Monif
to avoid unnecessary delay in institution of appropriate management, (1991) demonstrated that asymptomatic bacteriuria was associated
including both medical and surgical management. with postpartum endometritis, in that the same bacterium was iso-
lated from the urine and endometrium of postpartum women with
■■Postpartum endometritis endometritis.
Aside from the risk factors listed in Box 20.3, the endogenous vagi-
Risk factors nal microflora contributes to bacteriuria and therefore plays a role
Postpartum endometritis is more likely to occur in women delivered in early postpartum endometritis. Strep. agalactiae colonization of
by cesarean section compared with those delivered by the vaginal the vagina also is a significant risk factor in the development of early
route. Burrows et al. (2004) reported that women who went into labor postpartum endometritis and sepsis (Faro 1980, 1981).
and subsequently delivered by primary cesarean section had a 21-fold
increased risk of developing endometritis compared with women who Clinical presentation and diagnosis
delivered vaginally. Women delivered by primary cesarean section Patients with postpartum endometritis present with a cluster of
who did not go into labor had a 10-fold risk of developing endometritis findings that establish the diagnosis clinically. It is the rare patient
compared with women delivering vaginally. Additional risk factors who will present with a purulent lochia. Postpartum endometritis
are listed in Box 20.3. can be divided into two categories with regard to presentation; early
postpartum endometritis, occurs within the first 48 h of delivery, and
late postpartum endometritis, occurs 72 h and beyond delivery. Early
Box 20.3 Risk factors for the development of postpartum endo- postpartum endometritis tends to be unimicrobial and due mainly
metritis. to facultative anaerobic bacteria, e.g., Strep. agalactiae (a group B
Cesarean section streptococcus), Strep. pyogenes, and members of the Enterobacte-
Prolonged rupture of amniotic membranes riaceae, especially Escherichia coli. Patients who develop late-onset
Prolonged rupture of amniotic membranes and labor postpartum endometritis typically have a polymicrobial infection
Lack of prenatal care characterized by facultative and obligate anaerobic Gram-positive
Altered vaginal microflora (bacterial vaginosis, dominant coloni- and Gram-negative bacteria.
zation by group B streptococci or facultative Gram-negative rod) The clinical onset of postpartum endometritis is indicated by a
Presence of bacteriuria significant change in the patient’s vital signs, notably fever and tachy-
Nasal carriage of Staphylococcus aureus cardia. Fever as a sole indicator for the presence of infection is a poor
Multiple vaginal examinations indicator. Fever in the postoperative patient can be secondary to the
Use of intrauterine monitoring devices tissue trauma associated with the surgical procedure or periopera-
Obesity (body mass index ≥30 kg/m2) tive medications. The bacteria responsible for endometritis are likely
the result of contamination during some point in labor. There is no
doubt that bacteria endogenous to the lower genital tract migrate to
Patients with ruptured amniotic membranes are at risk, and this the uterine cavity during labor (Pinell et al. 1993). Once in the uterine
risk is enhanced if the patient is in labor for a prolonged period of time cavity these bacteria multiply and the longer the labor the greater the
because bacteria from the vagina can ascend into the uterus (Faro et al. numbers of bacteria. Thus, the microbiology of postpartum endome-
1990, Pinell et al. 1993). Once in the uterus and amniotic fluid, these tritis originates from the patient’s own endogenous lower genital tract
bacteria can multiply and achieve concentrations >106 bacteria/ml bacteriology. When the patient’s lower genital tract microbiology shifts
amniotic fluid. The longer the patient is in labor the greater the risk from a lactobacilli-dominant microflora to an altered microflora or
that bacteria can colonize the decidual layer of the uterus and invade bacterial vaginosis (e.g., dominated by E. coli or Strep. agalactiae),
the myometrium, thus setting the stage for endometritis. the threat of postpartum endometritis is significant.
Asymptomatic bacteriuria has been linked to early postpartum Postpartum endometritis can be mild and easily treated, or it can
endometritis. The Gram-negative facultative bacteria are the most be more severe with the development of myometrial microabscesses,
 Postoperative infections 231

leading to necrosis of the myometrium. Postpartum endometritis can be The cervix is usually dilated admitting one to two fingers, allowing
associated with bacteremia. Depending on the virulence of the bacteria palpation of the lower uterine segment, which is often necrotic and
causing postpartum endometritis, sepsis and septic shock can occur. not intact. The uterus is subinvoluted and boggy on palpation.
Patients with postpartum endometritis typically present with fever, The antibiotic regimen can be maintained and the patient should
defined as a temperature ≥38°C measured on two occasions and taken undergo an exploratory laparotomy. The antibiotic regimen most com-
at least 6 h apart, or a temperature ≥38.5°C occurring at any time with monly administered is clindamycin or metronidazole plus ampicillin
a corresponding pulse rate >90 beats/min. A pulse rate that parallels and gentamicin. Individuals who are allergic to ampicillin should
the fever is indicative of a patient with a significant postoperative infec- receive vancomycin, daptomycin, or linezolid. This complication is not
tion. In addition, the patient’s WBC count ≥12 000 and/or a differential because a resistant bacterium has assumed dominance but because
with ≥10% band forms is consistent with postpartum endometritis. the uterine tissue cannot be adequately perfused. Typically the uterus
In addition the pelvic examination should reveal a uterus that is not cannot be salvaged and a total hysterectomy is indicated. The ovaries
involuting appropriately, uterine tenderness to palpation and motion, are usually not involved in the infection nor is there any evidence of
adnexal or parametrial tenderness, and the lochia may be purulent ovarian thrombosis. Therefore, the ovaries do not need to be removed
with or without a foul odor. The presence of a foul-smelling lochia is at the time of hysterectomy (Figure 20.2).
indicative of the presence of anaerobic bacteria. Typically patients Postoperatively these patients do well. However, as a result of
treated for postpartum endometritis with broad-spectrum antibiotics having had postpartum endometritis and two major operations in a
who do not show significant improvement within 48–72 h should be relatively short period of time, there is the possibility of the patient
considered to have failed initial treatment. These patients require re- developing an ileus or bowel obstruction.
evaluation for having a resident bacterium, an abscess, necrosis of the Patients whose uterus is involuting and cervix is closing, but still
uterine incision, or myometrial microabscesses and microthrombosis exhibit signs of postpartum endometritis, should undergo ultraso-
of the uterine vasculature. nography to determine whether there are any retained products of
conception. This is unlikely if the uterus is involuting, firm, but tender
Management and the cervix is not dilated. It is very likely that a resistant bacterium
Pelvic examination reveals that the vaginal discharge may resemble has been selected, most likely a Gram-negative facultative anaerobe.
the color of port wine, contain particulate matter, or be purulent. A specimen obtained from the endometrium as well as venous blood

Figure 20.2  Treatment

strategies for the patient with
Patient with postpartum endometritis endometritis who fails to
fails to respond to antibiotic therapy respond to antibiotic therapy.

Pelvic examination

Ulterus involuting, cervix closed,

Mass palpable over anterior Uterus not involuting, cervix
lochia red and minimal,
uterine segment, infected dilated, uterus tender to
uterus tender, no mass palpable,
hematoma or mass in palpation, lochia dark red or
no retained
posterior cul-de-sac, abscess with particulate matter
products of conception

Probable resistant gram- CT or abdominal/transvaginal

negative bacteria ultrasonography

Microabsoesses and thrombosis

Obtain endometrial If infected hematoma: throughout the myometrium
specimen for culture. drain percutaneously.
Discontinue gentamicin, If posterior cul-de-sac
add amikacin abscess: drain through
the cul-de-sac.
Continue antibiotics Total abdominal hysterectomy.
Ovaries are usually not involved
and do not need to be removed.
Fallopian tubes may need removal
232 OBSTETRIC AND GYNECOLOGICAL INFECTIONS

cultures should be obtained. Discontinuing the gentamicin and

instituting amikacin would be appropriate because Gram-negative
■■Postoperative pelvic infection
bacteria resistant to gentamicin tend to be sensitive to amikacin. Patients undergoing pelvic surgery where the vagina was involved in
Once the culture and sensitivity are known, appropriate antibiotic the surgical procedure are at risk for the development of a postopera-
changes can be made. tive pelvic infection. The infection can be a relatively uncomplicated
infection such as pelvic cellulitis or a more complex infection such as
■■Episiotomy infections an abscess. Again, any time that the vagina is involved in the surgical
procedure post-surgical infection will most likely involve the endog-
Episiotomy continues to be a procedure that is still performed and enous vaginal microflora. In the gynecological patient the infection
the frequency varies from 13% to 85% depending on a variety of is typically polymicrobial, involving both Gram-negative and Gram-
circumstances (Hartmann et al. 2005). There are basically two types positive facultative as well as obligate anaerobic bacteria. Therefore,
of episiotomies that are performed: A midline, where the incision is knowledge about the status of the endogenous vaginal bacterial flora
made directly through the body of the perineum, and a mediolateral, before performing surgery can be of assistance in managing a post-
where the incision is made beginning at the 7 o’clock position at a operative infection.
45° angle avoiding the anal sphincter. The incision is carried through Pelvic cellulitis is the most frequent postoperative infection that
the bulbospongiosus, the deep and superficial transverse perineal occurs after a hysterectomy. This is an SSI because there is an incision
muscles. The perineal body or central perineal tendon consists of a in the vaginal epithelium and associated tissues. Typically there is no
fibromuscular structure formed by the conglomeration of the deep adipose tissue present in the area where the vagina is incised in close
and superficial transverse and bulbospongiosus muscles. proximity to the cervix. The vaginal epithelium, vaginal fascia and con-
Infection rates for episiotomy range from 0.2% to 1.9% (Yokoe et nective tissue, muscle, and peritoneum can easily become infected.
al. 2001). Infection of the episiotomy site has been categorized as: The cellulitis can easily be treated with broad-spectrum antibiotics
(1) Simple, midline involving the skin, mediolateral involving the and patients usually respond within 48–72 h.
skin and subcutaneous tissue; (2) superficial fascial; (3) superficial The more complicated postoperative pelvic infection is the pelvic
fascial necrosis; and (4) myonecrosis (Shy and Eschenbach 1972). The abscess or infected pelvic hematoma (Figure 20.3). The latter is more
microbiology of episiotomy infection can be monomicrobial or poly- frequently encountered than the former condition. The hematoma
microbial, involving bacteria such as Staph. aureus, Strep. agalactiae, typically forms at the vaginal apex because of blood oozing from
Strep. pyogenes, Clostridium sordellii, and C. perfringens, as well as the dissection accompanying excision of the cervix from the vagina.
Gram-negative and Gram-positive facultative and obligate anaerobes. Complete hemostasis is sometimes difficult to achieve in this area.
Infection of the episiotomy should be handled aggressively. Postoperative bleeding leads to formation of a hematoma at the vaginal
Typically the episiotomy will undergo dehiscence when it becomes
infected. If the episiotomy is surrounded by erythema and indura-
tion, and there is no evidence of fluctulancy, this may indicate that
there is cellulitis. The difficulty is determining which patient has an Suspected postoperative
uncomplicated cellulitis versus a complex infection (i.e., abscess pelvic infection
plus necrotizing infection). The patient who develops increasing
pain or erythema should be considered to have a complex infection
and undergo imaging studies. Time is of the essence and, therefore,
the physician should not delay in either obtaining imaging studies or
Speculum and bimanual pelvic and
exploring the episiotomy site.
rectal examination
Imaging of the area with ultrasonography or a CT can be used to
determine if there is a fluid collection and/or gas within the tissues.
If there is a fluid collection the surgical site can be aspirated and the
fluid sent for Gram stain, bacterial culture, and antibiotic sensitivity
Vaginal apical epithelium
testing of the bacteria isolated. The incision should be opened and all is erythematous, tender, and there is
necrotic tissue debrided. The wound should be left opened and packed no significant apparent drainage
with gauze moistened with an appropriate antiseptic solution (e.g.,
0.025% acetic acid). The packing should be removed and replaced
with a fresh moistened packing at least three times a day. Another
approach is to cleanse the wound, after debridement of necrotic
tissue, with 10% povidone–iodine solution, hydrogen peroxide, and
0.9% saline. Once a fine layer of granulation tissue has formed the No masses are Mass or masses are
wound can be sutured close (Hauth et al. 1986, Hankins et al. 1990, palpable palpable
Ramin et al. 1992, Uygur et al. 2004). The patient should be started on
broad-spectrum antibiotics (see Box 20.1). If the Gram stain results
are available then the antibiotic regimen can be guided by the Gram
stain results (see Table 20.3). Diagnosis: pelvic cellulitis Pelvic U/S or CT scan
The wound should not be closed until there is a fine layer of granu- Administer broad to determine location
spectrum antibiotics of the abscesses
lation tissue; this indicates that there is no infection present. Closing
an infected wound can lead to the development of serious complica-
tions, such as recurrent abscess formation, recurrent dehiscence, and Figure 20.3  Algorithm for the diagnosis of suspected postoperative
necrotizing fasciitis. pelvic infection.
 References 233

cuff, sited between the proximal side of the vaginal epithelium and of the anterior abdominal wall, less risk of anterior abdominal wall
distal to the pelvic peritoneum, if the pelvic peritoneum is closed. If hematoma formation, less risk of infection, and better exposure. If
the peritoneum is not closed then the hematoma will form in the floor there is a need to extend the incision to the upper abdomen this can
of the pelvic cavity. be easily accomplished.
Closing the vaginal cuff and pelvic peritoneum creates a space The dilemma occurs when the patient has a transverse lower
between the vaginal epithelium and the pelvic peritoneum (retro- abdominal incision and subsequently requires a laparotomy for a
peritoneal space). It has been demonstrated that an average of 40 ml postoperative pelvic or lower abdominal abscess. These abscesses
(range 10–200 ml) of serosanguineous fluid can accumulate in this are often surrounded by small and large bowel and therefore are
retroperitoneal fluid. This serves as an excellent incubator and cul- not easily accessible. Abscesses located in the posterior cul de sac
ture medium. The bacteria found to inhabit the lower genital tract, are typically densely adherent to the rectum, rectosigmoid, cecum,
especially when this flora is altered, contain combinations of bacteria and omentum. There may even be interloop abscesses of the small
that are abscessogenic. bowel. Approaching these abscesses through a transverse incision
Management of a vaginal cuff-infected hematoma or abscess de- can be difficult but can be accomplished safely. However, if the upper
pends on the exact location, whether or not it is uniloculated or multi- abdomen is involved, this approach may not be feasible and a vertical
loculated, and whether or not it extends to the deep pelvis or into the incision may have to be performed to allow for complete inspection
abdominal cavity. Simple abscesses that are confined to the vaginal cuff of the entire abdominal cavity. Once the abscess have been located
can be managed by opening the vaginal cuff, draining the abscess thor- and drained, the abdomen and pelvic should be irrigated with copious
oughly, and irrigating copiously with sterile 0.9% saline. A drain such as amounts of sterile saline. Enough saline should be used to completely
a Foley catheter can be placed into the abscess area; inflate the balloon cleanse the entire abdomen and pelvis of all purulent fluid and floating
and attach the Foley catheter to a suction device. Ultrasonography at debris. The saline irrigation should return clear when aspirated out
the time of drainage can be of significant assistance by delineating the of the peritoneal cavity.
abscess and determining its course. Care must be taken when draining Drains can be placed in the right colonic gutters as well as the pel-
the abscess and suctioning the abscess not to injure bowel that will be vis. Patients who have had a hysterectomy can have a drain placed in
adjacent to the abscess. A pelvic abscess is typically surrounded by both the pelvis and exit through the vagina. This drain should be attached
large and small bowel and the bowel is usually inflamed and edema- to a closed drainage system. Drains that are placed in the right and
tous. Use of even dull instruments can easily penetrate this fragile and left colonic gutters should exit through the right and left lower abdo-
edematous bowel, thus complicating the patient’s condition. men. They should be attached to suction devices to actively remove
A pelvic abscess that is not located adjacent to the vaginal apex any fluid that has accumulated. If the fluid is serous but cloudy, a
can be managed in one of two ways: Via either laparotomy or percu- specimen should be aspirated from the tubing, and sent for Gram
taneous drainage. The choice of procedure is based on location and stain and culture. If the fluid is bloody, serial specimens can be
complexity of the abscess (Johnson et al. 1981). The success rate for obtained and sent for a hematocrit; if the hematocrit is rising then a
percutaneous drainage of abdominal and pelvic abscesses is 80–90% diagnosis of intra-abdominal or pelvic bleeding can be made. In this
(Lambiase et al. 1992). The recurrence rate is between 5 and 10% (Von case an exploratory laparotomy is indicated to determine the source
Sonnenberg et al. 1984). Corsi et al. (1999) reported a success rate of of bleeding and correct it.
93% employing transvaginally guided drainage of tubo-ovarian and Whether or not percutaneous drainage is employed depends on the
postoperative pelvic abscesses. skill of the interventional radiologist and the location of the abscesses.
These criteria have been modified to include multiloculated Abscesses that are surrounded by bowel and do not permit direct
abscesses as well as abscesses that cannot be approached transab- access to the abscess should not be approached via percutaneous
dominally. Abscesses that are deep in the pelvis and in close prox- drainage. Penetration of the bowel, especially the large bowel, will
imity to the bladder, large and/or small bowel, and uterus may be contribute to the development of intra-abdominal sepsis.
approached transvaginally or transrectally (Von Sonnenberg et al. The patient who has a well-contained or walled-off abscess, is
1991). Laparotomy still remains as an acceptable approach; even afebrile, pulse rate <90 beats/min, and whose WBC count is within
when percutaneous drainage is attempted a surgeon must stand by the normal range or slightly elevated is the best candidate for percu-
to intervene if there are complications. taneous drainage. The patient who is significantly febrile and has a
Approaching a pelvic abscess via laparotomy requires that a verti- markedly elevated WBC count is probably not a good candidate for
cal incision be made to allow for adequate exposure to the pelvis and percutaneous drainage, and is best served by exploratory laparotomy.
abdomen. Many gynecologists continue to use a transverse lower Once the abscess has been successfully removed, the patient should
abdominal incision; however, performing an incision for cosmetic defervesce and the WBC count should return to normal with 48–72 h.
reasons is not in the best interest of the patient. A vertical incision Drains should be removed when there is <30 ml fluid accumulated in
placed in the midline of the lower abdomen allows for less dissection the drains over a 24-hour period.

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Chapter 21 Necrotizing enterocolitis
Shannon L. Castle, Henri R. Ford

Necrotizing enterocolitis (NEC) is the most common medical and

surgical emergency affecting the gastrointestinal tract of newborn
■■Role of enteral feeding
infants. Approximately 1–5% of all preterm infants develop NEC (Stoll Initiation of enteral feeds, particularly rapid advancement of feeding,
1994, Llanos et al. 2002). Up to 50% of neonates who develop NEC is a known risk factor for NEC. However, long-term hospitalization
eventually require surgical intervention (Guillet et al. 2006, Holman without feeds carries the risk of intestinal atrophy and inflammation,
et al. 2006), with the mortality rate for these patients varying from which also increases the risk of NEC. In fact, previous studies have
20% to 50% (Rowe et al. 1994, McElhinney et al. 2000). The mortality shown that trophic feeds are beneficial in the preterm population.
rate approaches 100% for infants with panintestinal NEC. Although Multiple trials have shown that low-volume feeding (2–24  ml/kg
most infants who develop NEC are premature with extremely low per day) does not increase the risk of NEC (Berseth 1992, Tyson and
birthweight, NEC can also affect term infants, especially those with Kennedy 2000). Optimal volume and rate of advancement of enteral
cyanotic heart disease. As advances in neonatal medicine have re- feeding in very-low-birthweight infants remain controversial (Bombell
sulted in increased survival of both preterm infants and those with and McGuire 2008, Hay 2008).
complex medical problems, the incidence of NEC continues to rise. Compared with formula, breast milk has been shown to protect
Risk factors that have been implicated in the development of NEC against the development of NEC in both human and animal studies
include prematurity, hypoxia, initiation of enteral feeding, congenital (Lucas and Cole 1990, Schanler et al. 1993). The exact mechanism
heart disease, and bacterial infection. NEC is characterized by intes- by which breast milk protects against NEC is unknown and remains
tinal inflammation and mucosal destruction, leading to gut barrier an active field of study. Breast milk contains a number of factors
failure. Infants with the most severe form of NEC typically develop believed to be protective against the development of NEC, including
full-thickness destruction of the intestinal wall, leading to intestinal the immunoglobulins IgM, IgG, secretory IgA, lysozyme, lactoferrin,
perforation, peritonitis, sepsis, and death. Those who survive may epidermal growth factor, and complement proteins, to name a few.
experience additional morbidity such as stricture formation or adhe-
sions, which may result in intestinal obstruction, or they may require Immunoglobulins
long-term parenteral nutrition due to intestinal failure (Horwitz et al. Human breast milk contains IgM, IgG, and secretory IgA. IgA is the
1995, Holman et al. 1997, Blakely et al. 2005). predominant immunoglobulin in breast milk. Its linkage with the
secretory component renders IgA resistant to proteolysis in the stom-
■■PATHOPHYSIOLOGY ach and intestine. This allows passive transfer of immunity from the
mother to the infant against a variety of bacterial and viral pathogens.
■■Immature intestinal barrier However, oral or intravenous administration of immunoglobulins has
not been shown to be protective against NEC (Foster and Cole 2004);
The intestinal epithelial barrier consists of a single layer of polarized in fact, the use of intravenous immunoglobulin in newborns with
epithelial cells (enterocytes) that serve to protect the host from inva- hemolytic disease has been linked to the subsequent development
sion by pathogenic organisms while tolerating commensal bacteria of NEC (Figueras-Aloy et al. 2010).
(Muller et al. 2005, Neu et al. 2005). Maintenance of gut barrier func-
tion depends on both structural and biochemical elements which
prevent the translocation of bacteria across the intestinal epithelium.
■■Abnormal bacterial colonization
Structural barriers include epithelial tight junctions, intestinal mucin At birth, the neonate’s intestine is sterile but it becomes rapidly
production, fluid secretion, and peristalsis, all of which serve to limit colonized by bacteria from the environment. Escherichia coli and
adhesion of bacteria to the cell surface, the first step in the process streptococci rapidly colonize most infants, followed by enterobacters,
of translocation (Berseth 1989, Kelly et al. 1993, Hecht 1999, Lin et al. and colonization with other bacteria such as enterococci, lactobacilli,
2008). In the proximal intestine, gastric acidity serves as a first line of clostridia, and Bacteroides spp. (Mackie et al. 1999, Enck et al. 2009).
defense against bacterial passage beyond the stomach. Biochemical The specific colonization pattern may be influenced by the route of
barriers to the entry of pathogenic bacteria include a- and b-defensins, delivery, whether vaginal or via cesarean section, the type of feeding,
which are specialized antimicrobial peptides secreted by Paneth whether breast milk or formula, and the environment during and after
cells and intestinal epithelial cells, respectively, as well as secretory birth. Bacterial colonization in preterm infants is heavily influenced
IgA, which serves as an antiseptic paint to bind bacteria and prevent by the hospital environment (Sharma et al. 2007). Abnormal bacterial
their adhesion to the intestinal epithelium. Paneth cells, specialized colonization patterns in neonates admitted to the neonatal intensive
enterocytes at the base of intestinal crypts, further contribute to the care unit (ICU) or other hospital environment may further increase
biochemical defense by producing phospholipase A2 and lysozyme. susceptibility to NEC (Stoll et al. 1996). Although most cases of NEC
In neonates, particularly premature infants, both the structural and are sporadic in nature and no specific bacteria or viruses have been
biochemical components that are responsible for maintaining gut consistently isolated in infants with NEC, the occurrence of occasional
barrier integrity are immature, thus predisposing them to the devel- outbreaks suggests a role for a transmissible agent in the pathogenesis
opment of NEC. of the disease (Emami et al. 2009).
236 NECROTIZING ENTEROCOLITIS

■■Inflammatory mediators and NEC Box 21.1 Modified Bell stages of necrotizing enterocolitis.
The current hypothesis regarding the pathogenesis of NEC is that a
hypoxic or infectious insult further compromises the already imma- I Suspected disease
ture intestinal barrier of the neonate, thereby allowing pathogenic IA
bacteria to translocate across the damaged epithelium and incite Mild systemic signs (apnea, bradycardia, temperature instability)
an inflammatory cascade that exacerbates the mucosal injury, and Mild intestinal signs (abdominal distension, gastric residuals, oc-
ultimately leads to full-blown gut barrier failure (Hsueh et al. 2003, cult blood in stool)
Emami et al. 2009). Multiple inflammatory mediators have been IB
implicated in the development of NEC, including tumor necrosis Mild systemic signs (apnea, bradycardia, temperature instability)
factor (TNF)-a, platelet-activating factor, interleukins IL-1, IL-6, Mild intestinal signs (abdominal distension, gastric residuals, oc-
IL-18, endothelin-1, thromboxanes, and oxygen free radicals, to cult blood in stool)
name a few (Caplan et al. 2005, Markel et al. 2006, Lugo et al. 2007, Non-specific or normal radiological findings
Chokshi et al. 2008). Nitric oxide (NO), the product of nitric oxide
synthase (NOS), has also been implicated as a key inflammatory II Definite disease
mediator in the pathogenesis of intestinal barrier failure in NEC. IIA
NOS exists in three isoforms, two of which, endothelial NOS and Mild systemic signs (apnea, bradycardia, temperature instability)
neuronal NOS, are expressed constitutively at low levels. The third, Additional intestinal signs (absent bowel sounds, abdominal
inducible NOS, is expressed at high levels during inflammation. The tenderness)
resultant overproduction of NO during inflammation contributes Specific radiographic signs (pneumatosis intestinalis or portal
to intestinal barrier damage by reacting with superoxide to form venous air)
the potent toxic intermediate, peroxynitrite (Potoka et al. 2003, Laboratory changes (metabolic acidosis, thrombocytopenia)
Chokshi et al. 2008). IIB
Prostanoids are inflammatory mediators formed by the conver- Moderate systemic signs (apnea, bradycardia, temperature instabil-
sion of the membrane lipid arachidonic acid to prostaglandin G2 by ity, mild metabolic acidosis, mild thrombocytopenia)
cyclooxygenase (COX). Prostaglandin G2 is then converted to multiple Additional intestinal signs (absent bowel sounds, abdominal ten-
biologically active prostanoids by specific synthases (Park et al. 2006). derness, abdominal mass)
Prostanoid production by the COX enzymes is critical for maintenance
of the intestinal barrier. COX-1 is produced at constitutively low levels III Advanced disease
and exerts a protective effect on mucosal barrier function, whereas IIIA
COX-2 is upregulated during inflammation and may contribute to Severe systemic illness (same as IIB with additional hypotension
epithelial injury. In NEC, increased activity of the COX enzymes, in and shock)
particular the COX-2 isoform, may exacerbate the level of inflamma- Intestinal signs (severe abdominal distension, abdominal wall
tion (Grishin et al. 2004). discoloration, peritonitis, intestine intact)
Severe radiographic signs (definite ascites)
■■DIAGNOSIS Progressive laboratory derangements (metabolic acidosis, dis-
seminated intravascular coagulopathy)
■■Clinical IIIB
Severe systemic illness (same as IIIA)
Infants with NEC may present with both gastrointestinal and systemic Intestinal signs (large abdominal abscess, abdominal wall discol-
signs including abdominal distension, feeding intolerance, bloody oration, peritonitis, intestinal perforation)
stools, hypoxia, respiratory distress, and hypoperfusion. In preterm Severe radiographic signs (definite ascites and pneumoperito-
infants, NEC tends to occur within the first few weeks of life, whereas neum)
in full-term infants, it may present in the first few days of life (Wiswell Worsening laboratory derangements (metabolic acidosis, dissemi-
et al. 1988, Andrews et al. 1990). nated intravascular coagulopathy)
Before 1978, no standardized system existed to diagnose and
study NEC. The grading system introduced by Bell et al. (1978), which
relies on clinical and radiographic criteria, has been widely adopted
since its publication. A single modification was made to distinguish
■■Laboratory findings
between perforated and non-perforated NEC (Box 21.1) (Kliegman Infants with NEC may have a variety of derangements in laboratory
and Walsh 1987). Recently, however, the utility of the Bell staging has values. Hematological abnormalities commonly include neutropenia
been questioned because the increased viability of infants at lower and thrombocytopenia, with roughly 37% of severe cases having a WBC
gestational ages due to improved critical care and surfactant therapy <1.5 x 109 (Hutter et al. 1976, Ragazzi et al. 2003). Metabolic abnor-
has significantly changed the population of infants in the neonatal malities include acidemia, hypercapnia, and hypoxemia (Hallstrom
ICU (NICU). Some authors have also argued that infants who are now et al. 2006). Although an elevated C-reactive protein (CRP) value is
better classified as having focal intestinal perforation were grouped not specific for NEC, it has been shown to predict the likelihood of
with NEC under the old system for purposes of research and treat- complications, such as abscess or stricture formation, or the need for
ment, and therefore the Bell classification needs to be re-evaluated surgical management (Pourcyrous et al. 2005). Gram stain and cultures
and revised (Gordon et al. 2007). will show bacteremia in up to 50% of patients (Sharma et al. 2007).
 Treatment 237

During the recovery phase, thrombocytopenia will often persist even

after other parameters have normalized because the megakaryocytes
are typically the last cells to recover from the generalized bone marrow
suppression that characterizes severe NEC.

■■Radiographic
Radiographic signs pathognomonic for NEC include intramural gas
on abdominal radiographs (pneumatosis intestinalis), portal venous
gas, and free intraperitoneal air in the case of perforation (Epelman
et al. 2007). Dilated loops of bowel may be present. Although it may
not be specific for NEC, the presence of a loop of bowel that remains
unchanged in position on multiple serial abdominal radiographs,
referred to as a “fixed loop,” is associated with full-thickness necrosis.
An anteroposterior and a left lateral decubitus abdominal radio-
graph are the diagnostic tests of choice in infants suspected of having
NEC. The use of abdominal ultrasonography may also be helpful a
because it may show increased bowel wall thickness and fluid collec-
tions with greater sensitivity than plain films. It is subject to operator
experience, however, and thus has not replaced plain films as the
standard of care.
Contrast studies are not indicated in the initial evaluation of an
infant with NEC, but patients who recover should be evaluated for
intestinal strictures with contrast studies should they develop signs
and symptoms of bowel obstruction (Radhakrishnan et al. 1991).

■■Differential diagnosis
The differential diagnosis for NEC includes infectious enterocolitis,
milk or formula allergy, sepsis, and ileus (Engum and Grosfeld 1998,
Gordon et al. 2007). Obstruction due to a number of causes, including
atresias, intussusception, and Hirschsprung disease, may also present
with feeding intolerance and abdominal distension. Focal intestinal
perforation (FIP) is now recognized as a distinct disease entity from
NEC, with different pathological and morphological characteristics b
(Aschner et al. 1988, Pumberger et al. 2002). FIP is more commonly
seen in very premature infants (fewer than 26 weeks’ gestation) and Figure 21.1  Hematoxylin and eosin-stained permanent section of ileum
seems to be related to inhibition of mucosal blood flow regulation with severe necrotizing enterocolitis (NEC). (a) Pan-necrosis, loss of villous
architecture, and neutrophil infiltration in the mucosa (× 40). Arrow indicates
in the distal ileum due, at least in part, to the use of COX inhibitors
area of necrosis. (b) The mucosa in severe NEC shows neutrophil infiltration
such as indometacin, which is frequently used to accelerate closure (arrow) and massive sloughing of necrotic epithelium (× 200).
of a patent ductus arteriosus (PDA). As a result, FIP tends to be truly
focal and more common in very premature babies with chronic lung
disease and symptomatic PDA.

■■PATHOLOGY
Histopathological examination of the intestine affected by NEC typi-
cally shows neutrophilic infiltration, epithelial sloughing, submucosal
gas, and edema (Figure 21.1) (Balance et al. 1990). Advanced NEC is
characterized by transmural necrosis and perforation. NEC may occur
anywhere in the bowel, but the terminal ileum is most commonly af-
fected. In very severe cases, the entire bowel may be affected, causing
pan-necrosis of the intestine (Figure 21.2).

■■TREATMENT
■■Medical management
Initial management of suspected or confirmed NEC consists of
cessation of oral feeds, placement of an orogastric tube for gastric
decompression, intravenous fluid resuscitation, and administration Figure 21.2  Intraoperative photo of pan-necrosis in necrotizing
of broad-spectrum antibiotics. In more severe cases characterized by enterocolitis.
238 NECROTIZING ENTEROCOLITIS

systemic sepsis or the neonatal form of the systemic inflammatory source of EGF for the intestine. However, neither EGF nor HB-EGF is
response syndrome, endotracheal intubation, and/or pressors may present in commercially available infant formula. Both EGF and HB-
be required for ventilatory and hemodynamic support respectively. EGF have shown promise as a preventive and therapeutic strategy in
Coagulopathy or thrombocytopenia should be treated with appropri- NEC. Research in a neonatal rat model of NEC has shown that oral
ate blood products. administration of EGF (Dvorak et al. 2002) or HB-EGF (Feng et al.
Antibiotics with broad activity against both Gram-negative and 2006) can decrease the incidence and severity of experimental NEC.
Gram-positive organisms should be administered at the first signs
of disease. There is insufficient evidence to support a single anti-
biotic regimen, but the high rate of bacteremia supports the use of
■■Surgical management
broad coverage, and evidence from multiple animal models show Indications for surgery
improved survival with antibiotic treatment (Bell et al. 1978, Brook The only absolute indication for surgical intervention in NEC is the
2008, Lin et al. 2008). Appropriate combinations include ampicillin presence of pneumoperitoneum, which indicates transmural intes-
with gentamicin or a third-generation cephalosporin (i.e., cefotaxime) tinal necrosis that has progressed to perforation. However, extensive
plus metronidazole or clindamycin. An alternative treatment widely necrosis can occur without evidence of free air on an abdominal
used in some NICUs consists of piperacillin–tazobactam with the radiograph. Surgery may also be indicated in the following settings:
addition of tobramycin for double Gram-negative coverage. In cases Significant abdominal wall erythema or cellulitis, which suggests the
complicated by suspected meticillin-resistant S. aureus (MRSA) or presence of a contained perforation; a fixed intestinal loop on serial
ampicillin-resistant enterococci, vancomycin should be added to plain abdominal radiographs; a palpable abdominal pass; a positive
the antibiotic treatment. Vancomycin levels should be measured to paracentesis; or clinical deterioration despite aggressive medical
ensure the therapeutic plasma concentration. Antibiotic choices can therapy.
then be tailored based on intraoperative or blood culture results, and Surgical options for the management of advanced or perforated
guided by an institution-specific antibiogram. If cultures indicate a NEC vary and are generally determined by the extent of intestinal
fungal infection, fluconazole or amphotericin B should be added for involvement and the clinical condition or hemodynamic stability
antifungal coverage. Antibiotics should be continued for at least 7 days of the infant. The primary goal of surgery is to control the source of
or until the patient recovers, as evidenced by hemodynamic stability, infection while preserving the maximum amount of viable intestine.
return of gastrointestinal (GI) function and normalization of labora-
tory values, although the thrombocytopenia may persist for weeks. Surgical approaches
Surgical management of NEC remains a subject of ongoing contro-
■■EXPERIMENTAL AND EMERGING versy. Ein et al. (1977) introduced the concept of peritoneal drainage
(PD) as a temporizing measure before definitive laparotomy in hemo-
SCIENCE ON TREATMENT dynamically unstable infants with perforated NEC. Since then, several
studies have advocated PD as definitive treatment, rather than simply
■■Probiotics as a temporizing measure for some unstable infants, and this approach
has gained popularity over the last three decades. Multiple retrospec-
Probiotics are non-pathogenic microbial organisms that colonize tive studies have advocated primary PD as definitive therapy in all
the intestinal tract and modulate the gut immune response (Caplan extremely low-birthweight infants with Bell stage III NEC (Lessin et
2009). The adult intestine normally includes a variety of commensal al. 1998, Rovin et al. 1999), but others report that most of these infants
anaerobes and facultative aerobes. There is an increasing body of eventually require laparotomy, and that in patients with birthweight
evidence to support the immunomodulatory effects of these bacteria >1000 g, the overall outcome is unchanged (Ahmed et al. 1998). In an
in inflammatory disorders of the intestine. Given the hypothesis that effort to determine the best strategy, Moss et al. (2001) performed a
altered bacterial colonization predisposes to NEC, administration of meta-analysis of 10 studies from 1978 to 1999, which failed to show any
several non-pathogenic bacteria, including lactobacilli and Bifido- superiority of PD over laparotomy. A similar retrospective analysis by
bacterium spp., have been studied as a preventive strategy for NEC. Baird et al. (2006) showed improved outcome in very-low-birthweight
These studies show a decrease in the rate of development of severe (VLBW) infants treated with primary laparotomy or rescue lapa-
NEC, mortality, and sepsis in premature infants given prophylactic rotomy after PD. A subsequent prospective, non-randomized, multi-
probiotics (Deshpande et al. 2010, Alfaleh et al. 2011). Although there institutional study by Demestre et al. (2002) of 44 neonates showed
have been isolated case reports of systemic infections (bacteremia) improvement in 86% of infants after PD; 54% required surgery after
caused by the administration of probiotics to some infants, large PD. Overall survival rate was 95% for infants >1000 g.
clinical trials or meta-analyses have failed to consistently document Blakely et al. (2006) prospectively studied the long-term outcome
this complication. in VLBW infants (<1000 g) undergoing primary PD versus laparotomy
for perforated NEC. They did not find a significant survival difference
■■Growth factor receptors between infants treated with primary laparotomy versus PD; 23% of
patients required subsequent laparotomy after initial PD. Notably,
Epidermal growth factor (EGF) is one of several components of breast this study included patients with FIP as well as NEC. PD was more
milk that may confer protection from NEC. EGF and another mem- likely to be used for FIP, whereas laparotomy was more likely to be
ber of the family of EGF-related peptides, heparin-binding EGF-like employed for the surgical treatment of NEC. When the NEC cohort was
growth factor (HB-EGF), are present in breast milk, although EGF is analyzed separately, the survival rate after PD without laparotomy was
two to three times more abundant than HB-EGF. Their actions on the only 32% in NEC compared with 57% in the cohort treated with initial
EGF receptor play a critical role in intestinal epithelial cell prolifera- laparotomy. Moss et al. (2006) subsequently conducted a prospective,
tion, maturation, and restitution. The fetal intestine is exposed to EGF multi-institutional, randomized controlled trial of PD versus laparotomy
in the amniotic fluid and, in the neonatal gut, breast milk is a major in 177 patients weighing <1500 g and >34 weeks’ gestational age with
 Complications 239

perforated NEC. This study found a similar mortality in the groups segments with borderline viability, can limit the extent of resection
treated with PD and laparotomy (34.5% vs 35.5%) and no difference without increasing morbidity and mortality (Luzzatto et al. 1996).
in length of hospitalization or need for parenteral nutrition. However, The “clip and drop-back” technique resects all nonviable bowel, but
roughly 38% of those randomized to PD needed subsequent lapa- avoids ostomy creation by closing the segments without anastomosis
rotomy for deteriorating status. In non-enrolled infants, those who at the time of initial laparotomy (Ron et al. 2009). A second-look
underwent PD had a 41% mortality rate compared with 15% for those operation is then performed after 4–72 h. The ideal management
undergoing initial laparotomy. remains controversial and further prospective studies are needed
Rees et al. (2008) also published a randomized multicenter study in to determine the best approach in such situations.
31 countries, with 69 infants with birthweight <1000 g and a diagnosis
of NEC or FIP enrolled. The authors found a trend toward increased
survival in those treated with primary laparotomy. Laparotomy was
■■COMPLICATIONS
ultimately required in 26/35 (74%) of those randomized to PD, and
thus only 11% of the infants received PD as definitive treatment. More
■■Acute
recently, Sola et al. (2010) conducted a meta-analysis, which showed Acute complications of NEC are due to infection and resultant inflam-
an increased mortality rate of 55% in patients treated with PD for mation. Infectious complications include sepsis, meningitis, peritoni-
NEC and FIP compared with those treated with laparotomy. Thus it tis, and intra-abdominal abscess formation. Resultant inflammation
is possible that better outcomes can be achieved with careful patient may lead to coagulopathy and disseminated intravascular coagulation,
selection for laparotomy. respiratory and cardiovascular compromise, and metabolic derange-
Based on these studies, we conclude that infants weighing >1500 g ments including acidosis and hypoglycemia.
and requiring surgical intervention for perforated NEC are probably
best managed with laparotomy and resection of the necrotic intestine,
with the goal to limit the extent of resection to avoid the complication
■■Chronic
of short bowel syndrome. The most common long-term problem in NEC survivors is stricture
In cases of NEC with segmental necrosis or isolated perforation, formation. Strictures occur in >30% of patients with medically or
surgical options include resection and ostomy creation or primary surgically treated NEC (Schwartz et al. 1980, Lemelle et al. 1994).
repair. Proponents of ostomy creation and thus intestinal diversion cite Strictures may occur anywhere in the affected bowel, but the most
a number of studies showing higher rates of survival with enterostomy common location is in watershed areas of the colon (Schimpl et
compared with primary anastomosis. In a retrospective study of 173 al. 1994). If a stricture is suspected based on clinical symptoms of
patients over 14 years, Cooper et al. compared 27 infants treated with obstruction such as abdominal distension, feeding intolerance, or
primary repair to those treated with resection and stoma formation. bilious emesis, a water-soluble contrast enema should be obtained.
They reported a 48% survival rate in the primary repair group versus Any stricture requires surgical resection. Short bowel syndrome is
72% in the enterostomy group (Cooper et al. 1988). a problem that affects up to 10% of infants requiring surgical inter-
Proponents of primary repair argue that there is significant morbid- vention for NEC (Horwitz et al. 1995). Short bowel syndrome occurs
ity in ostomy creation and subsequent ostomy closure, particularly when the intestine remaining after resection of diseased segments
in VLBW infants (O’Connor and Sawin 1998). In a study of 18 infants is insufficient to support full enteral nutrition (O’Keefe et al. 2006).
with perforated NEC treated by resection and primary anastomosis The resultant dependence on parenteral nutrition carries a risk of
(Ade-Ajayi et al. 1996). there was no anastomotic leaks and the mor- chronic cholestasis and recurrent central line infections (Cavicchi
tality rate (N = 2, 18%) was comparable to published rates in infants et al. 2000, Duro et al. 2008). The former may eventually lead to liver
treated with enterostomies. Although the mean weight of the infants failure. Recent retrospective studies of fish-oil-based fat emulsions
undergoing primary anastomosis was 1494 g, a subsequent report from as opposed to soybean lipid emulsions as an adjunct to parenteral
the same group demonstrated the efficacy of this approach in infants nutrition in these children show decreased cholestasis and liver
weighing <1000 g (Hall et al. 2005). Thus, the authors concluded that injury (Gura et al. 2008, Diamond et al. 2009). Prospective studies
primary anastomosis, in selected patients, has comparable morbidity of this emerging therapy are ongoing. Surgical treatment of short
and mortality to stoma formation. bowel syndrome includes intestinal lengthening procedures and
Pan-necrosis presents a major challenge for preserving intes- small bowel transplantation (Kaufman et al. 2001).
tinal length in the face of extensive involvement. Options include Infants who survive NEC have a particularly increased risk of
resection of diseased intestine with creation of multiple ostomies, neurodevelopmental impairment, which is seen in 43% of those with
proximal diversion with or without a “second-look” procedure, severe NEC and 15% of those with mild-to-moderate disease (Vohr
and the “clip and drop-back” technique introduced by Vaughn et et al. 2000). The incidence is higher in patients requiring surgical
al. (1996). Resection of necrotic intestine with creation of multiple intervention, presumably due to more severe disease, and in VLBW
enterostomies was once a popular approach, but it has been aban- infants, likely due to the increased comorbidities of prematurity (Hintz
doned because the multiple ostomies invariably lead to the loss of et al. 2005). Treatment strategies to minimize the neurodevelopmental
viable intestine. Proximal diversion, without sacrificing intestinal impact of NEC are a subject of ongoing research.
240 NECROTIZING ENTEROCOLITIS

■■REFERENCES
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Chapter 22 Postoperative infections of
the central nervous system
H. Richard Winn, Saadi Ghatan

The present chapter focuses on infections involving the central The spectrum of organisms involved in postoperative CNS infec-
nervous system (CNS) after cranial and spinal surgery. With rare tions is different from new infections of the brain and spine (McClel-
exception in a non-immunocompromised host, such infections are land and Hall 2007). Most of the organisms involved in postoperative
almost exclusively bacterial and, consequently, this review is primarily infections are skin contaminants. The most common organism is
devoted to bacterial infections. Staphylococcus aureus with some studies finding >50% incidence of
Common infectious disorders after craniotomy include meningitis, this organism (Gantz 2004). Coagulase-negative staphylococci are
epidural and subdural empyema, osteomyelitis (bone flap infections), the next most frequent, followed by enterococci, streptococci, Aci-
and brain abscess. Infections after ventriculoperitoneal shunts require netobacter spp., Pseudomonas aeruginosa, Klebsiella pneumoniae,
special attention because of their high frequency. This chapter also Citrobacter spp., Enterobacter spp., and Escherichia coli. There is some
highlights the factors associated with infections after simple and degree of correlation between the type of infection and organisms
complex spine surgery. In most circumstances, postoperative spinal cultured, e.g., Gram-negative bacilli are the most common organisms
infections do not affect the CNS directly, but rather involve the bone cultured with postoperative meningitis whereas Gram-negative bacilli
and soft tissue surrounding the spinal cord and the cauda equina. and polymicrobial infections are the most frequent in brain abscess.
Superficial incisional infections occurring after both cranial and spinal There is recent growing awareness that an anaerobic Gram-positive
surgery are also discussed although this topic is covered extensively bacillus and skin contaminant, Propionibacterium acnes, is involved
in earlier chapters. in indolent postoperative CNS infections (Nisbet et al. 2007)

■■SPECIAL CONSIDERATIONS ■■OVERVIEW OF RISK FACTORS FOR

OF CNS INFECTIONS POSTOPERATIVE CNS INFECTIONS
Postoperative evaluation and treatment of infections affecting the Patient-related and technique specific factors have been described as
brain and spinal cord function are difficult because of two unique being associated with the development of postoperative CNS infec-
aspects of the anatomy of the CNS. First, the brain and spinal cord tions in multiple studies (Korinek 1997, Olsen et al. 2003, McClelland
are surrounded by the boney skeleton of the cranium and vertebral and Hall 2007). These factors are displayed in Tables 22.1–22.3 and
spine. This protected position of the CNS makes the diagnosis of can be summarized as:
postoperative infections difficult. Rather than observing the direct ⦁⦁ General surgery studies have identified a variety of factors such
manifestations of infection, the surgeon must establish the diagnosis as diabetes, obesity, and age that correlate with the development
based on the consequences of infection: The symptoms and signs of postoperative infections. All of these conditions affect host
of dysfunction of the CNS or surrounding structures. Second, the immunological status. In addition, neurosurgery patients have
diagnosis of postoperative CNS infection is made more difficult by additional causes that will alter host immunological status such as
the pre-existing alteration of CNS function related to the patient’s CNS trauma, malignant brain tumors, stroke, steroid administra-
primary disease and/or the initial operation. tion, and radiation.
The other unique anatomic aspect of the CNS is the presence of ⦁⦁ Presumably, many of the observations made in general surgery
barriers that are designed to isolate the CNS from constituents in patients may be extrapolated to the neurosurgery patient. However,
blood and cerebral spinal fluid (CSF): The blood–brain barrier (BBB) differences exist, e.g., low body temperature has been shown in
and the CSF–brain barrier. These barriers are dependent on special general surgery patients undergoing abdominal surgery to cor-
anatomic and physiological features of the endothelial cells lining the relate with postoperative infections (Kurz et al. 1996). In contrast,
inner surface of the blood vessels of the CNS, and the ependymal cells no differences in postoperative infections (e.g., meningitis, inci-
lining the walls of the brain ventricles. These barriers limit the entry sional, bone flap, pneumonia, or urinary) were found in patients
of many drugs that are normally capable of perfusing and penetrating undergoing craniotomy for aneurysm clipping who were random-
non-CNS organs. Chemotherapeutic agents under normal conditions ized to normothermia versus moderate hypothermia (Todd et al.
thus have limited access to the CNS, making problematic routine 2005). However, the incidence of bacteremia was higher in the
treatment with antibiotics and other drugs. However, in the inflamed hypothermic group.
state, the integrity of the BBB and the CSF–brain barrier is altered and ⦁⦁ Prophylactic antibiotics have been demonstrated in randomized
antibiotic entry is enhanced. As the infectious process responds to trials to lower the incidence of postoperative infections in clean
medical therapy, these barriers return to a more competent, less leaky craniotomies and spinal procedures (Horwitz and Curtin 1975,
state, decreasing antibiotic penetrance and increasing the likelihood Young and Lawner 1987, Bullock et al. 1988, Dempsey et al. 1988,
of a persistent residual nidus of infection. Barker 1994), and their use has been extended to other types (i.e.,
244 POSTOPERATIVE INFECTIONS OF THE CENTRAL NERVOUS SYSTEM

Table 22.1 Risk factors for postoperative infection after craniotomy. Table 22.3 Risk factors for postoperative infection after spinal surgery.
PATIENT RISK FACTORS Association PATIENT RISK FACTORS Association
Immune state H Prolonged preoperative hospitalization H
Nutritional status H Diabetes mellitus H
Steroids M Immune state H
Radiation M Malignancy H
Chemotherapy M Nutritional state H
Trauma H Trauma H
Diabetes mellitus L Obesity H
Neurological status M Tobacco use M
SURGICAL RISK FACTORS Steroid use M
Postoperative CSF leak Very H Concurrent infection M-L
Duration >4 h H SURGICAL RISK FACTORS
Contaminated H Postoperative CSF leak H
Emergency H Duration H
Previous neurosurgery <4 months H Blood loss H
Use of foreign material H Approach H
Sinus entry M Extent (e.g., levels) H
Placement of drains L Graft M
CSF, cerebrospinal fluid; H, high; L, low; M, moderate; M-L, inconsistent. Instrumentation M
H, high; L, low; M, moderate; M-L, inconsistent.
Table 22.2 Risk factors for postoperative infection after
ventriculoperitoneal shunt.
PATIENT RISK FACTORS Association be supplemented during prolonged surgeries, and should be dis-
continued within 24 h of surgery (Fry 2001).
Age: <6 months old H
⦁⦁ Intraoperative factors and conditions influence the development
Diagnosis M-L of postoperative infections. Obviously, sterile conditions must be
Etiology of hydrocephalus M-L followed throughout the case. The skin should be prepared with an
Concurrent infection (e.g., UTI) M antiseptic, but no agent appears to be superior to any other. In the
past, hair shaving was a standard part of preoperative preparation,
Previous shunt M
but no or minimal hair removal has not been shown to increase
SURGICAL RISK FACTORS the risks of postoperative infections. The exception to leaving hair
Postoperative CSF leak Very H in situ may be shunt operations. If hair is to be removed, it should
Double gloving L be accomplished immediately before surgery. An electric shaver
or clipper should be used rather than a razor. The latter has the
Draping L
potential to cause small cuts and abrasions with consequent colo-
Type of preoperative skin prep L nization by skin flora.
Duration of operation L ⦁⦁ Specific, well-defined risk factors for craniotomy (Table 22.1)
have been identified as follows (Korinek 1997): CSF leak, re-
Surgical training L
operation, duration of surgery (3–4 h), emergency operations,
Type of shunt L clean-contaminated and contaminated operations. Of these risk
CSF, cerebrospinal fluid; H, high; L, low; M, moderate; M-L, inconsistent; UTI, urinary tract factors, CSF has the most robust association (Korinek 1997) and
infection. thus, when closing a cranial wound, careful, meticulous closure
is required. Other factors that may be associated with post-
craniotomy infections include the use of drains, diabetes mel-
contaminated) of CNS operations. Some individual randomized litus, opening paranasal sinuses, poor neurological status, and
studies, focusing on spinal operations, have failed to confirm the implantation of foreign material (e.g., shunts), to mention a few.
utility of prophylactic antibiotics. This failure may relate to the ⦁⦁ Specific factors that correlate with postspinal infections (Table 22.3)
low incidence of postoperative spinal infections in control groups include (Levi et al. 1997, Wimmer et al. 1998) site (posterior versus
and the small numbers of patients studied. In contrast, utilizing anterior), complexity (number of levels and approach), duration
pooled data and meta-analysis, Barker found that postoperative (may be an epiphenomenon reflecting complexity), trauma (may
infections were significantly lowered to 2.2% from 5.9% (Barker reflect duration and/or complexity), blood loss (correlates with
2002). To be effective and safe, the drug should be appropriate, trauma, surgical duration, complexity), and the implantation of
must be administered 1 hour before incision, if short acting should hardware.
 Postoperative cranial infections 245

■■POSTOPERATIVE markers of infection has been suggested, but definitive studies remain
to be done.
CRANIAL INFECTIONS Treatment of postoperative meningitis begins by establishing the
diagnosis as outlined above and instituting antibiotic therapy. Choice
In this chapter and for the purposes of clarity, craniotomy and cra- of antibiotic depends on isolating the causative agent by obtaining CSF
niectomy are considered as the same technique because there are by either lumbar puncture or ventricular sampling, and then determin-
no definitive studies that document any differences in postoperative ing the susceptibility of the agent to therapy. Initial broad-spectrum,
infection rates between these two operations. Furthermore, in most multidrug regimens are utilized until a positive culture is established.
circumstances maintenance of vascular perfusion and drainage is
viewed as an important component of infection prevention. Despite
much debate about the relative merits of craniotomies performed
■■Subdural empyema
with vascularized (i.e., muscle remaining intact) versus free bone flaps As with meningitis, symptoms of subdural empyema after craniotomy
(muscle stripped off the skull before creation of the bone flap), no firm are different from those observed anew. In the former situation, the
data demonstrate the superiority of either technique in decreasing or symptoms are more muted and headache and temperature elevation
increasing postoperative infections. are usually absent (Post and Modesti 1981, Tunkel 2005). Masking of
headache and fever may be related to the routine use of postoperative
■■Meningitis steroids. The most likely association with the presence of a postopera-
tive empyema is the presence of a superficial wound infection (Tunkel
Bacterial meningitis after cranial operations is fortunately uncommon, 2005). Subdural empyema is frequently found several weeks to months
occurring in <1% of craniotomies (McClelland and Hall 2007, Zarrouk after the initial craniotomy.
et al. 2007). However, undiagnosed and untreated, the mortality rate There are no definitive clinical, laboratory, and imaging findings.
is high (>20%). The symptoms, as with most other CNS postopera- A high degree of suspicion is required to establish the diagnosis of
tive infections, are frequently more muted and subtle as compared subdural empyema. As already noted, a subdural empyema typically
with meningitis occurring anew. The prerequisite of findings with occurs in a delayed fashion when postoperative systemic markers of
new infectious meningitis are fever, headache, alteration in mental inflammation, such as white blood cell count (WBC), ESR, and CRP,
or neurological status, and meningeal irritation (manifested by stiff have returned to normal ranges. Potentially, elevation of these sys-
neck and/or photophobia). In contrast, these findings are frequently temic markers could be of assistance in establishing the diagnosis of
incomplete, absent, or masked by the original entity that prompted a subdural empyema. However, ESR and CRP are rarely altered, e.g.,
craniotomy. in only 63% of cases of postoperative subdural empyema was the WBC
Many factors contribute to the difficulty in establishing the diag- elevated (Hlavin et al. 1994, Farrell et al. 2008). Lumbar CSF findings
nosis of infectious post-craniotomy meningitis. Sterile (also called are non-diagnostic and performing a lumbar puncture in the setting
chemical or aseptic) meningitis occurs in a high frequency (50–70%) of a subdural empyema may result in neurological deterioration.
of patients undergoing craniotomy and thereby may add to the con- Imagining studies (computed tomography [CT] or magnetic reso-
fusion in establishing the diagnosis of bacterial meningitis (Carmel nance imaging [MRI]) may reveal crescent-shaped, extra-parenchymal
and Greif 1993, Zarrouk et al. 2007). The etiology of this sterile men- fluid collections, but such fluid collections are frequently seen on
ingitis is undoubtedly related to contamination of the CSF by blood postoperative CT and MRI. Contrast enhancement of the pial surface
(subarachnoid hemorrhage or SAH). Some degree of SAH is observed can be indicative of a subdural empyema, but such changes are also
even after craniotomy for benign etiologies, and is always noted in the observed in uninfected patients postoperatively. In 29% of patients
preoperative state after trauma, aneurysm rupture, and frequently late with a subdural empyema, even diffusion changes in the brain paren-
in the course of brain tumors. SAH evokes the same symptoms (fever, chymal adjacent to the subdural empyema collection may be lacking
headache, alteration in mental or neurological status, and meningeal (Farrell et al. 2008). The most reliable diagnostic finding to establish-
irritation) as that observed with bacterial meningitis. ment of the presence of a subdural empyema is enlargement of fluid
Adding to the difficulty in establishing the diagnosis of postoperative collection on sequential imaging or progressive edema adjacent to
septic meningitis is the routine use of steroids in a variety of brain (and fluid collections.
spinal – see below) disorders. Steroids can mute the symptoms and The most likely organisms cultured from a subdural empyema
signs of both aseptic and septic meningitis. The use of anticonvulsants cavity are skin flora and Gram-negative bacilli. Antibiotic penetration
in the post-craniotomy period is frequent and these drugs can evoke a of the empyema cavity is poor and thus chemotherapeutics alone is
drug fever, thereby further confusing the clinical picture and diagnosis unlikely to result in control of the infection. Moreover, the coexistent
of meningitis (Temkin et al. 1990). inflammatory reaction in the pial veins often results in a thrombo-
Systemic markers of infection such as an elevation in the sedimen- phlebitis and resultant brain edema.
tation rate (ESR) and C-reactive protein (CRP), useful in new menin- Surgical treatment of subdural empyemas remains the most ef-
gitis and other infections, are non-specific because these parameters fective treatment. However, treatment depends critically on early
routinely rise after craniotomy: CRP peaks at approximately 1 week suspicion and rapid diagnosis. Unfortunately, definitive establishment
and ESR may remain elevated for 2–3 weeks. of the presence of a subdural empyema is often delayed. Controversy
A diagnosis of septic meningitis can be established only with a exists as to whether evacuation of subdural collections is best achieved
positive CSF culture. In contrast, the diagnosis of aseptic meningitis via burr holes or craniotomy. One advantage of craniotomy compared
requires a sterile CSF culture (Carmel and Greif 1993, Zarrouk et al. with burr hole drainage is that craniotomy provides greater access
2007). Studies using Gram stains are sufficiently inconsistent to not and therefore greater likelihood of achieving maximal removal of
be a reliable indicator of septic meningitis. In a similar fashion, the purulent material. Another advantage of craniotomy is that, in cases
CSF cell count and CSF glucose are non-specific because both can where significant brain edema exists, not replacing the bone flap al-
be altered with aseptic meningitis. Analysis of CSF using molecular lows decompression of the brain. In all cases, the surgical evacuation
246 POSTOPERATIVE INFECTIONS OF THE CENTRAL NERVOUS SYSTEM

is combined with prolong (4–6 weeks) coverage with the appropriate Alternative to the multistaged treatment course outlined above
intravenous antibiotic. Frequently, after cessation of intravenous is treatment with a prolonged course of antibiotics, assuming that a
antibiotics, the patient is maintained on oral chemotherapy for an culture and sensitivity can be established. In most cases, prolonged
additional 4–6 weeks. antibiotic treatment only delays definitive surgical treatment. In con-
trast, Bruce and Bruce (2003) have proposed a one-step procedure
■■EPIDURAL INFECTIONS AND with removal and debridement of the bone flap combined with im-
mersion of the flap in a solution of povidine and antibiotics. The flap
OSTEOMYELITIS OF THE is then placed back into the skull avoiding a cosmetic defect. Bruce
BONE FLAP and Bruce were successful in the short term with such an approach
in 85% (11 of 13) of cases.
Superficial infections of the surgical incision site after craniotomy
are similar to incisional site infections elsewhere in the body, but are
unique because the possibilities that, untreated or inappropriately
■■Brain abscess
treated, the bone flap or the underlying brain can become involved. Brain abscess is a much-feared complication after craniotomy, but,
Therefore, any hint of incisional inflammation must be addressed in a fortunately, an uncommon event. The etiology is either direct intra-
prompt fashion. In most cases, culture of the wound, establishment of operative inoculation or spread from more superficial infected sites.
drainage, and placement on appropriate antibiotic will prevent deeper The initial step in the development of a brain abscess is local-
infection and involvement of the bone and brain. ized cerebritis (Winn et al. 1979). Left untreated, this cerebritis will
The likelihood of developing an incisional superficial infection is progress to an organized focal infection over the course of 5–10
increased by previous surgery at the same site, radiation in the area of days. Wall formation results from fibroblastic migration from the
the surgical bed, poor nutritional status, and the presence of foreign pial surface and collagen deposition which, in its most classic form,
bodies (Hlavin et al. 1994, Korinek 1997, McClelland and Hall 2007). If is thinnest toward the ventricle and thickest toward the surface of
a non-biological material is used as a cranioplasty, the incision must be the brain (Figure 22.1).
designed to avoid placing the cranioplasty directly under the incision. In contrast to new brain abscesses, patients with post-craniotomy
The signs of a local infection are tenderness, erythema, and swell- abscess formation do not present with the classic findings of head-
ing. Any wound breakdown must be assumed to be related to an ache, focal neurological findings, and fever (Yang et al. 2006, Carpen-
underlying infection. Repetitive superficial infections may represent ter et al. 2007). Fever is evident in 25%, neurological deterioration in
an epiphenomenon of an underlying osteomyelitis of the bone flap. 55%, and seizure in approximately 20%. These findings are therefore
The most common organisms cultured from superficial infections not specific.
after craniotomy are Gram-positive cocci, including Staphylococcus The diagnosis is best established by changes on imaging studies
aureus, coagulase-negative staphylococci, and Propionibacterium by either CT or MRI. The characteristic location of new abscesses at
acnes (Post and Modesti 1981, Dempsey et al. 1988, Kurz et al. 1996, the gray–white junction is unlikely to be present in the postoperative
Mangram et al. 1999). period; more likely, the abscess is located in the operative bed or along
Infections of the bone flap, often associated with epidural empy- the access tract. The observable changes on imaging studies are related
ema, may or may not coexist with superficial infections. In the vast to the maturation of the abscess. Early on, the classic finding of cere-
majority of cases, the infection is located primarily within the free britis on CT is lucency whereas on MRI high T2-weighted signals with
bone flap and does not involve the vascularized, surrounding intact patchy enhancement may be seen. As the cerebritis progresses, the
bone of the skull. Bone flap infections can occur from a primary in- infection coalesces, wall formation occurs, and ring enhancement is
oculation by skin flora at the time of surgery or as a result of a delayed observed. However, similar changes may be seen after intraparenchy-
incisional infection. mal hemorrhage, tumor resection, and radiation. Moreover, the entire
Even in the uninfected state, bone flaps may become demineralized MRI profile and ring enhancement may be influenced by steroid use.
and disintegrate over the long term (months to years) and the appear-
ance on skull radiograph and CT may be difficult to distinguish from
osteomyelitis. Bone flap infections are usually delayed and therefore Figure 22.1  The
systemic findings, such as persistent fever and elevation of WBC, ESR, typical computed
and CRP, may aid in the establishment of a diagnosis of osteomyelitis. tomography findings
of a brain abscess.
The most effective treatment is removal of the bone flap, leaving
a cosmetically displeasing bone deficit. The flap removal is then
followed by appropriate and prolonged antibiotic therapy. In a de-
layed fashion, usually 3–6 months and after establishing compelling
evidence that the infection has been eradicated, the bone defect is
replaced using either a foreign substance (i.e., methylmethacrylate)
or an autologous split-thickness bone graft obtained from the ribs or
a second cranial site. The advantages of methylmethacrylate are the
ease of molding the material to conform to the contour of the bone
deficit and the simplicity of the procedure. The disadvantage is that,
in an inadequately treated infection, the cranioplasty may serve as a
nidus for a persistent infection. In contrast, split-thickness bone graft
operations are more complex, requiring an additional donor site inci-
sion, but may have a lower risk of infection. Free bone also has a small
risk of bony resorption.
 Epidural infections and osteomyelitis of the bone flap 247

Therefore, as with all other postoperative infections, with brain abscess al. 2007). Neurosurgeons have therefore intensively analyzed shunts,
there are no definitive diagnostic studies. shunt surgery, and postoperative sequelae in both children and adult
Treatment consists of surgery plus prolonged intravenous antibiotic patients. However, most of the data concerning shunt infections stem
therapy. As noted above, the first step is to have a high level of suspicion from the former group.
for the diagnosis. CSF sampling by lumbar puncture may be not only Under normal conditions, CSF is mainly formed by the choroid
dangerous because of high intracranial pressure, but also unlikely to plexus in the cerebral ventricles and then circulates through the ven-
yield a positive culture. With the usual scenario of broad antibiotic tricular system and the subarachnoid space. Egress of the CSF from the
treatment in a patient suspected to have a postoperative abscess, even CNS occurs through the arachnoid villi, which are primarily located
ventricular CSF sampling may not be rewarding. in the walls of the cerebral venous sinuses. Obstruction in any part of
Direct surgery is the preferred approach with the recognition that this pathway and process will result in hydrocephalus.
the postoperative abscess is likely to be more complex in its configura- Shunt operations are designed to overcome obstruction of CSF
tion than the new disorder. The operating surgeon needs to carefully flow, lower ICP, and decrease ventricular enlargement. Such op-
review the imaging studies and be familiar with the original operation erations involve the insertion of a catheter into the lateral cerebral
and any distorted anatomy. The goal is to drain pus, debride necrotic ventricle, usually by means of a small frontal skin flap and burr hole.
tissue, and relieve increased intracranial pressure (ICP). In extreme The ventricular catheter is then attached to a valve, which regulates
conditions, the bone flap will be not replaced to lower ICP. Potentially, CSF egress, and the valve is positioned subcutaneously under the
cranial decompression may require that the original skin and bone flap skin flap. The distal end of the valve is in turn attached to a small
be enlarged. Moreover, the removed bone flap may be contaminated catheter, which is tunneled subcutaneously from the frontal flap
and therefore might need to be discarded. down the neck and chest and inserted into the abdomen. Multiple
An alternative to open craniotomy is aspiration using stereotactic variations in approaches exist, each having advocates and detractors.
assistance. Such an approach, although less invasive, may be less In all cases, the location of the skin opening should be designed to
effective because of the distorted postoperative anatomy. Moreover, avoid placement of the shunt valve and tubing directly under the
the multiloculated postoperative abscess may be less amendable to surgical incision.
effective needle drainage and require multiple aspirations. There are multiple factors (see Table 22.2) that have been identi-
Once a specimen has been obtained, the usual preoperative fied as contributing to shunt infections (Casey et al. 1997). As with
broad-spectrum antibiotics can be narrowed and a targeted treatment all surgical procedures, there are systemic factors, such as nutrition,
tailored to the results of culture. However, in 30% of cases (Mampalam diabetes, and immunological status, that will contribute to the likeli-
and Rosenblum 1988) the patient will have been on broad-spectrum hood of a postoperative shunt infection. The age of the patient has been
antibiotics for a considerable time and, consequently, culture speci- shown to be related to the infection rate, with neonates and younger
mens may be sterile. In these cases, empirical broad antibiotic treat- children having a higher risk than older children and adults (Casey et
ment will be utilized. al. 1997). Prolonged preoperative hospitalizations, skin breakdown,
As in the treatment of subdural empyema and bone flap osteomy- and systemic infections (i.e., urinary tract infections) have also been
elitis, prolonged antibiotic treatment will be required. Consequently, suggested as being related to shunt infections.
the patient is at risk for the development of system complications and As most post-shunt infections are recognized within several (1–3)
superinfections such as Clostridium difficile. In addition, steroids, months after surgery and involve skin organisms, inoculation and
frequently used in an attempt to ameliorate brain edema, have the po- colonization during surgery appear to be the initiating event (Burke
tential for affecting wound healing and impairing systemic responses. 1963, Casey et al. 1997). Therefore, avoidance of surgical contamina-
Serial CT and/or MRI is useful to determine the success or failure of tion has been the main means of preventing postoperative shunt infec-
treatment. Failure of the abscess to regress or, conversely, any sugges- tion. Neurosurgeons have utilized a variety of intraoperative measures
tion of enlargement of the area of inflammation or brain edema over to decrease shunt infections, such as double gloving and a “no-touch”
time (i.e., days to weeks) should be considered as indicating failure technique for handling the shunt valve and tubing. Generous removal
of treatment and should suggest the need to consider re-exploration of hair with clippers (but not shaving) in the operating room has been
and drainage and/or alteration in antibiotic therapy. advocated to avoid potential contamination by a stray hair, especially
Lastly, brain abscess are highly epileptogenic. Whereas anticon- in adults, has been advocated in contrast to minimal hair removal in
vulsant therapy has not been proven to prevent epilepsy in the long most other cranial surgery. Only the use of perioperative antibiotics
term, such drugs should be routinely given during the acute period has been rigorously studied and, by meta-analysis, shown to be af-
to prevent seizures. In a patient with high ICP, a seizure can be fatal. fected (Haines and Walters 1994).
The downside of anticonvulsant therapy is that these drugs can cause Wound breakdown is highly associated with the development of a
fever and systemic responses, and therefore add confusion to the shunt infection and all incisions need to be carefully planned to avoid
clinical picture of a patient being treated for a CNS infection (Temkin having the shunt valve and tubing located directly under the surgi-
et al. 1990). cal site. Surgical technique plays an important role in complication
avoidance in shunt surgery. Therefore, the surgeon needs to remain
■■Shunt infections vigilant to tissue handling, avoidance of skin and subcutaneous injury,
and careful wound closure.
Of all clean neurosurgical procedures, operations designed to per- The symptoms and signs of a shunt infection will be influenced by
manently divert CSF, so-called “shunt” operations, have the highest the age of the patient. Infants may present with a range of findings,
(3–10%) postoperative infection rates (Kestle and Walker 2005). Shunt from subtle fussiness to a catastrophic picture of fully developed
operations, although appearing to be not technically challenging, are meningitis and elevated ICP. Adult patients, usually treated for normal
nevertheless complex and fraught with difficulties. In patients over the pressure hydrocephalus, may revert to their pre-shunt inability to am-
long term, as measured in years, 40% of shunts fail or need revision, bulate, decreased mental capacity, and/or urinary incontinence. Local
with infections being the primary cause (Casey et al. 1997, Gupta et wound inflammation should always be considered as a postoperative
248 POSTOPERATIVE INFECTIONS OF THE CENTRAL NERVOUS SYSTEM

shunt infection. Ventricular enlargement on imaging studies indicates in primary CNS sequelae (McClelland and Hall 2007). The lesser rate
a shunt failure that may be secondary to an infection. Repetitive shunt of infection may be related to the fact that most spine operations do
“failures” should always raise the concern of a low-grade, indolent in- not violate the dural covering of the spinal cord or cauda equina. Thus
fection, usually caused by skin flora such as Staphylococcus epidermis the isolation and integrity of the CNS remain intact and infectious
(Casey et al. 1997). processes tend to be primarily located in the surrounding bone, disk,
Confirmation of a shunt infection, in the absence of wound prob- soft tissue, and muscle.
lems, is usually established by CSF culture. CSF profile alone (i.e., cell
count, differential, glucose, and protein) may be misleading in both
directions: Non-infected CSF may reveal altered cell count, glucose,
■■Risk factors for infections
and protein, whereas infected CSF, especially in the setting of an after spinal surgery
indolent organism, may appear benign or equivocal. CSF is usually Patient risk factors for postspinal infections (see Table 22.3) are not
obtained by percutaneous tapping of a reservoir that is in series with dissimilar to those factors that have been noted earlier for infections
the valve. Lack of growth in the CSF does not rule out the presence after craniotomy, e.g., increased age, malnutrition, obesity, immuno-
of an infection – the absence of proof does not constitute the proof logical compromise, diabetes mellitus, trauma, prolonged pre-surgical
of absence. Prolonged culture of CSF might be required to establish hospitalization, and excessive alcohol use have all been found to be as-
an infection and isolate an organism, especially with an indolent sociated with postoperative infections after spinal surgery (Weinstein
organism. In some cases of distal infections (abdominal site), CSF et al. 2000, Olsen et al. 2003, Fang et al. 2005). The presence of malig-
culture may not reveal an infection, but abdominal ultrasonography nancy has been demonstrated to increase the risk of postoperative
will reveal cystic collections. spinal infections to >20% (McPhee et al. 1998, Weinstein et al. 2000).
Multiple strategies have been proposed for the treatment of shunt The interactions and interdependency of these multiple factors for
infections (James et al. 1980). In all cases, appropriate antibiotics postspinal infections are unclear, e.g., malignancy is associated with
must be administered, usually for a protracted duration. The most an altered immunological response and, in some patients, malnutri-
successful approach requires two operations. In the first, the existing tion. Prolonged pre-surgical hospitalization may reflect a patient’s
infected shunt is removed and replaced with a ventricular catheter concurrent diseases (i.e., cancer, diabetes, to mention a few) and/
that allows CSF drainage and frequent assessment of CSF profile and or nutritional status. Obesity may be an epiphenomenon related to
culture. After sterilization has been achieved, a second operation is length of surgery because surgical durations in obese individuals
performed and a new shunt placed. This multi-operation approach are frequently longer than in non-obese patients. Additional factors
has been shown by series and randomized trial to achieve the highest playing a role in the obese patient could be excessive retraction, larger
cure rate (James et al. 1980). deep space, and more complex and difficult closures. Obese patients
An alternative surgical strategy involves only one operation. In are more likely to have diabetes and therefore the increased risks as-
this approach, antibiotics are continued with the existing shunt in sociated with obesity may reflect only the underlying metabolic and
place and CSF being sampled frequently from the shunt reservoir. microvascular effects of glucose intolerance. Patients with diabetes
When CSF sterilization is achieved, the old shunt is removed in its undergoing spinal surgery have been reported to have a 24% chance
entirety and replaced with a new ventricular catheter, valve, and shunt of developing a postoperative infection (Simpson et al. 1993, Fang et
tubing. This approach avoids a second procedure, but has a slightly al. 2005).
lower success rate (90%) compared with the two-stage strategy (100%) Prolonged tobacco use is associated with osteoporosis and an in-
(James et al. 1980). creased risk of degenerative spine change. In addition, smokers have
Lastly, a non-surgical strategy involves treatment with antibiotics an increased risk of having a postoperative infection after surgery
alone. This method of treatment has only a 30% likelihood of achiev- (Sorensen et al. 2003, Fang et al. 2005). The mechanisms involved are
ing success and the length of hospital stay is longer than with either unclear, but may be related to well-described neutrophil malfunction
surgical approach (James et al. 1980). A factor in the low rate of success and/or decreased arterial levels of oxygen and resultant tissue hypoxia
for medical treatment alone may be the observation that many of the observed in smokers.
usual organisms (i.e., coagulase-negative staphylococci and Staphy- Surgical risk factors are similar to those observed with crani-
lococcus aureus) responsible for shunt infections have the capability otomy, but are mainly correlated with the severity of the surgical
to form a protective biofilm or slime around the shunt tubing (Tessier procedure itself. Thus, the surgical length (>5 h), extent of exposure,
2011). Antibiotics are less able to penetrate this slime matrix which is and amount of blood loss (>1000 ml) have all been associated with
devoid of vascular supply. Moreover, organisms immersed in this slime increased chances of a patient developing a postoperative infection
become less metabolically active and enter into a stationary phase of (Weinstein et al. 2000, Olsen et al. 2003, Fang et al. 2005). In addition,
growth, further impeding the effectiveness of antibiotics. Both of these allografts and instrumentation have been shown to increase the
factors contribute to the reduced cure rate with antibiotic therapy postoperative infection risk (Weinstein et al. 2000, Fang et al. 2005).
alone (Tessier 2011) Surgical approaches have been observed to be related to the risk
of developing a postoperative infection (Weinstein et al. 2000, Olsen
■■POSTOPERATIVE SPINE et al. 2003), e.g., the risks for posterior single level discectomy alone,
lumbar laminectomy without fusion, and lumbar laminectomy with
INFECTIONS non-instrumented fusions are <1%, 2%, and >2%, respectively (Davis
1994, Fang et al. 2005). Instrumentation increases the risk for lumbar
In contrast to post-craniotomy infections, infections after spinal opera- procedures to 3–8% (Levi et al. 1997, Weinstein et al. 2000). Anterior
tions are less common even though the frequency of spinal surgery approaches in the lumbar spine, while having a higher complication
is considerably higher on a population basis than cranial procedures rate, do not appear to have an increased infection rate, although most
(Davis 1994, McClelland and Hall 2007). Furthermore, postspinal series are small in number (Levi et al. 1997). Combined posterior and
surgical infections tend to be more superficial and less likely to result anterior approaches appeared to have the highest infection rate which
 Postoperative spine infections 249

may reflect the length of surgery, blood loss and replacement, and second and third weeks, respectively. Consequently, persistent eleva-
other factors, rather than the complexity of the surgery itself (Olsen tion or an increase in these parameters in the setting of an elevated
et al. 2003, Fang et al. 2005). The spinal level involved does not appear fever suggests the diagnosis of a postoperative infection.
to influence the rate of postoperative infection, although the anterior Radiological and imaging studies can be useful in assisting in the
approach to the cervical spine routinely reports very low infection diagnosis, but postoperative expected changes on plain films, CT,
rates. On the other hand, anterior cervical spinal surgery has the po- and MRI may be difficult to separate from the findings with infection,
tential for an esophageal injury and the development of devastating especially in the early stages of an infection. Comparison of sequential
mediastinitis. The recent development of endoscopic techniques may postoperative studies will provide the best approach and should be
allow a reduction in postoperative spinal infections. evaluated in the context of systemic markers of infection as outlined
above. Postoperative baseline imaging studies may also document
■■Prevention alignment and instrument placement, but whether such studies are
cost-effective is unclear.
Assuming that the patient and surgical factors listed above are caus- In general, 2–3 weeks are required before an infectious process will
ally related to the risks of developing a postoperative infection, the sufficiently alter bone, disk elements, and/or the disk to be seen on
surgeon preoperatively should maximize the patient’s nutritional plain radiographs. CT is more sensitive to these changes and is also
status, encourage weight loss, and effectively treat any systemic or more likely to diagnose paravertebral collections and other soft-tissue
local infections. Cessation of smoking has been demonstrated to lower changes. Contrast-enhanced CT will increase the chances of imaging
postoperative infections, but the duration of non-smoking is unclear. changes suggestive of a postoperative infection. CT can also assist in
Prophylactic antibiotics have been demonstrated by meta-analysis surgical planning.
to lower postoperative infection rates, although individual studies However, among imaging techniques, MRI is the most useful in diag-
have reported both non-supportive and supportive data (Horwitz and nosing a postoperative infection; specificity and sensitivity in this setting
Curtin 1975, Bullock et al. 1988, Dempsey et al. 1988, Barker 2002). are >90%. Plain and contrast-enhanced studies on multiple sequences
Nevertheless, perioperative antibiotic therapy has been considered have a high probability of revealing changes in the bone marrow, end
the standard of care since the 1970s. Antibiotics ideally should be plate, disk and disk elements, and the development of paravertebral
administered 30–60 min before skin incision to allow achievement of collections. The latter is the best indicator of a postoperative infection,
appropriate blood and tissue levels. Additional doses should be given but to document “change” requires a baseline postoperative study.
every 4–6 h and with blood loss (>1500 ml), but discontinued after 24 h.
Prolonged administration has been associated with the development
of resistant organisms and superinfections.
■■Treatment
Three are many other intraoperative measures that may decrease Optimal treatment is critically dependent on early establishment
postoperative infections, e.g., during prolonged surgery, the surgeon of the diagnosis. Less clear among treatment options is the definitive
can periodically release retractors to lessen tissue pressure and in- treatment. With regard to chemotherapy, in most circumstances, the
crease tissue blood flow. The use of copious irrigation and the addi- patient will already be on antibiotics effective against the most com-
tion of bacitracin to the irrigation fluid have been advocated in many mon responsible organism, Staphylococcus aureus. Not infrequently,
studies. Chang et al. (2006) have demonstrated in a randomized trial these hospital-acquired infections are due to meticillin-resistant S.
that dilute (0.35%) povidone–iodine (Betadine) reduced post-bone aureus. Delayed infections are more likely to be a result of low virulent
grafting infections to 0% from 3.4%. On the other hand, prophylactic skin contaminants. Therefore, antibiotic choice ideally depends on
antibiotics for the duration of drain placement have not been shown culture and sensitivity.
to be effective in lowering the infection rate. Surgical debridement is dictated by location and extent of the
infection, but definitive clinical approach has not been clearly es-
■■Diagnosis tablished in randomized trials. Superficial wound infections usually
respond to antibiotics alone. Discitis likewise responds to antibiotic
The diagnosis of postoperative infections after spine surgery can be therapy alone, but the causative agent can usually be established by
challenging. In comparison to the post-craniotomy state, the post blood cultures or percutaneous biopsy. The latter usually involves
-spinal surgery clinical picture is not as confusing, and without the intraoperative navigation or utilizing CT direction. Biopsies in the
overlay of neurological changes related to the initial surgical interven- lumbar and cervical regions are less problematic than in the thoracic
tion into the brain. The baseline neurological status of the postoperative spine where endoscopic techniques may be beneficial. The duration
spinal patient should, in most cases, be unaffected by the surgery and of antibiotic therapy has not been established definitively, but 6 weeks
be similar or improved compared with the preoperative clinical state. of intravenous therapy followed by an addition 6 weeks of oral therapy
Delayed deterioration from this postoperative state should suggest the is a frequent treatment paradigm.
possible diagnosis of an infection, although there are other causes for Infections that do not respond to medical therapy and/or have
neurological deterioration such as displacement of hardware or change caused wound dehiscence, significant bone or soft-tissue destruction,
in bony alignment. In many cases where the clinical and neurologi- or fluid collection, especially in deep aspects of the surgical bed, should
cal status remain stable, the surgeon will be alerted to postoperative be treated with surgical debridement. Such an approach also allows
infection by systemic signs and radiological changes. reassessment by culture of the causative agent. Obviously, if stabiliza-
Unlike post-craniotomy infections, the timing of postspinal sur- tion has been affected by the infection, realignment should also be ad-
gical infections is often more delayed. Consequently, the systemic dressed with reoperation. Considering the complexities of the clinical
changes related to surgical intervention, such as ESR, WBC, and CRP, scenario, thoughtful planning, consideration of all contingencies, and
have usually returned to or are tending toward normal by the time a careful evaluation of imaging studies are required before reoperation. In
post-surgical spinal infection is evident. As indicated earlier, in the general, all aspects of the previous surgical field should be exposed and
postoperative period, CRP and ESR start to return to baseline by the necrotic and purulent tissue vigorously removed. Multiple specimens
first postoperative week and are usually in the normal range by the should be sent for culture at all levels of the wound. Various techniques
250 POSTOPERATIVE INFECTIONS OF THE CENTRAL NERVOUS SYSTEM

for irrigation, both with and without antibiotics and during and after Multiple options exist for wound closure after surgery for post-
debridement, have been advocated, but none has been rigorously operative infections. Drains of various types are routinely placed
compared. Another area of controversy relates to whether stabilizing to facilitate decompression of residual fluctuancy. In some cases,
hardware should be removed in the setting of a postoperative infec- secondary closure will be required, although every effort should be
tion. Older steel instrumentation has been associated with recurrent made to approximate the wound in a primary fashion. In severe cases,
infections whereas more recent titanium constructs appear to have a a planned staged “second-look” surgery may be necessary. In all cases,
lower likelihood of incurring a persistent infection. However, even with frequent monitoring of systemic parameters and imaging studies are
titanium implants, reoccurrence of infection can occur. required to document recovery.

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diffusion-weighted imaging in the diagnosis of postoperative infections. incisional wound infection: a randomized controlled trial. Ann Surg
Neurosurgery 2008;62:577–83. 2003;238:1–5.
Fry DE. Basic aspects of and general problems in surgical infections. Surg Infect Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A randomized,
(Larchmt) 2001;2(suppl 1):S3–11. double-blind study of phenytoin for the prevention of post-traumatic
Gantz NM. Nosocomial central nervous system infections. In: Mayhall CG (ed.), seizures. N Engl J Med 1990;323:497–502.
Hospital Epidemiology and Infection Control. Philadelphia: Lippincott Williams Tessier JM. Basic science of central nervous sytem infections. Winn HR (ed.),
& Wilkins, 2004: 415–39. Youmans’ Textbook of Neurological Surgery, 6th edn. Philadelphia, PA:
Gupta N, Park J, Solomon C, Kranz DA, Wrensch M, Wu YW. Long-term Saunders/Elsevier, 2011: 544–58.
outcomes in patients with treated hydrocephalus. J Neurosurg 2007;106(5 Todd MM, Hindman BJ, Clarke WR, Torner JC. Mild intraoperative hypothermia
suppl):334–9. during surgery for intracranial aneurysm. N Engl J Med 2005;352:135–45.
Haines SJ, Walters BC. Antibiotic prophylaxis for cerebrospinal fluid shunts: a Tunkel AR. Subdural empyema, epidural abscess, and suppurative intracranial
metanalysis. Neurosurgery 1994;34:87–92. thrombophlebitis. In: Douglas RG, Bennett JE et al. (eds), Mandell,
Hlavin ML, Kaminski HJ, Fenstermaker RA, et al. Intracranial suppuration: a Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 6th edn.
modern decade of postoperative subdural empyema and epidural abscess. Philadelphia, PA: Elsevier/Churchill Livingstone, 2005:1164–71.
Neurosurgery 1994;34:974–80; discussion 980. Weinstein MA, McCabe JP, Cammisa FP. Postoperative spinal wound infection: a
Horwitz NH, Curtin JA. Prophylactic antibiotics and wound infections following review of 2,391 consecutive index procedures. J Spinal Disord 2000;13:422–6.
laminectomy for lumber disc herniation. J Neurosurg 1975;43:727–31. Wimmer C, Gluch H, Franzreb M, Ogon M. Predisposing factors for infection in
James HE, Walsh JW, Wilson HD. Prospective randomized study of therapy in spine surgery: a survey of 850 spinal procedures. J Spinal Disord 1998;11:124–8.
cerebrospinal fluid shunt infection. Neurosurgery 1980;7:459–63. Winn HR, Mendes M, Moore P, Wheeler C, Rodeheaver G. Production of
Kestle JR, Walker ML. A multicenter prospective cohort study of the Strata valve experimental brain abscess in the rat. J Neurosurg 1979;51:685–90.
for the management of hydrocephalus in pediatric patients. J Neurosurg Yang, KY, Chang WN, Ho JT, et al. Postneurosurgical nosocomial bacterial brain
2005;102(2 suppl):141–5. abscess in adults. Infection 2006;34: 247–51.
Korinek AM. Risk factors for neurosurgical site infections after craniotomy: a Young RF, Lawner PM. Perioperative antibiotic prophylaxis for prevention
prospective multicenter study of 2944 patients. The French Study Group of postoperative neurosurgical infections. A randomized clinical trial. J
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Epidemiologie Hygiene et Prevention. Neurosurgery 1997;41:1073–9; Zarrouk V, Vassor I, Bert F, et al. Evaluation of the management of postoperative
discussion 1079.* aseptic meningitis. Clin Infect Dis 2007;44:1555–9.
Chapter 23 Bioterrorism
Donald E. Fry

A reality of the current world is that microbes or microbial products of potential biological agents is extensive with the virulence of the
may be used as weapons to inflict harm on civilian populations. In putative pathogens being quite variable (Table 23.1) The full scope of
the last decade anthrax spores have been distributed through the mail planning, recognition, triage of patients, development of alternative
service to political targets. In the current era of genetic engineering, patient care sites, and decontamination is beyond the scope of this
the possibilities of manipulating microbes to have unusually virulent presentation and is detailed elsewhere (Fry 2006). This chapter focuses
characteristics is a reality that makes bacteria and viruses potential on the reality of potential biological pathogens and their management.
weapons in military or civilian events.
Surgical care will be required for patients exposed to microbes used
as weapons. Surgeons will be participants in disaster planning and
■■ANTHRAX
implementation. They will be mobilized when disaster events occur Anthrax has been an infectious disease that has received the great-
and will need to be informed about potential agents and processes of est amount of attention as a biological weapon. Anthrax infection is
microbial decontamination. As biological agents as weapons pose lo- caused by Bacillus anthracis, a Gram-positive aerobic rod that exists
gistical challenges of delivery by the assailant, it would not be surpris- as a spore when exposed to adverse environmental conditions (Swee-
ing to find biological payloads accompanying conventional explosive ney et al. 2011). As is true of all spore-forming bacteria, B. anthracis
devices as a variant on the concept of the “dirty” bomb (Fry et al. 2005). transitions into the vegetative form if environment conditions exist to
The disaster plan of communities must take into consideration promote growth and replication. The spores are ubiquitous in soil and
the possibilities of biological weapons in civilian populations. The list have traditionally posed problems for lethal infections of cattle and

Table 23.1  Categorization of the currently recognized bioterrorism threats (Centers for Disease Control 2012).
Potential agents of interest Comments
Category A Category A agents are considered of greatest threat to be used in a bioterrorism attack
Anthrax Easily disseminated, airborne, fulminant inhalational disease
Botulinum toxin Fine powder; extremely potent biological toxin
Bubonic plague High mortality rate; human-to-human transmission
Smallpox Vulnerable, unvaccinated population; human-to-human transmission
Tularemia Incapacitating disease with a low death rate
Viral hemorrhagic fever Fulminant and highly fatal illness
Category B Category B agents are easily disseminated but low mortality rates
Brucellosis Small inoculum for infection; protracted infection
Epsilon toxin of Clostridium perfringens Airborne powder
Food poisoning (e.g., Salmonella) Malicious contamination of fresh fruits and vegetables
Water poisoning (cholera) Potential contaminant of drinking water supplies
Glanders/Melioidosis Small inoculum and high mortality with acute infection
Psittacosis Severe pulmonary infection by this natural avian pathogen
Q fever Small inoculum for infection, protracted clinical course
Ricin Easily produced castor bean product
Staphylococcal enterotoxin B Potent airborne powder
Typhus An intracellular parasitic rickettsial infection
Equine encephalitis Easily grown and stored; very infectious to humans
Category C Emerging pathogens with potential for production and dissemination
Nipah virus Encephalitis or respiratory infection; human-to-human transmission
Hantavirus Airborne pathogen with a hemorrhagic fever clinical picture
Influenza viruses Selected influenza viruses (H1N1) are severe and contagious
Severe acute respiratory syndrome An airborne transmitted coronavirus
252 BIOTERRORISM

sheep. Anthrax infection was a major focus of Robert Koch in proving

the germ theory of disease, and anthrax was used by Pasteur in the de-
velopment of a vaccine for prevention of infection in grazing animals.
Anthrax infection occurs in three separate scenarios. Cutaneous
anthrax occurs when spores contaminate an open wound and cause
a necrotizing local infection. The black eschar of cutaneous anthrax
(Greek anthracis for coal) was the first recognized infection of this
pathogen in humans, and was noted to be “wool sorters’ disease”
among workers handling spore-laden wool from contaminated sheep.
The infection is painful, tends to spread progressively, and is fatal in
about 20% of untreated cases. Effective treatment has reduced death
rates to 1%.
Gastrointestinal anthrax follows the ingestion of a critical number
of spores, which survive the acidity of the stomach and then result in
invasive infection from the gut. This is an uncommon cause of infec-
tion in humans but extrapolation from animal observations indicates
that the spore is likely transported to regional lymph nodes where
the vegetative form of the bacteria results in invasive infection. This
is likely to have a very high mortality rate (>50%) but epidemiological Figure 23.1  The black necrotic lesion of cutaneous anthrax infection.
(From http://phil.cdc.gov/phil/details.asp, courtesy of CDC/James H. Steele. ID
studies in humans are not available.
no.: 2033, 1962.)
Inhalational anthrax is of greatest concern as a biological weapon.
The spore is very small (1 µm) which escapes the normal mucociliary
defense mechanisms of the lung. Inhalation of as few at 2500 spores is from systemic anthrax infection is illustrated by positive Gram stains
sufficient to cause pulmonary anthrax infection (Inglesby et al. 1999). of blood that are positive for the Gram-positive rod. The reality is the
The spores are transported by macrophage cells to regional lymph inhalational form of anthrax will be diagnosed only post mortem and
nodes, where they germinate and cause invasive infection. The bacteria must trigger an investigation into the source of the spores.
produce exotoxins and have a capsule that retards phagocytosis of the Antibiotics and supportive care are the principal treatments for
vegetative form. Fulminate bacteremia occurs from the pulmonary anthrax infection. Penicillin (12–24 MU/day) or doxycycline (200 mg
lymph nodes with a resultant systemic infection that is uniformly fatal initially; then 100  mg every 12 h) are the approved treatments. In
without prompt treatment. Thus, it must be understood that anthrax- vitro data would support the use of quinolones (e.g., ciprofloxacin
infected patients have the lung as the entry site of the spore, but the 400 mg every 8–12 h). A theoretical case can be made for the addi-
infection originates within the regional lymph nodes. This is not a pul- tion of clindamycin as a second drug to any of the above choices to
monary infection. The established infection is not contagious to others inhibit exotoxin production by the anthrax bacilli. Effective antibiotic
because neither spores nor vegetative organisms are transmitted from therapy for cutaneous anthrax before systemic dissemination is effec-
the patient’s lung to the environment. The risk to healthcare workers tive with a 1% mortality rate. Inhalational anthrax will have mortality
would be ineffective decontamination of the acute contaminated rates exceeding 90%.
patients from spores in clothing and on the surface of the patient, and Postexposure preventive antibiotic administration is recom-
not bacteria transmitted from infected patients. mended, although clinical effectiveness is unproven. Oral doxycycline
Clinical infection from anthrax is quite uncommon, and accord- or ciprofloxacin is associated with efficient bioavailability after oral
ingly the diagnosis of the infection is difficult. The cutaneous infection administration and is a recommended choice. An anthrax vaccine
has the initial appearance of a cutaneous abscess, which evolves into has been developed, but requires six doses over 18 months for recom-
an umbilicated black eschar (Figure 23.1). This is a painless lesion mended effectiveness. Annual booster doses are required after full
that differentiates it from the cutaneous infection of community- immunization. The vaccine is considered only for use in high-risk
associated meticillin-resistant Staphylococcus aureus or a brown military personnel.
recluse spider bite. The evolving local cutaneous infection becomes Infection control with a suspected anthrax exposure event is to
invasive with clinical lymphangitis and lymphadenitis. Lymphatic effectively decontaminate the patients by standard methods. Cloth-
and vascular invasion can result in systemic infection. The anthrax ing, hair, and cutaneous surface contamination are the risk of spores
bacilli are readily identified on blood agar cultures. The occurrence to healthcare personnel, and these risks are managed with standard
of cutaneous anthrax infection in the absence of exposure to livestock decontamination procedures. It is likely that public exposure events
should trigger concern about malicious dissemination of the spores. may not be appreciated until infected patients are presented to the
Ingestion of the spores may result in the black eschar lesions in the healthcare facility. Fear and panic among healthcare personnel require
oropharynx, but true gastrointestinal anthrax will have non-specific the repeated emphasis that the effectively decontaminated patient
abdominal pain and tenderness and is difficult to recognize. The in- with inhalational anthrax infection is not infectious to others.
halational form of the disease begins as a flu-like syndrome with fever,
leukocytosis, malaise, and rapidly evolves to a systemic inflammatory
response syndrome (SIRS). The chest radiograph may demonstrate
■■Plague infection
hilar adenopathy and characteristically evolves into the typical ap- Yersinia pestis is the pathogen of bubonic plague that has ravaged
pearance of adult respiratory distress. Pneumonic infiltrates would Europe and Asia with pandemics in centuries past. This Gram-
be evidence against inhalational anthrax. Blood cultures are positive, negative rod has been speculated as a biological weapon because
but bacteremic patients have a natural history of infection that will it is an airborne pathogen, it requires a small inoculum of bacteria
likely be fatal before results are available. The massive bacteremia to cause clinical infection, the evolution of the pulmonary form is a
 Anthrax 253

fulminant infection with a high mortality rate, but most significant and death in 24–48 h from onset of symptoms. Pulmonary aspirates
is the efficiency of human-to-human transmission (Inglesby et al. will demonstrate Gram-negative rods on Gram stain. Sputum and
2000). Y. pestis has virulence due to surface antigens that facilitate its blood cultures will identify the pathogen.
binding to pulmonary epithelium, and its endotoxins and secreted Recommended antibiotic therapy for both cutaneous and pulmo-
exotoxin products. Amplification of virulence and enhancement of nary infection is streptomycin, tetracycline, or doxycycline. Strepto-
antimicrobial resistance can be engineered by the use of plasmids. mycin is generally not available and other aminoglycoside choices are
Infection with the plague bacillus can occur through two routes. substituted. Quinolones have been used in experimental infections,
Cutaneous infection is the classic bubonic plague. Flea bites were the but do not have a record of use in human infection. Tetracycline or
traditional route of inoculation for cutaneous infection, but inocula- doxycycline is recommended for postexposure prophylaxis. Ventilator
tion of cuts or abrasions from environmental contamination is pos- support will be necessary for the pulmonary infections.
sible. Invasive cutaneous infection results in lymphatic dissemination Infection control for pulmonary infections is important because
with the classic “buboe” developing in the regional lymph nodes. The of human transmission from expectorated, airborne organisms. This
lymphadenopathy measures up to 10  cm in size, and the infected requires isolation of patients and full use of respiratory isolation pro-
lymph nodes may ulcerate and drain. Necrosis and ulceration are cedures. With appropriate antibiotic therapy, the patients are gener-
uncommon at the primary site of cutaneous infection. The progression ally thought to no longer be infectious by 48 h of treatment. Full and
of infection leads to dissemination via the lymphatics with systemic complete disinfection is necessary for rooms and all equipment used
infection and death in 50% of cases. Cutaneous infection may be di- in the management of these patients.
rectly invasive into the circulation and bypass the classic lymphatic
manifestation of infection. The rapid vascular dissemination of the
infection leads to ischemic necrosis of digits (Figure 23.2), systemic
■■Tularemia
evidence of severe infection, and death in nearly all who do not have Tularemia is caused by Francisella tularensis, which is an aerobic,
lymphatic containment of the primary cutaneous infection. Gram-negative coccobacillus. There are multiple subspecies variants
Although naturally occurring cutaneous plague infection is quite of F. tularensis. It has been proposed as a biological weapon because
uncommon, it does have a characteristic presentation. Recognition of the organism can be easily aerosolized and only a small inoculum of
the large buboes should be sufficient to raise the index of suspicion. bacteria (<100) is necessary to cause human infection (Dennis et al.
Gram stains of drainage from ulcerated nodes, or aspirated specimens 2001). This clinical infection has a relatively low mortality rate among
from the enlarged lymph nodes, may identify the Gram-negative rod. proposed bioweapons, but rather is an incapacitating infection that
Cultures by standard methods from Gram-negative bacteria will con- would pose an enormous logistical issue for management. It has
firm the pathogen. Other diagnostic methods with antigen detection been the focus of efforts to “weaponize” this pathogen by engineer-
or polymerase chain reaction (PCR) assays might be useful in early ing resistant strains.
detection among patients suspected of exposure, but are unlikely to It is a naturally occurring infection in rabbits, squirrels, and other
be of value in those in whom clinical infection is identified. small mammals. It is transmitted to humans by mosquitoes and ticks,
Pulmonary infection is the second and most important route of or from environmental inoculation of cutaneous wounds. F. tularensis
infection when considering this bacterium as a biological weapon. is an intracellular parasite that infects macrophage cells, where it re-
Pulmonary infection begins 2–4 days after exposure, and has a char- sides as an intracellular parasite. It retards intracellular killing by the
acteristic pattern of symptoms that are similar to other community- host phagocytic cells due to a cellular capsule. It has recently been
acquired pneumonias. Cough, fever, dyspnea, and leukocytosis are identified to infect erythrocytes (Horzempa et al. 2011). Intracellular
present. Chest radiographs will identify bronchopneumonia. Without replication leads to lysis of the host cell. The full scope of the virulence
appropriate treatment, pulmonary infection results in dissemination of this bacterium is not fully elucidated.
Tularemia infection occurs in different patterns. Local cutaneous
infection follows skin inoculation and results in ulceration within
3–5 days. Lymphadenitis follows and regional lymph nodes become
enlarged and tender. The infection from lymph nodes may ulcerate
locally, or no ulceration may occur. Systemic access of bacteria pro-
ceeds from the lymph nodes. Oculoglandular infection may follow
eye inoculation which results in a severe conjunctivitis syndrome
with head- and neck-associated lymphadenopathy. Orophargneal
infection follows ingested of infected food or water and has been
associated with ulceration, non-specific mucositis, and usually with
regional lymphadenopathy. A typhoidal variant of tularemia occurs
after cutaneous exposure where infection may have limited or no lo-
cal manifestations or no lymphadenitis, and proceeds to a systemic
infection with SIRS.
Inhalational tularemia is of greatest concern as a bioweapon. In-
fection follows 3–5 days after exposure, and follows either a pattern of
severe fulminant pneumonia or a more protracted form of pulmonary
infection. The infection pattern may demonstrate acute hemorrhagic
edema with necrosis of lung parenchyma, or may have the indolent
pattern of a caseating, granulomatous infection. Both patterns of pul-
Figure 23.2  Digital necrosis due to plague infection. (From http://phil.cdc. monary infection are associated with hilar adenopathy. In all forms of
gov/phil/details.asp, courtesy of CDC. ID no. 1957.) tularemia the infection has a variable rapidity of progression, and for
254 BIOTERRORISM

many patients pursues a slow and indolent pattern. Human-to-human Brucellosis is not a pulmonary infection and sputum cultures are not
transmission has not been documented. Overall mortality rates are of value. The organism grows slowly in vitro, and positive cultures
reported at 7%, but timely and effective treatment has reduced this may require several weeks. Antibody detection methods and PCR
rate to <2%. studies are useful in earlier detection by reference laboratories. Chest
Infections have a non-specific clinical presentation and make cul- radiographs are not helpful. Echocardiography may be necessary to
ture identification of the pathogen essential. The organism can be seen evaluate possible endocarditis.
on Gram stains. Cultures of cutaneous exudates, sputum, and tissue Long courses (≥6 weeks) of antibiotic therapy are required for man-
samples from ulcerated lesions will recover the organism. Chocolate agement both to reduce the duration of the illness and to avoid meta-
agar has been recommended. The organisms grow slowly in vitro and static infection. Combination doxycycline (100 mg twice daily) and
identification may take up to 5 days. Other diagnostic methods include rifampin (600–900 mg daily) have been recommended. Tetracyclines
fluorescent antibody stains, immunohistochemistry methods, and and aminoglycosides have also been used. Gentamicin (1 mg every 8 h)
PCR identification from reference laboratories. has replaced streptomycin because of availability, and is used only in
Naturally occurring pathogens are sensitive to aminoglycosides, the acute phase of treatment when intravenous administration is nec-
and gentamicin is the recommended treatment. Therapy is recom- essary. Quinolone antibiotics have in vitro activity but limited clinical
mended for a full 10 days. Doxycycline and quinolone antibiotics experience. The long course of antibiotic therapy including even triple
have also been used successfully for treatment. Relapse of infection agents (doxycycline, rifampin, gentamicin) is recommended because
has been a concern with the use of bacteriostatic drugs, and intrave- of the risk of bacterial endocarditis. Postexposure prophylaxis remains
nous treatment has generally been recommended with a bactericidal of uncertain value, but suspected exposure events will likely lead to
agent (e.g., aminoglycoside). Tularemia infection responds promptly doxycycline utilization. The duration of postexposure prophylaxis is
to antibiotic therapy and clinical failures must lead to an evaluation of by physician choice.
the engineered resistant microbe. Standard infection control practices Standard infection control practices are recommended. Human-
should be employed in managing patients. Oral doxycycline or cipro- to-human transmission is very unlikely, because the organisms are
floxacin has been recommended for postexposure prophylaxis for 14 not expectorated and only cutaneous infection is a potential source
days of administration. Effective disinfection practices are adequate of infection to others. Standard disinfection practices are appropriate
for medical facilities and equipment after the treatment of tularemia. after management of the cases.

■■Brucellosis ■■Cholera
Brucellosis is a naturally occurring infection in sheep, goats, and cattle Cholera is a well-known infection to those areas of the world where
(Franco et al. 2007). Transmission to humans occurs from contract a safe water supply is problematic. It continues to be a major source
with infected animals or consumption of infected animal products of epidemic infection. This enteric infection is caused by Vibrio chol-
(e.g., milk or cheese). Brucellosis is a suspected agent of bioterrorism erae. It is an aerobic Gram-negative rod which produces a potent
because only small inocula are required for clinical infection, incuba- enterotoxin. Malicious contamination of food or water becomes the
tion time after exposure can be prolonged, diagnosis can be difficult, mechanism for this organism to be an agent of bioterrorism.
and the disease has a protracted course. Although not a spore-forming bacterium, it has both a metaboli-
Human infection occurs from four different strains with Bru- cally active and a dormant state. Adverse environmental conditions
cella melitensis as the most virulent strain. These bacteria are aerobic result in the dormant state. Favorable environmental conditions result
Gram-negative rods. A unique lipopolysaccharide with only modest in active replication. Ingestion of a critical inoculum of V. cholerae
pyrogenic effects is a major component of virulence. Brucella spp. are results in binding of the organism to the enterocyte and production
intracellular pathogens within macrophages and neutrophils. of the enterotoxin (Raufman 1998). The result is a severe secretory
Like other suspected bacterial bioweapons, brucellosis infection diarrhea. Death from cholera occurs not from invasive infection, but
occurs in a cutaneous, gastrointestinal, or inhalational form. Cutane- due to loss of extracellular volume and circulatory collapse.
ous infection follows contact in a pre-existing open wound with in- The onset of profuse diarrhea is the major clinical sign for this diag-
fected animals, animal carcasses, or infected food products. Naturally nosis. Abdominal cramping is uncommon but tachycardia, tachypnea,
occurring brucellosis infection commonly follows ingestion of the and hypotension follow the onset of the diarrhea. The motile organ-
organisms. Inhalational disease occurs very uncommonly. Gastroin- isms can be recognized with phase microscopy of diarrheal stools.
testinal and inhalational infections share the common pathophysi- Cultures on specific media will identify the organism, but the severity
ology of the pathogen being ingested but not killed, and then being of the diarrhea will require therapy before culture results.
transported to regional lymph nodes. Thus, the infection arises from Volume resuscitation of the patient is the critical component of
the regional lymph nodes and is not primary to the gastrointestinal treatment. Ringer’s lactate or isotonic NaCl solution (0.9%) is used.
or pulmonary portal of entry. Clinical infection may not occur until Bicarbonate may be necessary to manage metabolic acidosis. Intrave-
8 weeks after exposure. nous fluid support must be continued until the diarrhea has subsided
Clinical brucellosis persists initially as a flu-like syndrome. Mild and normal oral intake has resumed.
fever, myalgia, arthralgia, and malaise give the appearance of viral Antibiotic therapy is used. Tetracycline (500  mg, every 6 h x 3
disease. The infection pursues a protracted course and dissemina- days) or doxycycline (100  mg every 12 h x 3 days) is the preferred
tion is associated with visceral abscesses, meningitis, endocarditis, choice. A large single dose (1 g) of azithromycin has been success-
and other remote infections. Chronic infection is associated with fully used for treatment (Saha et al. 2006). Other antibiotic choices
substantial weight loss. (quinolones, erythromycin, trimethoprim–sulfamethoxazole) have
The diagnosis requires culture identification of the pathogen. been used. Antibiotics appear to reduce the duration and severity of
Blood, bone marrow aspirates, or cultures of tissue/exudates from the infectious event, but intravenous fluid support is the key to suc-
remote sites of infection are necessary for recovery of the organism. cessful management. Postexposure antibiotic prophylaxis has not
 Viruses 255

been well studied but would likely be employed in circumstances of inoculum of bacteria is necessary to cause the infection and high
a recognized exposure event. Standard infection control processes mortality rate of the acute infection, this organism has been actively
with appropriate handling of diarrheal stools should avoid human- pursued as a possible bioweapon.
to-human transmission. Standard disinfection practices are used for Cultures of infected cutaneous lesions or of sputum will recover
patient rooms and equipment. the pathogen with specific media (e.g., meat nutrient agar). Blood
cultures are usually negative. Complement fixation tests, agglutina-
■■Q fever tion tests, immunoflorescence assays, and PCR are used by reference
laboratories.
Coxielia burnetii is the pathogen of Q fever as a proposed agent of As the number of cases that have been managed with each drug
bioterrorism (Parker et al. 2006). It is a bacterium that has pathological regimen is small, uncertainty exists for antibiotic treatment and is
and clinical characteristics similar to Rickettsia spp. It is an intracel- based on in vitro sensitivities (Dow et al. 2010). For localized infec-
lular parasite but maintains viability and infectivity outside host cells. tion trimethoprim–sulfamethoxazole, doxycycline, amoxicillin/
It is an endemic infection to goats, cattle, sheep, and birds. It has been clavulanate, and quinolones have been used for 2–5 months in dura-
labeled as a potential bioweapon because infection may occur after tion. Combinations of drugs are used for severe cases with systemic
exposure to only a single organism and because of the airborne route manifestations. No evidence supports postexposure prophylaxis with
of transmission. Infection may occur after ingestion or inhalation of the antibiotics. Human-to-human transmission is considered a low risk,
pathogen. The organism adheres to the plasma membrane of the target so standard isolation precautions and standard disinfection of the
cell population, and is internalized into a phagosome. The organism healthcare environment are recommended.
may survive for years within the host as an intracellular parasite. A disease commonly associated with glanders is melioidosis
The hallmark of Q fever is a persistent low-grade fever. The patients (Cheng 2010). This infection is caused by Burkholderia pseudomal-
characteristically have a flu-like syndrome with myalgias and malaise. lei. It is genetically similar to B. mallei and has many similar clinical
A viral-like pneumonia is present on chest radiographs in about half and management features to glanders. Worldwide, it appears to be a
of patients, and 20% will have a maculopapular rash. It is associated more common infection in humans because of the presence of the
with endocarditis and a hepatitis syndrome. The infection may be of organism in the soil. Treatment includes a broader array of antibiot-
limited duration and severity in younger patients, but can be quite ics, including ceftazidime and the carbapenems, in addition to those
severe in elderly people. The acuity and severity of the infection de- drugs used in glanders. This bacterial pathogen has also been explored
pend on the inoculum size, route of exposure, and patient host factors. as a bioweapon.
Plasmid-mediated variability may make specific strains quite virulent.
The major pathological consequences of the disease are from chronic
infection that persists over years.
■■VIRUSES
Culture identification of the organism has proven to very difficult
for the routine laboratory. The diagnosis is best established through
■■Smallpox
the use of serological methods of antibody detection. PCR has also Without question smallpox is the one infection that is viewed with
been more recently proposed for diagnosis. greatest concern as a bioweapon to be used against civilian popula-
The treatment for acute infections is doxycycline (100  mg twice tions (Henderson et al. 1999). Smallpox epidemics have been associ-
daily) for 14 days. The treatment of chronic infection is prolonged ated with large numbers of deaths and human misery in the past. The
antibiotic therapy because the agents that are used are bacteriostatic, eradication of smallpox with a vigorous international immunization
and the organisms are intracellular in location. Doxycycline and hy- program has been one of the most remarkable success stories of public
drochloroquine for 18 months are the current recommendation. The health efforts. The last identified infection was in 1977. By the mid-
hydrochloroquine is thought to adversely increase the pH within the 1980s, public immunization programs were discontinued. Only two
phagosome that contains C. burnetii. Quinolones in combination with repositories of the virus are known to exist at the Centers for Disease
doxycycline have been used, but this therapy may be required for ≥3 Control in Atlanta in the USA and the Institute for Viral Preparation
years. Vaccine development is being pursued for areas with high rates in Moscow. As public immunization has been discontinued, it means
of infection. Transmission from human to human has been reported that an entire generation under age 30 is unvaccinated and at risk. It
but is rare. Standard infection control processes are used for infected is likely that remote immunization of the older population still affords
patients, and standard decontamination of rooms and equipment is significant protection. As the infection has airborne transmission
appropriate. and is readily passed from human to human, there has been real fear
about viral cultures of the smallpox virus being in the possession of
■■Glanders political dissidents.
This infection is caused by variola virus. Variola is a member of the
Infection with Burkholderia mallei is referred to as glanders. This Orthopox genera which includes cowpox, monkeypox, vaccinia, and
pathogen is an aerobic Gram-negative rod that is a human bacterial other viruses that share a common antigenic character. It was suc-
infection contracted from horses, mules, and donkeys. It is contracted cessful vaccination of large populations of people with vaccinia that
by cutaneous exposure of non-intact skin, ingestion, or inhalation of has provided immunological protection against smallpox infection.
the microbe. Cutaneous infection results in ulcerated lesions with Smallpox has a well-defined pathogenesis and humans are the
regional adenopathy. Ingestion is associated with ulcerated lesions natural host. Expectorated droplets containing virus are inhaled by
of the oropharynx. Pulmonary infection is an acute pneumonia or the susceptible host. A small inoculum of inhaled virus is necessary
miliary disease. Fever, leukocytosis, and splenomegaly occur with to cause infection. The virus adheres to the oropharynx or respiratory
acute glanders. The acute disease is usually fatal. A chronic and highly mucosa. By 3–4 days after exposure, the virus has migrated to regional
variable form of the infection occurs about 14 days after exposure of lymph nodes where proliferation occurs. An asymptomatic viremia
the host. The chronic form of the infection may proceed to resolution occurs with dissemination to the spleen, bone marrow, and the regional
or relapse into an acute exacerbation with death of the host. As a small lymph nodes of the infected host. A second viremia occurs about 8 days
256 BIOTERRORISM

after the original exposure and the patients then experience fever and (Wharton et al. 2003). There remains no evidence that smallpox viral
systemic symptoms. By 14 days, the patients experience a generalized cultures have fallen into undesirable ownership and the world remains
viral syndrome of fever, headaches, myalgias, and even abdominal free of this infection for nearly 35 years. Nevertheless, a continued
pain. A maculopapular rash occurs at this point which progresses to understanding of smallpox is necessary for prompt recognition should
vesiculation and then pustule formation. The rash evolves into the it re-emerge for any reason.
classic crusting, umbilicated lesion (Figure 23.3). The patients remain
infectious to others until the rash has resolved. Smallpox has a histori-
cally defined 30% mortality rate.
■■Equine encephalitis virus
The characteristic cutaneous lesions of smallpox have tradition- The three equine encephalitis viruses (EEVs) are endemic infections
ally made it a clinical diagnosis. The crusted, umbilicated lesions are for equine species (horses, mules, donkeys). They are transmitted by
most densely identified on the face and extremities, as opposed to the mosquitoes to humans. Exposure of humans from mosquito contact
predominantly truncal crusted lesions that are typical of chickenpox. results in hematogenous transport of the virus to the central nervous
Scrapings from the skin lesions will show Guarnieri bodies on light system (CNS) to initiate the encephalitis process.
microscopy, the virus can be visualized on electron microscopy, and it The three types of EEV include the Venezuelan EEV, Eastern EEV,
can be cultured. PCR techniques can be used to identify the viral DNA. and Western EEV. Each virus has unique virulence characteristics.
Early efforts in antiviral chemotherapy included treatment of small- Venezuelan EEV has been primarily identified in Central and South
pox with cytosine arabinoside and adenine arabinoside, but validation America and is a severely incapacitating disease, but has only a 1%
of effectiveness was not established before eradication of the infection. mortality rate. Eastern EEV has a distribution of natural infection
Animal studies supported cidofovir as another potential treatment. that is similar to Venezuelan EEV but also includes the eastern USA.
The care of the smallpox patient is supportive management. Smallpox Mortality rates with Eastern EEV are 50–70%. Western EEV occurs
patients were isolated in negative pressure rooms until resolution of with multiple serotypes, in both North and South America, and has
cutaneous lesions was complete. All personnel obviously required a 10% mortality rate.
immunization themselves. Strict barrier precautions were used. Dis- Each of the three EEVs has been proposed as a bioweapon (Smith
posable supplies were incinerated. Reusable linens were autoclaved et al. 1997). They are easily grown in culture, easily stored, and quite
before being laundered. infectious to humans, and the multiple types and subtypes will make
Concerns about the re-emergence of smallpox as a bioweapon has the development of vaccines very difficult. As opposed to naturally
led to discussions about the resumption of immunization programs. occurring infection EEV as a bioweapon would be delivered as an
However, vaccination is not without significant complications, de- aerosol, binds to respiratory epithelium, and is then transported to
tailed in Table 23.2. These complications can lead to major disability the CNS. It does not cause a viral pneumonia, and human-to-human
and even death. As these complication statistics come from clinical transmission is thought to be a minimal risk. Some evidence suggests
studies of ≥40 years ago (Lane et al. 1970), the prevalence of immu- transmission of aerosol infection may be directly through olfactory
nosuppressed patients in current society may make the frequency nerves and then direct entry into the CNS.
of immunization-associated complications greater than previously Clinical disease begins 1–10 days after exposure. The disease
observed. The Advisory Committee on Immunization Practice has begins as fever, myalgia, and malaise. It transitions into headaches
recommended to the Centers for Disease Control and Prevention and encephalitis. Leukopenia is observed. The diagnosis is made by
(CDC) that immunization of the general population is not warranted. cultures of the virus, and IgM antibody detection is useful but not
They have recommended immunization of emergency response teams positive until a week into the infection. Only supportive care is used,
and personnel in hospitals where identified cases would be managed without any recommendations for antiviral chemotherapy. Standard
infection control and disinfection are recommended.

■■Viral hemorrhagic fever

An array of different viruses are viral hemorrhagic fever (VHR) patho-
gens (Table 23.3). The number of different viruses and subspecies
of recognized groups continue to expand. They share the common
characteristics of fulminate febrile illnesses which are associated with
clinical bleeding, shock, and death. These viruses can be cultured in
large quantities, have the potential for airborne transmission, and
have potential for human-to-human transmission. For these reasons,
these agents have been evaluated by governments as bioweapons and
represent a risk for use in bioterrorism (Marty et al. 2006).
The VHR viruses are single-stranded RNA viruses and have a lipid
envelope (see Chapter 1). They commonly have rodent reservoirs and
are transmitted by mosquitoes or ticks. Human-to-human transmis-
sion is by contact with infected blood or infected body fluids, or by
inhalation of a fine aerosol. The endothelial cell is the host target. The
incubation time for clinical infection after exposure may vary from
only 2–3 days, to several weeks for the specific virus. Mortality rates
Figure 23.3  The pustules and crusting cutaneous lesions of smallpox. approach 90% for selected infections (e.g., Marburg, Ebola).
(From http://phil.cdc.gov/phil/details.asp, courtesy of CDC/Dr John Noble Jr. ID The clinical presentations of these infections are highly variable,
no.: 10480, 1968.) but have the hallmarks of the generic viral syndrome. Fever, myalgia,
 Biological toxins 257

Table 23.2  Complications following primary and revaccination for smallpox.

Primary vaccination Revaccination rate/million*
Complication Rate/million Death rate of event
Generalized vaccinia 241.5 0% 9.0
Progressive vaccinia 1.5 75% 3.0
Post-vaccinal encephalitis 12.3 25% 2.0
Eczema vaccinatum 38.5 10% 3.0
*Deaths are rare.

Table 23.3 Currently identified viruses of viral hemorrhagic fever. ■■BIOLOGICAL TOXINS
Disease Natural Locale
Arenaviruses
■■Botulinum toxin
Argentine hemorrhagic fever South America Botulinum toxin is an exotoxin product of Clostridium botulinum. It
is considered one of the most potent toxins known. It can be readily
Bolivian hemorrhagic fever South America
produced and stored. There is an extensive military history concern-
Brazilian hemorrhagic fever South America ing potential use as a bioweapon, and it represents a real threat for
Lassa fever Africa civilian populations (Arnon et al. 2001).
Venezuelan hemorrhagic fever South America
This toxin produces paralysis and has lethal effects from respira-
tory arrest. The toxin can be inhaled or ingested. By either route, the
Flavivirus toxin gains systemic distribution and binds to the membrane of the
Dengue fever Africa, Americas, Asia presynaptic motor neurons. The toxin is internalized within the motor
Kyasanur forest disease Africa, South America nerve cells and results in inhibition of acetylcholine release. The result
disrupts the propagation of neurotransmission.
Omsk hemorrhagic fever Eastern Europe
Rapid onset of paralysis is the characteristic finding of botulinum
Yellow fever Africa, South America toxin paralysis within a few hours to several days after exposure. Dys-
Others arthria, dysphonia, and diplopia are early findings because the cranial
Ebola/Marburg hemorrhagic fever Africa nerves tend to be the first affected by this toxin. Paralysis proceeds in
(filovirus) a descending fashion with the most severe motor nerve compromise
being in the head and neck area. The paralysis is symmetric and there
Hantavirus infection (hantavirus) Asia, Europe, south-western USA
are no sensory changes. There are no changes in sensorium before
Crimean–Congo hemorrhagic fever Africa, Asia, Europe hypoxemia. There is no febrile or other acute inflammatory response.
(nairovirus)
The diagnosis of botulinum poisoning is a clinical one. It should
Rift Valley fever (phlebovirus) Africa be clinically separated from Guillain–Barré syndrome or myasthenia
gravis. Serum, gastric aspirate, stool specimen, and suspected food
sources are sampled and submitted for the mouse bioassay. The
malaise, headaches, nausea/vomiting, diarrhea, and abdominal pain mouse bioassay exposes the animals to the clinical specimen with
are commonly seen. Leukopenia and thrombocytopenia are common. and without the presence of the anti-toxin. The mouse bioassay is
Hemoconcentration may be an early finding due to plasma volume available only in special reference laboratories. Direct measures of
loss, until clinical bleeding becomes significant. Shock and the evolu- the toxin are not available.
tion of pulmonary, hepatic, and renal failure follow the rapid evolution The management of botulism is prompt administration of the
of the clinical infection. equine-derived antitoxin and supportive care for the associated fail-
Although the clinical syndrome is readily recognized, documen- ure of ventilation (Sobel 2005). Treatment cannot be delayed until the
tation of the specific viral agent is challenging. The responsible virus laboratory mouse bioassay results are available. Patients should not
can be cultured, but may require 3–10 days before identification is receive the antitoxin before the clinical specimens for the bioassay are
established. Detection of specific antibodies by enzyme-linked im- recovered. As the antitoxin is effective only against extracellular toxin,
munosorbent assay (ELISA) methods, and identification of the viral the earliest possible administration is necessary to hopefully avoid the
RNA through reverse transcriptase PCR via reference laboratories are full impact on motor neurons. Toxin already internalized within cells
usual methods for prompt diagnosis. in not affected by the antitoxin. As the antitoxin is of equine origin, a
The treatment of VHF is supportive care. Maintenance of systemic test dose is given before the full treatment is administered. Up to 10%
perfusion and oxygenation are necessary for survival. Ribavirin therapy of patients may have hypersensitivity reactions, and 2% may have ana-
has been considered a potential treatment for these infections, but phylaxis. The full treatment is the 10 ml vial in 100 ml of 0.9% saline and
very little evidence supports use of this drug. Rigid infection control is infused slowly over 30–60 min. For infant cases, human botulism im-
important for personnel treating the patients and for laboratory workers munoglobulin is used instead of the equine antitoxin (Chalk et al. 2011).
handling the specimens for diagnosis. Disposables should be inciner- The supportive care of these patients may extend for weeks or even
ated and linens autoclaved before laundry. Disinfection after patient months. As the affected motor neurons have to regenerate new axo-
care should be rigorous. International travel makes exposure events in nal twigs to restore muscle function, prolonged ventilator support is
remote areas of the world a risk for infection occurring at any location. necessary. Tracheostomy may be necessary. The prolonged ventilator
258 BIOTERRORISM

support puts these patients at risk for ventilator-associated pneumonia. benefit from either gastric lavage or activated charcoal administration
Nutritional support is also necessary because of paralysis of the muscles before the onset of symptoms. Inhalational cases will require ventilator
of deglutition. It must be emphasized that botulism is a poisoning and hemodynamic support. Decontamination of potentially exposed
and not an infection. Antibiotics should not be employed unless a patients is necessary to avoid additional ricin exposure for patients and
documented focus of infection is identified. The prolonged course of healthcare personnel. Secondary contamination from ricin-exposed
hospitalization requires that selection pressures for resistant organisms patients is not a risk after effective decontamination. Standard envi-
be avoided. If antibiotics become necessary, drugs associated with ronmental disinfection is employed within the hospital.
neuromuscular blockade (e.g., aminoglycosides) should be avoided.
In the event of a proven or suspected exposure event to botulinum
toxin, patients should be decontaminated with removal of clothing,
■■Other microbial toxins
cleansing of skin, and washing or removal of hair. Decontaminated The number of potential toxins to be derived from microbes and
patients are not a risk for healthcare personnel. Standard infection plants are numerous. Many may not have been appreciated as
control practices and disinfection of medical equipment are employed. potential weapons of terror. An array of mycotoxins cause contact,
gastrointestinal, and inhalational risks. Staphylococcal enterotoxins
■■Ricin have been appreciated as potential ingestion or inhalation risks from
naturally occurring clinical infections or from laboratory accidents.
Ricin is a protein that is extracted from the castor bean (Audi et al. The exposures to the various toxins are quite similar, with patients
2005). It is extraordinarily toxic in humans with only 2 mg identified having a food poisoning clinical picture. Inhalation causes the non-
as a lethal dose in adults. It has been investigated by several govern- specific respiratory distress syndrome requiring ventilatory support.
ments as a bioweapon because of its ease of production and small Clinical specimens are obtained for analysis by reference laboratories.
doses necessary for a lethal effect. Ricin has actually been used in a Treatment is supportive care.
political assassination.
Ricin can be delivered by injection, ingestion, or inhalation. In-
gested ricin may be digested, with symptoms being gastrointestinal
■■RECOGNITION OF BIOTERRORISM
but with limited systemic uptake. Toxin gastrointestinal effects are A reality of life in the twenty-first century is that microbes or microbial
vomiting and diarrhea, with extracellular fluid loss and hypovolemic products may be used as bioweapons against civilian populations. It
shock being the major source of morbidity for the patient. Injected or means that surgeons and other healthcare professionals engaged in
inhaled ricin is distributed systemically and results in the inhibition the care of acutely injured and acutely ill patients need to be sensitized
of protein synthesis. Ricin accesses all cell populations. Symptoms to this possibility. The character of such an assault is totally unpre-
begin within 6–8 h of exposure. dictable. It may vary from a crop duster scattering particles across an
With inhalation, a necrotizing pneumonitis is seen due to local toxic urban area, or contaminants placed into a ventilation system of an
events of the compound. Severe pulmonary failure may supervene auditorium. Contamination with spores or powders on a pedestrian
the systemic effects of ricin as a cause of death in inhalation cases. thoroughfare might result in multiple people being exposed unknow-
Considerable discussion has focused on the weaponization of ricin for ingly over time. A public exposure event may not be appreciated until
inhalational delivery. The powder product has to be finely processed to infected or poisoned patients actually arrive at the emergency facility.
yield a size ≤5 μm to reach the alveolar region. The processing neces- Of course conventional explosions may have biological contaminants
sary to create the fine particle size has been a factor in discrediting ricin that will expose injured casualties, but also rescue personnel. For sur-
as a legitimate bioweapon by airborne exposure (Schap et al. 2009). geons and emergency personnel, it means that all malicious clinical
The diagnosis of ricin poisoning is suspected when a group of events with the intention of hurting civilian or political targets may
patients present with common symptoms after a suspicious public represent more than immediately meets the eye. It means that report-
exposure. Gastrointestinal symptoms will be similar to food poison- ing mechanisms must be in place for the identification of unusual
ing. Acute ventilator distress will herald inhalational injury. Clinical infections or unknown sicknesses, so that public health officials can
studies to detect ricin in serum specimens are not available in clinical identify a cluster of unusual clinical events occurring within a com-
laboratories, but detection of ricin or by antibody responses may be munity and among patients within a common geographical locale.
available through sophisticated reference laboratories. With the vast number of bacteria, viruses, and microbial cell products
The treatment for ricin poisoning is supportive care. There is no in a world with widely disseminated technology for the production of
antidote available. Gastrointestinal exposure will require volume and these agents, it is not a matter of whether a biological event will occur
hemodynamic support. Cases suspected of acute ricin ingestion may among civilian populations, but when it will happen.

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Audi J, Belson M, Patel M, Schier J, Osterloh J. Ricin poisoning: a comprehensive medical and public health management. JAMA 2001;285:2763–73.
review. JAMA 2005;294:2342–51. Dow SW, Estes DM, Schweizer HP, Torres AG. Present and future therapeutic
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Chalk C, Benstead TJ, Keezer M. Medical treatment for botulism. Cochrane Franco MP, Mulder M, Gilman RH, Smits HL. Human brucellosis. Lancet Infect Dis
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Inglesby TV, Henderson DA, Bartlett JG, et al. Anthrax as a biological weapon. separating fact from fiction. Environ Int 2009;35:1267–71.
JAMA 1999;281:1735–45. Smith JF, Davis K, Hart MK, et al. Viral encephalitides. In: Zajtchuk R, Bellamy RF
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Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological weapon: Sweeney DA, Hicks CW, Cui X, Li Y, Eichacker PQ. Anthrax infection. Am J Respir
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Biodefense. JAMA 1999;81:2127–37. Wharton M, Strikas RA, Harpaz R, et al. Recommenation for using smallpox
Horzempa J, O’Dee, Stolz DB, et al. Invasion of erythrocytes by Francisella vaccination in a pre-event vaccination program. Supplemental
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Chapter 24 Microbial translocation, gut
origin sepsis, probiotics,
prebiotics, selective gut
decontamination
Edwin A. Deitch, Jordan E. Fishman, Gal Levy

■ INTRODUCTION microorganisms. Likewise, several clinical and laboratory studies

indicate that impairment of upper intestinal antibacterial defenses is
Since the late twentieth century, the role of the gut in the pathogenesis important in the development of nosocomial pneumonias (Driks et
of infection, sepsis and organ failure in surgical and intensive care al. 1987, Tryba 1987), whereas life-threatening infection with bowel-
unit (ICU) patients has evolved considerably. Until this time, evalu- associated bacteria, in which no infective focus can be found even
ation of intestinal function had been limited largely to monitoring at autopsy, is a major clinical problem in several groups of patients
gastric pH and intestinal motility. This approach has led clinicians to including burns patients (Jarrett et al. 1978, Chitkara and Feierabend
equate normal intestinal motility with normal intestinal function and 1981), victims of trauma (Garrison et al. 1982, Border et al. 1987),
to assume that, if stress-induced gastric bleeding can be prevented, and patients with MODS (Goris et al. 1985, Carrico et al. 1986).
all will be well. However, over the last three decades it has become Thus, although still controversial, the phenomenon of bacterial
increasingly clear that the gastrointestinal (GI) tract is not a passive translocation has assumed clinical importance with the recognition
organ and that intestinal dysfunction is not limited to ileus and up- that intestinal barrier failure may play a role in the development of
per GI bleeding. Instead, today we recognize that the GI tract and its systemic infection, sepsis originating in the gut, and MODS in the
microbial contents may influence the patient’s clinical outcome and critically ill or injured individual.
that the gut has important endocrine, immunological, metabolic However, to fully understand the implications of bacterial translo-
and barrier functions in addition to its traditional role in nutrient cation and gut-derived sepsis, it is important to fully understand and
absorption, e.g., it is the intestinal barrier that prevents the spread of define these key terms, because these terms mean different things to
intraluminal bacteria and endotoxins to systemic organs and tissues. different people. Therefore, before we explore each of these topics,
Failure of intestinal bacteria function, leading to the escape of bacteria we will establish a common vocabulary (Box 24.1) and clarify the
or their products (endotoxin), has been termed “bacterial transloca- important point that bacterial translocation and gut-derived sepsis
tion” (Berg and Garlington 1979). When one considers the enormous may occur independently of each other, i.e., bacterial translocation
concentrations of bacteria and endotoxins present in the distal small
bowel and colon (1010 anaerobes and 105–108 each of Gram-positive
and Gram-negative aerobic and facultative organisms), the fact that Box 24.1 Bacterial translocation and gut-derived sepsis: a
sepsis originating in the gut and endotoxemia do not occur in normal, common vocabulary.
healthy individuals is in many respects a testimony to the effectiveness
of the intestinal mucosal barrier. Bacterial translocation is best defined as the process by which
Nevertheless, under certain pathophysiological conditions, in- intestinal bacteria or Candida spp. cross the intestinal mucosal
testinal barrier function can be impaired or overwhelmed to such an barrier to reach the mesenteric lymph nodes, from which they may
extent that bacterial (endotoxin) translocation does occur (Deitch or may not spread systemically and cause infection.
1990). The three basic mechanisms documented experimentally to The diagnosis of bacterial translocation requires the identification
promote bacterial translocation (Deitch 1990) are as follows: of intestinal bacteria in the intestinal lymph nodes.
1. Disruption of the ecological balance of indigenous intestinal flora, Gut-derived sepsis is best defined as the process whereby
resulting in the overgrowth of Gram-negative enteric bacilli gut-derived, proinflammatory, tissue-injurious, microbial and
2. Impairment of host immune and antibacterial defenses non-microbial factors induce or contribute to the development
3. Physical disruption of the intestinal mucosal barrier. of systemic inflammatory response syndrome (SIRS), acute respi-
These same conditions that experimentally are associated with loss ratory distress syndrome (ARDS), or multiple-organ dysfunction
of intestinal barrier function are commonly observed in the critically syndrome (MODS). This process may or may not occur in the
ill or injured patient at risk for enteric bacteremia or the multiple- presence or absence of systemic infection originating in the gut
organ dysfunction syndrome (MODS), e.g., these at-risk patients or bacterial translocation.
are frequently immunocompromised and the antibiotic, anti-ulcer, The diagnosis of gut-derived sepsis is based on measurements of gut
and dietary regimens that they receive may disrupt the normal barrier function (permeability) together with the clinical response
ecology of the intestinal flora, resulting in intestinal overgrowth of the patient.
with Gram-negative enteric bacilli and other potentially pathogenic
262 MICROBIAL TRANSLOCATION, GUT ORIGIN SEPSIS, PROBIOTICS, PREBIOTICS, SELECTIVE GUT DECONTAMINATION

may occur in the absence of gut-derived sepsis or the patient may have of uremic dogs (Schweinburg and Frank 1949). In the 1960s, Fine et
gut-derived sepsis in the absence of documented bacterial transloca- al. published some of the earliest clinical studies establishing that
tion. Therefore, when applying these two terms to clinical practice, intestinal bacteria and endotoxin originating in the gut are capable of
the two terms should not be linked together but looked at separately. gaining entry into the systemic circulation during shock states (Ravin
In fact, as discussed later in this chapter, the phenomenon and clini- and Fine 1962, Caridis et al. 1972, Woodruff et al. 1973). These authors
cal relevance of bacterial translocation have been largely studied in proposed that a relationship existed for shock, intestinal ischemia, and
patients undergoing abdominal surgery as well as animal models. systemic endotoxemia. However, over the next 20 years, the concept
In contrast, the incidence and clinical importance of gut-derived of an “intestinal factor” in shock-induced sepsis fell out of favor. This
sepsis and its consequences, such as organ failure, have been largely was largely due to experiments in germ-free animals indicating that
studied in the critically ill or injured ICU patient populations, where these germ-free animals were only modestly more resistant to certain
the diagnosis is based on measurements of gut permeability and not shock states than animals with a normal gut microflora.
bacterial translocation. Thus, the abdominal surgery population in The concept of sepsis originating in the gut lay dormant for almost
which bacterial translocation can be directly measured are not gen- 20 years. However, experimental animal studies performed in the late
erally critically ill and have a low likelihood of developing MODS. In 1970s and early 1980s by Wolochow et al. (1966), Berg and Garlington
contrast, bacterial translocation cannot be directly measured in the (1979), and Deitch et al. (1985), and subsequently in the mid-1980s
critically ill patient population, who are at the highest risk of develop- by Wells et al. (1986) and Inoue et al. (1988), established that bacteria
ing gut-derived sepsis and MODS. can translocate from the gut to systemic organs and tissues. It was
at this time that the term “bacterial translocation” was coined. This
■ BACTERIAL TRANSLOCATION concept of bacterial translocation provided a biological explanation
for how bacteria could breach the intestinal mucosal barrier and lead
AND GUT-ORIGIN SEPSIS: A to systemic infections (Figure 24.1). Shortly thereafter, it was pro-
HISTORICAL PERSPECTIVE posed that gut barrier failure leading to the translocation of bacteria
and endotoxin could lead to septic states originating in the gut and
This notion that the gut can be the reservoir for bacteria or fungi that the gut was the “motor of multiple organ failure” (Carrico et al.
causing systemic infections is not new, e.g., beginning in the late 1986, Border et al. 1987, Deitch et al. 1987, Deitch 1992). Thus, by the
1800s, it was postulated that peritonitis could result from virulent mid- to late 1980s, the gut hypothesis of MODS had appeared. During
bacteria migrating across an intact intestinal wall (Balzan et al. 2007), the decade from 1985 to 1995, bacterial and endotoxin translocation
and this concept was experimentally validated in the 1940s when across the compromised gut became viewed as a major contributor
enteric-origin bacteria were recovered from the peritoneal washings to systemic infection and MODS after shock, mechanical trauma, and

Figure 24.1 Potential route of

bacterial translocation from
intestine to systemic organs
and tissues, which include
lymphatic and blood-borne
(portal vein) routes.
 Bacterial translocation and gut-origin sepsis: A historical perspective 263

burns, and in ICU patients as well as in patients undergoing major with the development of ARDS and MODS in these high-risk patients
surgery (Deitch 1992). were unsuccessful. In an attempt to directly correlate bacterial and
Early clinical studies attempting to validate the bacterial transloca- endotoxin translocation with the subsequent development of ARDS
tion model in patients used the strategy of culturing the mesenteric and MODS, Moore et al. (1991) carried out a prospective study where
lymph nodes of patients undergoing surgery, because translocation to portal vein catheters were placed in severely injured trauma patients
the mesenteric lymph node was viewed as the initial and key step in the shortly after their arrival at hospital. Serial portal blood samples were
bacterial translocation process. These initial proof-of-principle clinical then tested for bacteria or the presence of endotoxin. Although 30% of
studies documented that bacterial translocation to the mesenteric the enrolled patients subsequently developed MODS, only 2% of all the
lymph nodes occurred in patients undergoing abdominal surgery for portal vein cultures collected were positive for bacterial growth and
inflammatory bowel disease (Ambrose et al. 1984), simple small bowel endotoxin was not present in any of the portal blood samples. Given
obstruction (Deitch 1989), or trauma (Moore et al. 1992). However, no the compelling results of this study, doubt was cast on the clinical
such studies were carried out in patients with systemic inflammatory relevance of bacterial translocation to the development of MODS.
response syndrome (SIRS), sepsis, acute respiratory distress syndrome Although bacterial translocation did appear to predispose to infec-
(ARDS), or MODS. These positive studies prompted additional clinical tious complications in postoperative surgical patients, this study and
studies examining the peripheral blood, abdominal fluid, and portal others caused a reassessment of the role of bacterial translocation in
blood of organ donors. In one such study, translocation of bacteria the pathogenesis of MODS.
and endotoxin was observed in over half of all organ donors despite One potential explanation for the failure of Moore et al. to find
normal light and electron microscope examination of the bowel wall bacteria or endotoxins in the portal system is that MODS-inducing
(Van Goor et al. 1994). Of more import, however, the bacteria cultured factors were exiting the gut via the intestinal lymphatics rather than
from the mesenteric lymph nodes (MLNs) were found to be identical the portal blood. This observation would be consistent with preclini-
to the GI flora, thus strengthening the hypothesis that the bacterial cal studies showing that the primary route of translocating bacteria
source was the GI tract. This finding was further strengthened by exiting the gut is via the lymphatics (Mainous et al. 1991). It would
studies demonstrating that, in patients with both a documented post- also help explain why increased gut permeability and gut ischemia
operative septic source and bacterial translocation, as evidenced by a are better predictors of the development of MODS than the presence
positive MLN culture, the bacteria isolated from the MLN culture was of gut-derived bacteremia or endotoxemia. Based on an extensive
identical to the bacteria isolated from the septic source about half the series of studies, it was shown that gut-derived factors, carried in the
time (Sedman et al. 1994, O’Boyle et al. 1998, MacFie et al. 1999, 2005, intestinal lymphatics rather than the portal vein, are responsible for the
Woodcock et al. 2000, Chin et al. 2007). early development of ARDS and MODS in stress conditions (Magnotti
In addition, bacterial genomic studies comparing the bacteria et al. 1998, 1999, Deitch et al. 2004a, Senthil et al. 2006). The synthesis
collected from MLN cultures with the indigenous colonic bacteria of of these observations into a coherent, experimentally testable hy-
patients undergoing colon resection found that the cultured bacteria pothesis occurred over the last decade and has been termed the “gut
were identical to those in the colon, thus serving to further strengthen lymph hypothesis” of SIRS, ARDS, and MODS (Deitch and Xu 2006).
the notion that the gut served as a bacterial reservoir for infection This theory postulates that the early onset of SIRS and organ failure
(Reddy et al. 2007). The transition from phenomenology to clinical after trauma or shock is due to non-bacterial, tissue injury-related,
relevance followed with the publication of six additional clinical series, proinflammatory factors liberated from the stressed gut which reach
totaling 2125 patients undergoing abdominal surgery. In these studies, the systemic circulation via the mesenteric lymphatics (Deitch and
the incidence of bacterial translocation to the MLN ranged between 5% Xu 2006). This hypothesis is based on several major experimental
and 21%, and the rate of infectious complications was two- to threefold observations. First, ligation of the major intestinal lymph duct, which
higher in patients with bacterial translocation (Sedman et al. 1994, prevents intestinal lymph from reaching the systemic circulation,
O’Boyle et al. 1998, MacFie et al. 1999, 2005, Woodcock et al. 2000, prevents the development of early ARDS and MODS. Specifically, it
Chin et al. 2007). Thus, studies in surgical patients undergoing major prevents acute lung injury, cardiac dysfunction, neutrophil activation,
operations appeared to validate the concept of bacterial translocation increased endothelial permeability, bone marrow suppression, and
and found a significant association between the occurrence of bacte- red blood cell dysfunction in multiple preclinical models of trauma,
rial translocation and an increased risk of postoperative infections. shock, burn injury, or gut ischemia. Second, in vitro studies of mes-
However, although bacterial translocation had been documented enteric lymph from shocked animals, but not sham-shocked animals,
to occur in patients undergoing major operations and in organ donors, leads to neutrophil activation, and cardiomyocyte and endothelial cell
the studies linking bacterial and endotoxin translocation to MODS injury, as well as red blood cell dysfunction. Last, injection of shock
in critically ill or injured patients in the ICU was indirect, and used lymph into healthy mice and rats recreates a systemic sepsis state
increased intestinal permeability as a marker for patients at increased and causes ARDS and MODS. Thus, the gut lymph hypothesis fulfills
risk for developing gut-derived sepsis or MODS. These studies showed a modified set of Koch postulates (Box 24.2). Although no human
that gut permeability was increased in thermally injured, trauma, and clinical studies directly testing this hypothesis have been performed
ICU patients, but only about a third of these studies found a clear to date, this hypothesis has been verified in multiple rodent, porcine,
association between the magnitude of the increase in gut perme- and non-human primate studies. The strength of this working hypoth-
ability and infectious complications, although the evidence linking esis is that it helps resolve the paradox of how gut-derived sepsis and
increased gut permeability to the development of MODS was stronger MODS can occur, and yet neither bacteria nor endotoxins are found
(Pisarenko and Deitch 2010). Further support for the concept of gut in portal vein blood samples. It also explains the relationship between
injury contributing to MODS came from studies in ICU and trauma increased gut permeability and MODS. Thus, currently, the original
patients, indicating that gut ischemia, as reflected by gastric tonom- bacterial translocation paradigm has been expanded to include the
etry, was a better predictor of the development of ARDS and MODS gut lymph hypothesis (Figure 24.2).
than global indices of oxygen delivery (Ivatury et al. 1995). On the other Although it seems important to maintain normal intestinal barrier
hand, studies trying to correlate increased plasma endotoxin levels function in the critically ill or injured patient, maintenance of barrier
264 MICROBIAL TRANSLOCATION, GUT ORIGIN SEPSIS, PROBIOTICS, PREBIOTICS, SELECTIVE GUT DECONTAMINATION

the need to optimize intestinal barrier function in high-risk patients

Box 24.2 Application of a modified Koch postulates paradigm presents a clinical challenge. To develop strategies to maintain normal
to the gut–lymph hypothesis of acute lung injury. intestinal barrier function as well as limit bacterial translocation, it is
necessary to understand each of the components that contribute to
First postulate: The factor (trauma/hemorrhagic shock [T/HS] the intestinal barrier.
lymph) is present when the injury (T/HS-induced lung injury) is
present
First observation: Gut-derived T/HS lymph reaching the systemic
■ THE INTESTINAL BARRIER:
circulation is associated with systemic inflammatory response DEFENSES AND MECHANISMS
syndrome (SIRS), acute respiratory distress syndrome (ARDS), and
multiple-organ dysfunction syndrome (MODS) The initial step in the translocation of bacteria from the intestinal tract
Second postulate: In the absence of the factor, injury does not is the adherence of bacteria to the epithelial cell surface or to ulcerated
occur areas of the intestinal mucosal surface. Once adherence occurs, the
Second observation: Mesenteric lymph duct ligation, which pre- bacteria then cross the mucosal barrier and reach the lamina propria
vents gut lymph from reaching the systemic circulation, prevents/ in a viable state, at which point bacterial translocation has technically
limits SIRS, ARDS, and MODS occurred. However, unless the bacteria or their products (endotoxins)
Third postulate: The isolated factor demonstrates injurious activity are able to invade the lymphatics or bloodstream and then spread
Third observation: The in vitro activities of T/HS lymph mimic systemically, the process is unlikely to be of significance. In fact, there
the in vivo cellular responses observed in animals subjected to is increasing evidence that a limited amount of bacterial transloca-
actual T/HS tion may be a physiologically normal process that is important in the
Fourth postulate: Challenge with the factor can recreate the injury development and maintenance of intestinal and systemic immunity.
Fourth observation: Injection of T/HS lymph into naive rats recre- The host has a complex series of defense mechanisms to prevent
ates the lung injury observed after actual T/HS or limit potentially pathogenic bacteria from adhering to the intes-
In this paradigm, T/HS lymph is viewed as this factor. tinal mucosa. These defense mechanisms of barrier function consist
of three basic elements: The stabilizing influence of the normal
intestinal microflora, and mechanical and immunological defenses
function is exceedingly difficult. As previously mentioned, these pa- (Box 24.3). One major component of the barrier worthy of special
tients are frequently immunocompromised and their bowel flora is mention is the indigenous (normal) microflora. The protective role
often disrupted. In addition, they may have had major blood loss or of the normal intestinal microflora was initially described by van
hypotension and may be receiving vasoactive drugs. All can result der Waaij et al. (1971), who showed that intestinal colonization
in splanchnic vasoconstriction and intestinal mucosal injury. Thus, or overgrowth with potentially pathogenic microorganisms was

Figure 24.2 Schematic overview showing the

Disease/insult-induced different potential pathways and mechanisms
splanchnic ischemia by which a systemic insult can lead to bacterial
translocation and/or gut-derived sepsis. In
this paradigm, shunting of blood away from the
splanchnic circulation leads to a gut ischemia–
reperfusion injury, which in turn results in gut
Intestinal injury (loss of barrier function) and inflammation. In
I/R injury addition to the process of bacterial translocation,
the stressed and inflamed gut appears to be the
source of non-microbial sepsis and multiple-organ
dysfunction syndrome-inducing factors that reach
the systemic circulation via the intestinal lymphatics.
Loss of barrier Disease/insult-induced
funtion splanchnic ischemia

Bacterial Escape of Release of

translocation to bacterial tissue injurious
MLN products inflammatory mediators

Via mesenteric
Systemic Mesenteric
lymphatics
infection lymph
and/or portal

Septic response with SIRS, ARDS, MODS

 The intestinal barrier: Defenses and mechanisms 265

combination of events promotes bacterial penetration through the

Box 24.3 Components of the intestinal barrier. mucus and facilitates bacterial translocation.
The intestinal immune system, known as the gut-associated lym-
Mechanical phoid tissue (GALT), regulates the local immune response to soluble
⦁ Intestinal peristalsis and particulate antigens within the bowel. The exact role of the GALT
⦁ Mucous layer in preventing bacterial adherence and translocation is unclear; how-
⦁ Epithelial desquamation ever, it appears that secretory IgA produced by antigen-primed B
⦁ Epithelial barrier lymphocytes lining the mucosal surface prevents mucosal invasion
Microbial by binding to bacteria and blocking their attachment to epithelial
⦁ Bacterial antagonism cells, without activating other arms of the immune system (Tomasi
⦁ Colonization resistance et al. 1983). However, the importance of the GALT as opposed to the
⦁ Contact inhibition systemic immunoinflammatory system in the prevention of bacterial
Immunological translocation or sepsis originating in the gut is unclear.
⦁ Secretory immunoglobulins Although both an intact epithelial barrier and a normal function-
⦁ GALT (gut-associated lymphatic tissue) ing immune system are important for adequate gut barrier function,
⦁ Bowel–liver axis it appears that an intact mucosa will prevent bacterial translocation
⦁ Bile salts in rats with selectively impaired cell-mediated immunity (Suzuki et
⦁ Reticuloendothelial function al. 2010). Thus, the physical barrier of the mucosa may be of primary
Other importance in preventing or limiting bacterial translocation, especially
⦁ Gastric acidity in a host with a normal gut flora, whereas the immune system may
serve a secondary or supportive role to the intestinal mucosal bar-
rier. This is a similar role played by other mechanical barriers, such
promoted by the disruption of the normal intestinal flora. They as the skin. The importance of loss of mucosal barrier function in the
coined the term “colonization resistance” to describe this protective pathogenesis of bacterial translocation after thermal injury (Ma et al.
role of the normal intestinal flora. It is now clear that the obligate 1989), limited periods of hemorrhagic shock (Deitch et al. 1988), or
anaerobic bacteria are one major element responsible for coloni- endotoxin challenge (Deitch et al. 1988) was highlighted by the results
zation resistance, because the anaerobes outnumber the enteric of early studies documenting that bacterial translocation can be largely
Gram-negative and aerobic Gram-positive bacteria by 1000- to prevented by limiting mucosal injury. In fact, one of the factors that
10 000-fold. By associating closely with the intestinal epithelium, most of the stress and injury models of bacterial translocation have in
they form a physical barrier limiting the direct binding of potential common is reduced splanchnic blood flow and histological evidence
pathogens with the mucosa. Due to increased sensitivity of the obli- of mucosal edema or injury. Mucosal injury in these models, as well as
gate anaerobes, this anaerobic barrier is lost when broad-spectrum in stressed patients, appears to be due to a gut ischemia–reperfusion
antibiotics are administered (Berg 1981) as well as during periods injury. This ischemia–reperfusion-induced mucosal injury is mediated
of physiological or nutritional stress (Deitch 1990). Consequently, in part by xanthine oxidase-generated oxygen free radicals, as well as
loss of this anaerobic “barrier” facilitates the association of potential by the tissue destructive products generated by increased nitric oxide
pathogenic bacteria with the intestinal epithelium. As discussed synthase (NOS) activity. Consequently, a major concept from these
later, these physiological observations were the rationale behind studies is that splanchnic circulation is very sensitive to alterations
the development and the clinical use of anaerobic-sparing oral in intravascular volume, and injury- or stress-induced splanchnic
antibiotics to selectively decontaminate the intestinal tract as well vasoconstriction, which may ultimately lead to an ischemia–reperfu-
as the use of prebiotics and probiotics. sion (I/R) injury of the intestinal mucosa, impaired intestinal barrier
A second line of defense against bacterial translocation or the ab- function, and intestinal inflammation.
sorption of endotoxins is provided by the mechanical defenses of the The mechanisms by which gut I/R leads to gut injury has also
bowel, which include the intestinal mucous layer (Kim and Ho 2010), evolved over the last decade, with the recognition that injury-induced
intestinal peristalsis, and the intestinal epithelium. The intestinal epi- loss of gut barrier function and the generation of non-microbial factors
thelium is coated by a mucous gel layer 30–50 μm thick. This gel layer carried in the lymphatics appears to be more important in the patho-
prevents the adherence of bacteria to epithelial cell surface receptors genesis of gut-induced MODS than translocating bacteria. Based on
and also provides a favorable environment for anaerobic bacteria. this recent work, it appears that gut injury during low flow states is not
The presence of a normal continuous, mucous layer prevents tissue just due to systemic factors but also involves processes occurring on the
colonization by potential pathogens (Kim and Ho 2010). Elimination luminal side of the gut wall (Figure 24.3), i.e., although previous studies
of this mucous layer has been shown to result in bacterial overgrowth investigating the mechanisms of gut I/R-induced injury have focused
with Gram-negative enteric bacteria and to increase the numbers of on the systemic factors associated with the gut I/R response, they have
these bacteria adhering directly to the intestinal epithelium. Most largely ignored the non-microbial intraluminal contents of the gut, es-
recently, loss of the mucus layer has been shown to allow digestive pecially the mucous gel layer. However, if the mucous gel hydrophobic
enzymes and other toxic factors within the gut lumen to reach the barrier is lost, this would allow luminal digestive enzymes, especially
underlying intestinal epithelial layer, leading to autodigestion and the pancreatic proteases, to come into direct contact with the underly-
increased gut permeability (Sharpe et al. 2008). In the small intestine, ing epithelial layer of the intestinal villi. In this circumstance, the host’s
normal peristalsis prevents the prolonged stasis of bacteria in close intestinal lining would be enzymatically digested in a fashion similar
proximity to the intestinal mucosa, and thereby reduces the chances to that of ingested proteins and other foodstuffs. Thus, if the mucous
that bacteria will have adequate time to penetrate the mucous layer. gel barrier were damaged and/or gut barrier failure occurred, the host
When peristalsis is impaired, as occurs with intestinal obstruction or would be in danger of being not only significantly injured by its own gut
ileus, bacterial stasis and overgrowth result (Savage et al. 1968). This bacteria but also digested by its own intraluminal digestive enzymes.
266 MICROBIAL TRANSLOCATION, GUT ORIGIN SEPSIS, PROBIOTICS, PREBIOTICS, SELECTIVE GUT DECONTAMINATION

Figure 24.3 Schematic overview of the

Trauma/hemmorhagic shock multifactorial processes leading to the
development of increased gut permeability
and biologically active mesenteric lymph that
includes both systemic events (ischemia–
Systemic Gut luminal reperfusion) and luminal factors within the gut
compartment compartment lumen. The luminal components include loss of
the protective mucus barrier, the deleterious effects
of digestive enzymes, as well as bacteria and their
Oxidants products.

Splachnic Chemical change to

ischemia/reperfusion the mucus layer

Increased gut Loss of mucus

permeability layer

Pancreatic
proteases,
bacterial
translocation

Potentiation of gut inflammation.

Release of gut-derived tissue injurious factors

Biologically active mesenteric lymph

Systemic inflamatory response syndrome, acute

respiratory distress syndrome, multiple organ failure

Although the concept of the mucous layer being an important the gut is more of a barrier to the egress of compounds within the gut
protective barrier is well established in the stomach, where stress- or lumen than the enterocyte layer (Nimmerfall and Rosenthaler 1980).
ischemia-induced loss of the gastric mucous layer contributes to gas- This concept of the major protective role of the gut mucous layer
tric mucosal injury by intraluminal acid, few studies have investigated was convincingly shown in a recent proof-of-principle study of the
the consequences of loss of the mucous layer in other parts of the normal intestine, where removal of the mucous layer was associated
intestine. One potential reason for the limited attention being focused with increased gut permeability and pancreatic protease-induced gut
on the mucous layer under conditions of gut ischemia or stress is that necrosis (Sharpe et al. 2008).
the mucous layer is dissolved and lost during ordinary histological Although the role of the pancreas as a factor in the pathogenesis
fixation procedures. Thus, what is not seen is not studied. In this light, of shock has a long history (Glenn and Lefer 1971, Lefer and Glenn
recently published studies evaluating the mucous layer in gut I/R and 1971), this area was neglected for almost 30 years, until experiments
trauma/hemorrhagic shock (T/HS) models document that T/HS leads showed that pancreatic enzymes are critical factors in intestinal
to a significant loss of the unstirred mucous layer as well as increased I/R-induced shock and neutrophil activation in 2000 (Kistler et al.
villous injury, enterocyte apoptosis, and gut permeability (Rupani et al. 2000, Mitsuoka et al. 2000). The studies investigating the effects of
2007, Qin et al. 2008, 2011). In addition, gut permeability was greatest pancreatic proteases in gut I/R and T/HS models have generated the
at the time of maximal mucus loss. The importance of maintaining following four conclusions about the role that pancreatic proteases
the gut mucous gel layer is highlighted by a recent study showing that play in gut injury and the development of SIRS, ARDS, and MODS
the enteral administration of high-molecular-weight polyethylene (Sharpe et al. 2008):
glycol (a mucus surrogate) prevented lethal sepsis originating from 1. Pancreatic proteases contribute to gut injury in gut I/R models
the gut (Wu et al. 2004). In addition, pharmacological studies have and this may be potentiated by the augmented destruction of the
documented that the decisive barrier to the transport of a compound mucous layer.
across the gut wall was related to the mucous layer and not the lipid 2. The interaction of pancreatic proteases with the ischemic gut
membrane of the underlying enterocytes. Thus the mucous layer of contributes to T/HS- and gut I/R-induced SIRS, ARDS, and MODS
 Therapeutic options and approaches 267

through the generation of non-microbial proinflammatory and 4. Non-gut based therapies directed at limiting the systemic conse-
tissue injurious factors. quences of gut-origin sepsis (Box 24.4).
3. After T/HS, pancreatic proteases are necessary for the production
of biologically active factors in mesenteric lymph, which transforms
gut ischemia into a systemic toxic and inflammatory response. Box 24.4 Therapeutic options to maintain gut barrier.
4. Although T/HS decreases splanchnic blood flow resulting in a gut
I/R injury, in the absence of pancreatic proteases, this systemic 1. Support commensal gut flora and maintain microbial ho-
hemodynamic insult is not sufficient to produce toxic mesenteric meostasis
lymph, neutrophil activation, or lung injury. a. Probiotics/prebiotics/synbiotics
Thus, pancreatic proteases appear to be a necessary component in b. SDD/SOD
the pathogenesis of T/HS-induced MODS originating from the gut c. Limiting therapies that disrupt gut flora (antacids, broad-
(Schmid-Schönbein et al. 2001, Mitsuoka et al. 2002, Deitch et al. spectrum antibiotics)
2003, Kramp et al. 2003, Waldo et al. 2003, Cohen et al. 2004, Caputo 2. Support gut barrier function
et al. 2007). a. Probiotics
An additional component of the intraluminal compartment that b. Early enteral feeding (Including tropic feeding regimens)
has become important in understanding the pathogenesis of gut injury c. Antioxidants (especially selenium)
and gut-origin sepsis is the intestinal bacteria. Experimental studies in d. Specific nutrients (glutamine, omega-3 fatty acids)
germ-free animals subjected to hemorrhagic shock (Ferraro et al. 1995) 3. Prevent additional injury by adhering to basic critical care
or superior mesenteric artery occlusion (Souza et al. 2004) indicate practices
that these germ-free animals have better survival and less intestinal
injury than their wild-type litter mates with normal gut flora. Studies
in animals with intestinal bacterial overgrowth also indicate that the Although some therapies have overlapping effects, this conceptual ap-
gut flora can amplify the magnitude of gut-related distant organ injury proach has the advantage of providing a rationale therapeutic frame-
in non-lethal gut I/R models (Magnotti et al. 1999). Recent studies of work. Consequently, the remainder of this section discusses each of
normal animals document that bacterial overgrowth can induce the these four basic therapeutic goals separately.
production of biologically active, proinflammatory, mesenteric lymph
(Deitch et al. 2004b). Thus, it appears clear that the normal gut flora,
as the conditions within the gut change, has the capacity to potentiate
■ Prevention
organ injury and contribute to the systemic septic response under con- The best management of intestinal barrier failure and bacterial trans-
ditions of stress or injury, even in the absence of bacterial translocation. location unquestionably lies in its prevention. The two most important
Consequently, although the normal intestinal bacterial flora does not preventive goals are to maintain intestinal perfusion and avoid or limit
appear to play a direct role in the initial pathogenesis of shock-induced therapies that disrupt the normal ecology of the gut flora. As inad-
mucosal injury (Deitch et al. 1990), once the mucosal barrier has been equate tissue (intestinal) perfusion, a persistent inflammatory state,
breached, translocating bacteria do contribute to the problem. Thus, infection, and inadequate nutritional support appear to be the most
the gut flora and their products, although not initiating gut injury or common clinical factors predisposing to intestinal barrier failure and
adverse systemic effects, act as secondary insults to the damaged or MODS, it seems logical that therapeutic efforts should be directed at
stressed gut, thereby potentially exacerbating the local and systemic their early treatment or prevention. Prevention takes different forms in
consequences of the initial insult. Of note, this ability of the gut flora different patients, e.g., in patients with pancreatitis, it has been shown
to potentiate gut injury and MODS can occur even in the absence of that early and aggressive volume resuscitation is the most effective
measurable signs of systemic bacterial translocation or endotoxemia. current therapy to limit the progression of pancreatitis and hence its
systemic consequences, including gut barrier failure (Fritz et al. 2010,
■ THERAPEUTIC OPTIONS Talukdar and Swaroop Vege 2011). Likewise, an early definitive surgery
approach, including prompt repair of injuries, avoiding abdominal
AND APPROACHES compartment syndrome, debridement of necrotic tissues, control of
bacterial contamination, and early fixation of fractures is associated
As a general principle, therapies directed at preventing or limiting bac- with a significant reduction in the incidence of gut-derived sepsis and
terial translocation and/or gut injury are based on an understanding MODS (Diaz et al. 2010, Cotton et al. 2011). The basic concept behind
of the host’s physiological defenses which maintain normal intestinal this approach is that immediate treatment of all treatable injuries is the
barrier function, limit stress-induced gut injury, and help maintain a best way to limit the inflammatory response and thereby restore a more
stable gut flora. Therapies also include management of pathophysiol- normal physiological state for maintenance of splanchnic perfusion.
ogy changes associated with bacterial translocation and gut barrier Similar principles apply to the non-trauma patient, for whom early
failure. Conceptually, these therapeutic approaches can be divided definitive primary or reoperative surgery to remove necrotic tissue and
into four basic groups: control infection is of major benefit in preventing the secondary failure
1. Preventive therapies of other organs including the bowel. In considering prevention, it is
2. Therapies directed at maintaining a stable gut flora, thereby limiting wise to remember that systemic inflammation and/or infection can
the risk of bacterial translocation and the development of systemic result in shunting of blood away from the gut and, thereby, increase
infections the risk of gut injury and dysfunction. Therefore prompt resolution of
3. Therapies focused on limiting the development of gut injury and inflammatory states and control of infections will reduce the likelihood
dysfunction, thereby supporting gut barrier function and hence of secondary changes in gut function including ileus, disruption of the
reducing the incidence of gut-origin sepsis and MODS normal gut flora, and increased intestinal permeability.
268 MICROBIAL TRANSLOCATION, GUT ORIGIN SEPSIS, PROBIOTICS, PREBIOTICS, SELECTIVE GUT DECONTAMINATION

■ Therapies directed at maintaining have been shown experimentally to decrease intestinal hyperperme-
ability and modulate immunity, the mechanisms by which this occurs
a stable gut flora are less clear (Walker 2008).
Similar to probiotics, prebiotics can also have gut-beneficial effects,
Probiotics, prebiotics, and synbiotics especially in the presence of probiotics. Intraluminal intestinal fer-
Probiotics are food supplements containing viable bacteria, and mentation of prebiotics by probiotics serves both to support probiotic
prebiotics are food supplements consisting of non-digestible fibers, growth and to provide colonocyte nutrient sources, such as omega-3
whereas synbiotics are the combination of probiotics and prebiotics. fatty acids (Bengmark 1999). Therefore most clinical studies have used
Both probiotics and prebiotics are distinguished by their ability to synbiotic combinations of probiotics and prebiotics. Furthermore, as
exert beneficial effects on the host (Table 24.5). Over the last decade, certain probiotic strains are able to act synergistically (Timmerman et
the use of these agents as adjuncts to more traditional therapies has al. 2004), most current clinical trials use a combination of probiotics
emerged and there is a growing body of data to suggest their usefulness and prebiotics to optimize the therapeutic potential.
in the treatment of both acute and chronic illnesses. The clinical use of probiotics and synbiotics is a relatively recent
The rationale for the development and use of probiotics was based event with the first prospective randomized clinical trial (PRCT) test-
on the following four major lines of evidence: 1) that many postopera- ing the ability of synbiotics to decrease infections being published in
tive infections are caused by the patient’s own gut flora, 2) basic and 2002 (Rayes et al. 2002). In this German study of patients undergoing
clinical therapeutic strategies directed at maintaining a normal gut major abdominal surgery, the patients receiving synbiotics had a 10%
flora reduces bacterial translocation and systemic infections, 3) studies versus a 30% postoperative infection rate in the control group. Since
demonstrating that enteral nutrition and selective gut decontamina- this pioneering clinical trial, PRCTs of probiotics/synbiotics have
tion are associated with a decreased incidence of infection and 4) been carried out, largely in four major patient populations. These are
experimental studies indicating that certain members of the normal patients undergoing major abdominal operations, patients with severe
gut flora, such as probiotic lactobacilli, limit experimentally-induced acute pancreatitis, patients undergoing liver transplantation, and
bacterial translocation and are gut-protective (Ruan et al. 2007). This mechanically ventilated patients in the ICU. The rationale for studying
ability of probiotics to limit bacterial translocation is due to influences these four patient populations is their documented increased risk of
upon all three pathogenic mechanisms associated with bacterial trans- bacterial translocation and sepsis originating from the gut. The largest
location; which include preventing/limiting intestinal bacterial growth number of studies were performed in patients undergoing elective
with potentially pathogenic bacteria, loss of gut barrier function and major abdominal procedures and a meta-analysis of these studies
impaired immunity (Box 24.5), e.g., probiotics stabilize the gut flora was published in 2009 (Pitsouni et al. 2009). This meta-analysis of
by preventing intestinal overgrowth with potential pathogenic bacteria nine clinical studies documented that the perioperative administra-
through their direct antimicrobial effects (i.e., lactic acid production) tion of probiotics and/or synbiotics reduced the overall postoperative
as well as by competitive growth (Servin 2004). Although probiotics infection rate by more than 50% and significantly decreased length of
stay, although there was no mortality advantage. This failure to show a
mortality benefit is not surprising, because the mortality rate of these
studies was low and averaged about 3% (Pitsouni et al. 2009). In spite
Box 24.5 Probiotics, prebiotics, and synbiotics. of the overall benefits observed in this meta-analysis, two of the nine
studies did not find a reduction in the incidence of postoperative
1. Definitions infections due to the heterogeneity in the types of probiotics used as
⦁ Probiotics: food supplements containing live bacteria that well as the exact probiotic/synbiotic treatment regimen employed.
theoretically have beneficial effects on the host. These are Consistent with this 2009 meta-analysis, an earlier review of 14 stud-
commercially available viable microorganisms which, when ies documented that, in most of the studies, perioperative probiotic/
administered in adequate amounts, either as individual strains synbiotic therapy reduced the incidence of postoperative infections
or in various combinations have health benefits for the host. (van Santvoort et al. 2008). However, four of the five studies that failed
⦁ Prebiotics: Non-digestable, non-absorbable, non-ferment- to show clinical benefit were from the same group with unique regi-
able orally delivered fibers(sugars) that stimulate the growth mens, further stressing the concept that not all probiotics/synbiotics
or activity of certain bacteria of the gastrointestinal tract, to are clinically equivalent. Thus further work needs to be done to better
the benefit of the host. define optimal clinical probiotic, prebiotic, and synbiotic regimens.
⦁ Synbiotics: food supplements containing both probiotics However, most of the studies carried out since 2005 used a synbiotic
and prebiotics. regimen consisting of four different lactic acid bacteria and four pre-
2. Biology biotics (Symbiotic).
⦁ Probiotics: The second largest group of PRCT studies was carried out in me-
− stabilize gut flora by maintaining non-pathogenic bacteria chanically ventilated ICU patients, with the first study being published
− stabilize intestinal barrier by blocking adhesion sites for in 2006. A meta-analysis of these PRCT trials was published in 2010
pathogenic bacteria testing whether probiotics/synbiotics decreased the incidence of
⦁ enhances immune system ventilator-associated pneumonia (VAP). This study found that the
⦁ Prebiotics probiotic-treated patients had 40% less VAP than the control group
− act as “nutrient source” for probiotics and other beneficial (Siempos et al. 2010). This decreased incidence of VAP was associated
intestinal bacteria with a decreased length of stay but not an improvement in mortality.
− when fermented by probiotics provide a colonocyte food In most of these studies, Synbiotic 2000 FORTE, consisting of five
source bacterial species and four prebiotics, was used. In the same year
− encourage growth of non-pathogenic bacteria while that this meta-analysis was published, a French group published
inhibiting growth of pathogenic bacteria a single-center PRCT trial designed to assess whether probiotic/
 Therapeutic options and approaches 269

synbiotic therapy improved survival in mechanically ventilated ICU

patients (Barraud et al. 2010). They used a commercial multi-bacterial Box 24.6 List of commercial probiotics/synbiotics.
product called 5 Ergyphilus. Although they found no difference in
overall mortality between the groups, a subgroup analysis found 1. Single strains
that the administration of probiotics improved survival in patients ⦁ Lactobacillus plantarum 299V (Rayes et al. 2002, van Sant-
with severe sepsis. However, of concern, this therapy increased the voort et al. 2008, Pitsouni et al. 2009, Siempos et al. 2010)
mortality rate of patients with non-severe sepsis. The explanation ⦁ Lactobacillus casei rhamnosus (Siempos et al. 2010)
for the differential effects of synbiotic therapy on mortality between 2. Commercial prebiotic/synbiotic formulations
the severely septic patients versus patients with non-severe sepsis is ⦁ Symbiotic 2000 Forte (Rayes et al. 2005, van Santvoort et al.
unclear. It does, however, stress the need for more and larger studies 2008, Pitsouni et al. 2009, Siempos et al. 2010)
in ICU patient populations. ⦁ Symbiotic 2000 (van Santvoort et al. 2008, Pitsouni et al. 2009)
Although the data are more limited, most of studies testing the ⦁ Trevis (van Santvoort et al. 2008, Pitsouni et al. 2009)
ability of probiotics/synbiotics to reduce infections in patients with ⦁ Yakult BL Seichoyaku (van Santvoort et al. 2008, Pitsouni
severe acute pancreatitis, as well as in patients undergoing liver trans- et al. 2009)
plantation, have shown efficacy (Oláh et al. 2002, Rayes et al. 2005). The ⦁ Yakult 400 (van Santvoort et al. 2008, Pitsouni et al. 2009)
important exception is a study by Basselink et al. (2008). In this study ⦁ Bifies (van Santvoort et al. 2008)
of severe acute pancreatitis, termed “PROPATRIA,” patients treated ⦁ 5-Ergyphilus (Barraud et al. 2010)
with the probiotic Ecologic 641 had increased infectious complica- ⦁ Ecologic 641 (Besselink et al. 2008)
tions and a higher mortality. The explanation for these conflicting 3. Commercial prebiotic formulations
results remains to be resolved. However, in a subsequent subgroup ⦁ Oligomate 55 (van Santvoort et al. 2008, Pitsouni et al. 2009)
analysis of the patients enrolled in the PROPATRIA study, the adverse ⦁ Raftilose (van Santvoort et al. 2008)
effects of the probiotic therapy were largely confined to the group of A recent Google search of the term probiotic has revealed that
patients who had early organ failure (Besselink et al. 2009). From this there are upwards of 1000 probiotic formulas that are commercially
observation, they (Besselink et al. 2009) and others (Soeters 2008) have available. Commercial probiotic formulations are not regulated by
proposed that probiotics may result in adverse consequences when the US Food and Drug Administration, and, as such, not all may
administered into compromised GI tracts with increased permeability be equally effective. Above is a list of the probiotic formulations/
and compromised oxygen delivery. strains used in prospective randomized clinical trials mentioned
Although the Basselink acute pancreatitis study (Besselink et al. in this chapter.
2008) raises concern, the meta-analyses and most of the PRCTs us-
ing probiotics show clinical benefit. However, it is difficult to directly
compare the individual trials because both the probiotic agent and
dosage used vary from trial to trial. Yet, based on findings from studies in reducing infections and shortening length of hospital stay, they ap-
of the basic biology of the probiotics, differences in the exact probiotic pear to be a worthwhile clinical tool. Lastly, in thinking about the use
bacteria administered between the different clinical trials may be of of probiotics, prebiotics, and synbiotics, we believe that the timing of
significant potential clinical importance, e.g., to have a beneficial ef- their administration may be critical, e.g., the prophylactic administra-
fect, the probiotic administered must adhere to the intestinal epithe- tion of these agents electively before major operations seems to have
lium via the same receptor as the target pathogenic bacteria. In this been a uniformly beneficial strategy. This may be because gut barrier
fashion, the probiotic bacteria can prevent pathogenic attachment or function is intact and the patient’s gut flora has been at most modestly
even displace attached pathogenic bacteria. This point is highlighted perturbed. In contrast, administering probiotic bacteria at high doses
by the work of Collado et al. (2005), who demonstrated that the ability to patients with established gut injury and increased permeability may
of different probiotic bacteria to prevent pathogenic intestinal bacterial result in these low virulence bacteria translocating across the injured
binding as well as displace previously bound pathogenic bacteria to mucosa, thereby contributing to increased systemic inflammation and
human intestinal epithelium varied based on the potentially patho- altered immune defenses. Hopefully, as more information becomes
genic bacteria. Thus, if the specific pathogenic bacterium is known, available, these types of questions can be answered.
the most appropriate probiotic can be selected that optimally inhibits
future adherence and displaces adhered pathogens. Consequently,
as different probiotics may differentially occupy specific intestinal
■ Selective digestive tract
epithelial cell receptors, the inhibition of pathogen adhesion is highly decontamination
variable and strain dependent. The use of oral non-absorbable prophylactic antibiotic administration
Which probiotic/synbiotic formulation is best for which clinical is another therapeutic approach employed to prevent intestinal colo-
situation is currently the most important clinical question to be an- nization or overgrowth with potentially pathological bacteria. The first
swered. Not only must the question of which species or combinations clinical study of selective decontamination of the digestive tract (SDD)
of species to use in specific clinical scenarios be addressed, but also it was published by Stoutenbeck et al. in 1984, where this technique
would be important to better define the optimal doses of these agents was found to reduce the infection rate in a cohort of trauma patients.
as well as the best methods and vehicles for their delivery. Current Since then, the clinical efficacy of SDD has been tested in multiple
commercial prebiotic, probiotic, and synbiotic products are attempt- different patient populations. The current technique of SDD has three
ing to address this notion that different prebiotic fibers and probiotic parts and was designed primarily to selectively suppress and eradicate
bacteria may exert different effects and/or interact synergistically by potentially pathogenic Gram-negative aerobic bacteria and fungi in
producing products that contain multiple different probiotics and the oropharynx and upper and lower intestines (Box 24.7). The three
prebiotics (Box 24.6). Nevertheless, based on the high safety profile of basic concepts on which SDD is based are that (1) nosocomial infec-
these products and evidence from most studies that they are effective tions are a common problem in the ICU, (2) these infections directly
270 MICROBIAL TRANSLOCATION, GUT ORIGIN SEPSIS, PROBIOTICS, PREBIOTICS, SELECTIVE GUT DECONTAMINATION

contribute to mortality, and (3) most of these infections are caused by

Box 24.7 Prophylactic antibiotic decontamination regimens. bacteria and fungi that have colonized the oropharynx, stomach, and
Three different regimens have been used, from most to least ag- intestine. Consequently, the goals of SDD are to decrease the coloniza-
gressive: selective digestive tract decontamination, selective gut tion rate of these high-risk patients, thereby reducing the incidence
decontamination, and selective oral decontamination. of infection and improving survival. As documented by multiple
PRCTs and summarized in meta-analyses (van Nieuwenhoven et al.
1. Selective digestive tract decontamination (SDD) 2001, Chan et al. 2007), SDD has been repeatedly shown to decrease
⦁ Targets oral pathogens, intestinal pathogens, and respira- the absolute rate of infections in multiple ICU patient populations
tory tract flora ranging from trauma patients to postoperative patients. Although the
⦁ Goal of therapy: non-absorbable antimicrobial oral/intes- absolute reduction in infection rates has varied from series to series,
tinal therapies targeting Gram-negative organisms, Staphy- on average the incidence of pneumonias, urinary tract infections, and
lococcus aureus, and yeasts to prevent infection after gut primary bacteremias has been reduced by 50% or more. Although
barrier failure plus systemic antimicrobial therapy targeting most of the early studies were not able to consistently document
respiratory flora-mediated pneumonias a survival advantage with SDD, selected single-center prospective
⦁ Regimen: 4 days of intravenous cefotaxime (1000  mg ev- trials, as well as new, recent meta-analyses, have documented that
ery 6 h); application of topical paste to the oral cavity and SDD significantly reduces mortality in medical, surgical, and trauma
pharynx (polymyxin E, tobramycin, and amphotericin B, ICU patients (D’Amico et al. 1998, Nathens and Marshall 1999, van
each at a concentration of 2%), and gastric lavage every 6 h Nieuwenhoven et al. 2001, Krueger et al. 2002, de Jonge et al. 2003,
with an antibiotic solution (10 ml of a suspension of 100 mg Stoutenbeek et al. 2006, Dellinger et al. 2008, de Smet et al. 2009).
polymyxin E, 80 mg tobramycin, and 500 mg amphotericin B) Although the reduction in mortality observed with SDD has varied
⦁ Benefits: 40–50% reduction in the rate of nosocomial infec- between studies, most studies have shown an absolute reduction in
tion and a lesser reduction (3.5%) in mortality mortality rate of >3–4%, which translates into an overall reduction in
⦁ Perceived detriments (to date unproven): Increased risk of mortality of approximately 11%.
development of resistant organism pneumonia. Increased As a result of the risk of antibiotic resistance, several studies have
threat of Clostridium difficile colitis. used a selective oral decontamination (SOD) approach rather than
2. Selective gut decontamination (SGD) SDD as an alternative to the prevention of VAP (Pugin et al. 1991, Berg-
⦁ Provides total decontamination of oral cavity and gastroin- mans et al. 2001). The advantage of SOD is that no systemic antibiotics
testinal tract without systemic antibiotic therapy are given and the need for oral antibiotics is reduced (Box 24.7). This
⦁ Goal of therapy: Non-absorbable antimicrobial oral/ approach is based on the key role of oropharyngeal colonization in the
intestinal therapies targeting Gram-negative organisms, pathogenesis of VAP and evidence that SOD is effective in preventing
S. aureus, and yeasts to prevent infection after gut barrier VAP (Bonten et al. 2004, Chan et al. 2007). The efficacy of SOD versus
failure. Maintenance of normal gut flora through avoidance SDD in preventing VAP and improving mortality was recently tested
of anti-aerobic antibiotics in a multicenter clinical trial enrolling 5939 patients (de Smet et al.
⦁ Regimen: Application of topical paste to the oral cavity and 2009). The results of this study showed that the two therapeutic ap-
pharynx (polymyxin E, tobramycin, and amphotericin B, proaches were comparable with SDD reducing 28-day mortality by
each at a concentration of 2%), and gastric lavage every 6 h 3.5% and SOD reducing mortality by 2.9%. Thus, the use of SDD or SOD
with an antibiotic solution (10 ml of a suspension of 100 mg to control oropharyngeal and intestinal colonization with potentially
polymyxin E, 80 mg tobramycin, and 500 mg amphotericin B) pathogenic bacteria appears a viable therapeutic option.
⦁ Benefits: Reduction in the rate of hospital-acquired infec-
tion and a decrease in mortality greater than that of SOD but
less than that of SDD (3%). Risk of development of resistant
■ Therapies direct at supporting
organism pneumonias is theoretically decreased gut barrier function
⦁ Perceived detriments (to date unproven): Increased threat As previously discussed, gut barrier failure and increased intestinal
of C. difficile colitis. permeability have been found to be relatively common in critically
3. Selective oral decontamination (SOD) ill patients, major injury and major surgery, in several clinical stud-
⦁ Provides decontamination of the oral cavity only. Thought to ies, have been found to be associated with increased morbidity and
prevent contamination of endotracheal tube colonization- mortality (Pape et al. 1994, Reintam et al. 2006). Consequently, sig-
mediated pneumonia and aspiration pneumonia. nificant investigative effort has been directed toward understanding
⦁ Goal of therapy: Non-absorbable antimicrobial oral therapy the mechanisms leading to gut injury, to develop effective therapies
targeting Gram-negative organisms, S. aureus, and yeasts to to prevent and/or limit gut barrier failure and restore the failed gut
prevent secondary infections barrier. To date, the most effective therapies involve various nutritional
⦁ Regimen: (1) Application of topical paste to the oral cavity and and gut-barrier-enhancing strategies; one of the most important con-
pharynx (polymyxin E, tobramycin, and amphotericin B, each cepts is that the gut has specific nutritional needs distinct from the rest
at a concentration of 2%) or (2) chlorhexidine gluconate (0.12% of the body. Importantly, the lack of enteral feeding itself can result in
oral rinse, 0.2% oral rinse, or 2% oral gel) applied every 8 h impaired gut barrier function (Gatt and MacFie 2010). This concept is
⦁ Benefits: Reduction in the rate of systemic infection from based on both clinical and preclinical studies documenting that lack
ventilator-associated pneumonia and aspiration pneumonia. of enteral feeding (starvation), as well as standard total parenteral
No risk of C. difficile colitis; no risk of generating a multidrug- nutrition (TPN), leads to gut atrophy as well as major changes in gut
resistant pneumonia from prophylaxis function (Figure 24.4). The direct benefits of enteral as opposed to
⦁ Detriments: Reduction in mortality less than that of regimens parenteral nutrition in reducing infection was first reported by Moore
in which systemic or gastrointestinal tract decontamination et al. (1989), who demonstrated that abdominal trauma patients
occurs randomized to the total enteral nutrition group had a reduced rate of
 Therapeutic options and approaches 271

Morphologic • Villous atrophy Figure 24.4 Schematic illustration of the effects

Biochemical • Decreased mucosal protein, DNA, or RNA of total parenteral nutrition on the gut and the
Immunological • Decreased secretory IgA production gut flora as well as representative illustrations
TPN • Decreased cellular immunity of the profound atrophy of the gut which occurs
• Increased level of gram-neg. enteric bacilli after even 5 days of starvation. (a) Normal gut. (b)
Intestinal flora • Increased intestinal permeability Following TPN administration
Barrier function • Bacterial translocation

a b

infection (37% vs 17%) and septic morbidity (3% vs 20%), compared indicate that either parenteral or enteral glutamine supplementation
with patients receiving TPN. Since then, many studies, in multiple is clinically beneficial (Avenell 2006, 2009). Similar to the studies with
patient populations, have validated the clinical benefits of early enteral glutamine, recent work has shown that the administration of enteral
feeding, e.g., one recent meta-analysis of 30 PRCTs comparing enteral diets high in omega-3 fatty acids (fish and borage oils) rather than
with parenteral nutrition in hospitalized patients found that enteral omega-6 fatty acids (vegetable oil and main component in intralipid)
nutrition was associated with a significantly lower rate of infectious reduces mortality in patients with severe sepsis (Pontes-Arruda et al.
complications and a reduced length of hospital stay (Peter et al. 2005). 2006). In fact, intravenous omega-3 fatty acids also show a survival
Furthermore, a meta-analysis of five PRCTs of enteral versus par- benefit in ICU patients (Heller et al. 2006). Although extensive pre-
enteral nutrition in patients with acute pancreatitis found that the clinical and limited clinical studies have implicated numerous other
mortality rate of the enterally fed patients was significantly reduced nutrients, vitamins, and minerals as well as prebiotic fibers as having
compared with parenterally fed patients (4% vs 16%) (Petrov et al. potential gut protective effects, too little is known to accurately assess
2008). Support for enteral nutrition in patients undergoing major their therapeutic benefits. Nevertheless, it is clear that early enteral
abdominal surgery was documented in a Cochrane review of patients feeding and the enteral and/or parenteral administration of glutamine
undergoing colon surgery, in which enteral feeds were found to sig- and omega-3 fatty acids are gut protective and clinically beneficial in
nificantly reduce mortality (Andersen et al. 2006). This reduction in high-risk surgical as well as ICU patients.
overall mortality was later confirmed in a meta-analysis (Lewis et al. A second hypothesis of why enteral nutrition appears superior to
2008). As a result of these and other such studies, early enteral nutri- parenteral is based on the concept that enteral feeding induces a num-
tion has been included in the enhanced recovery after surgery group ber of gut-supportive mechanisms, e.g., enteral feeding stimulates the
recommendations for colorectal surgery (Lassen et al. 2009). production and release of gut-derived intestinal hormones and growth
The exact reasons why enteral nutrition is superior to parenteral factors, several of which have been shown to have gut tropic properties.
nutrition in maintaining intestinal barrier function, reducing sepsis In addition, as exemplified by prebiotics, the intraluminal digestion of
originating from the gut and decreasing the incidence and/or severity fibers by the host microflora releases various nutrients, such as omega-3
of MODS in high-risk ICU patients has been extensively investigated. fatty acids which are preferred enterocyte fuels. This hypothesis has
One hypothesis is that gut barrier failure and sepsis originating from been validated in animal studies, where limited amounts of enteral
the gut may be more severe in ICU patients receiving TPN due to feeding have been documented to preserve or improve gut function and
the fact that current parenteral nutrition formulations lack bowel- morphology (Omura et al. 2000, Ohta et al. 2003, Ikezawa et al. 2008). As
specific nutrients and tropic factors (Wilmore et al. 1988). For this it is not always possible to successfully administer full enteral support in
reason, these intravenous nutrition solutions will not fully support critically ill patients, several studies have investigated whether limited
intestinal structure and function. Advances in nutrient pharmacology enteral feeding would be comparable to full enteral feeding in these
and physiology have shown that specific nutrients, such as glutamine high-risk patients. One such PRCT study by Rice et al. (2011) found
and short-chain fatty acids, as well as trace minerals and even certain that mechanically ventilated patients randomized to a 6-day course of
non-digestible fibers (prebiotics), exert beneficial tropic effects on tropic levels of enteral feeding (10 ml/h) versus full enteral feeding had
the gut. Most of the work in this area has been directed at studying similar rates of organ failure and no difference in mortality was found
glutamine, because, in addition to being an enterocyte-specific nu- between the groups. This and other studies support the concept that
trient and having important antioxidant activities, plasma glutamine even limited amounts of early enteral feeding can have gut-protective
levels rapidly drop during stress states (Avenell 2009). Although the effects which can translate into clinical benefits.
results of clinical trials testing the efficacy of glutamine are confusing, In trying to put this nutritional information into clinical perspective
due to a number of confounding factors, two recent meta-analyses it is important to consider the patient population being treated as well
272 MICROBIAL TRANSLOCATION, GUT ORIGIN SEPSIS, PROBIOTICS, PREBIOTICS, SELECTIVE GUT DECONTAMINATION

as the therapeutic goal, e.g., preoperative as well as early postoperative (Heyland et al. 2005). A subsequent PRCT of parenteral selenium
nutrition can be administered to patients undergoing elective surgery, supplementation in patients with septic shock, sepsis, and SIRS
a strategy that has been shown to reduce postoperative infectious documented a reduction in the 28-day mortality rate from 50% in
complications (Okamoto et al. 2009). However, this prophylactic the control group to 40% in the selenium group (Angstwurm et al.
perioperative approach is not possible in trauma, emergency surgery, 2007). Although additional studies are necessary to determine the
or other high-risk patient groups, such as those with severe acute effect of enteral selenium supplementation, the Society of Critical
pancreatitis. In these patient groups, therapies are initiated after the Care Medicine and the American Society for Parenteral and Enteral
disease process has become established, and thus the prevention of Nutrition recommend that selenium be specifically included as part
gut-barrier dysfunction and sepsis originating from the gut may not of an antioxidant supplementation (Martindale et al. 2009). Thus, the
be fully possible. Instead, the goal is to limit the magnitude of gut dys- role of antioxidants other than selenium remains unclear.
function and to restore gut function to normal as quickly as possible.
Intestinal barrier failure and subsequent sepsis originating from
the gut may be exacerbated by non-intestinal as well as intestinal
■ CONCLUSION
factors, such as hypotension, hemodynamic instability, or vasoac- Much has changed since the original view of the gut as a digestive
tive agents that decrease intestinal perfusion (i.e., I/R injury) and organ. Today, it is well recognized that gut failure has important
thereby increase intestinal permeability. All these systemic insults, physiological and clinical implications for many groups of surgical
as well as severe septic states, are associated with oxidant-mediated and ICU patients. Thus, beginning with studies showing that early
intestinal injury and experimental antioxidant therapies have been enteral feeding can be clinically beneficial, efforts have been made
shown to successfully reduce bacterial translocation as well as gut to bolster gut function. Several of these strategies have focused on
injury in preclinical animal studies (Deitch 1990). Consequently, maintaining a normal gut flora and limiting gut overgrowth with po-
antioxidant therapies directed at preventing or limiting oxidant- tential pathogens. In the case of probiotics and prebiotics, most early
mediated intestinal injury during stress states are a promising area studies are encouraging. Yet, more work is needed to better define the
of research. A limited number of clinical studies have examined optimal patient groups for this therapy as well as the optimal probi-
whether antioxidants added to resuscitation fluids reduce infections otic/prebiotic/synbiotic formulae to be used in these specific patient
and organ failure; the results are inconclusive. In contrast, a large populations. These gut-directed therapies are further supported by
number of PRCTs have studied antioxidants in ICU patients. As most emerging evidence that the intestinal microflora are capable of up-
of these studies focused more on the role of antioxidants as a group regulating and downregulating mammalian gene products through
rather than individual antioxidants, there are few prospective trials receptor-based cross-talk (Kinross et al. 2009, Tsujimoto et al. 2009).
evaluating the effect of individual agents. However, a meta-analysis This work highlights the potential benefits to the host of a normal gut
has suggested that parenteral antioxidant supplementation is as- flora as well as the fact that changes in the gut microflora may initiate
sociated with a significant decrease in mortality, with this benefit corresponding changes in the host’s own tissues which can modify the
being largely associated with parenteral selenium administration host’s responses to various stresses and insults.

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Chapter 25 Sepsis: systemic inflammation
and organ dysfunction
John C. Marshall

Sepsis is one of the most common and potentially treatable causes of human genome and the cellular building blocks of life are partially
morbidity and mortality for surgical patients. Sepsis claims more than microbial in origin.
200 000 North American victims a year – exceeding the annual toll of As multicellular organisms evolved, they acquired microbial
acute myocardial infarction (Angus et al. 2001) – and its prevalence populations that established residence on epithelial surfaces such
has been increasing (Martin et al. 2003). Its diagnosis and optimal as the oropharynx, gut, vagina, and skin. The gastrointestinal tract of
management remain incompletely understood by clinicians, and the healthy human is colonized by as many as 5000 distinct species of
significant advances in its treatment have proven elusive. Yet a robust bacteria, and the total number of bacterial cells is 10 times greater than
understanding of the optimal management of the septic patient is the number of human cells (Ley et al. 2006). Patterns of colonization
emerging in recent years, and strategies for improving survival are are complex, but stable over time, and strikingly similar from one per-
becoming increasingly well established. son to the next (Lee 1985). Epithelial colonization by microorganisms
plays a critical role in the normal function of that surface. The normal
■■SEPSIS: THE EVOLUTION flora of the gut plays a critical role in gut development and homeo-
stasis, promoting the expression of epithelial cell enzymes involved
OF A CONCEPT in digestion, and even the development of the microvasculature of
the intestinal villi (Xu and Gordon 2003). In the absence of a normal
Microorganisms are the most prevalent and diverse forms of life. Not gut flora, host resistance to external infectious threats is significantly
only were primitive bacteria the first living species on the planet, but impaired (Dubos and Schaedler 1960). Moreover bacterial products
viable bacteria have been found in environments that would usually such as lipopolysaccharide or endotoxin exert hormone-like effects,
be considered inimical to life – in deep sea thermal jets, in Antarctic activating innate immune cells such as neutrophils and macrophages
ice, and in rock from deep below the earth’s surface. Microbes play a for increased antimicrobial activity (Marshall 2005). Our health and
beneficial role in processes such as the breakdown of dying vegetable vitality are fundamentally dependent on our normal interactions with
matter to form soil or the fermentation of plants and fruits to yield the microbial world.
alcohol. But they are also agents of diseases that have, on occasion, At the same time, bacteria and viruses represent one of the most
wreaked havoc on human populations. The impact of this threat is ap- significant threats to our individual and collective survival. During
parent in our genome. The most highly polymorphic genes are those the Middle Ages, the bubonic plague killed a quarter of the popula-
involved in antibacterial defenses. A single organism – Plasmodium tion of Europe, and endemic infections such as tuberculosis, malaria,
sp., the cause of malaria – has been credited with the emergence and dengue, or epidemic infections such as severe acute respiratory
of many polymorphisms in the hemoglobin gene, including the syndrome (SARS) and influenza continue to exact a substantial toll.
mutations responsible for sickle cell diseases and thalassemia. An Infection is both an important cause of the diseases that surgeons treat,
understanding of the complex interactions between the microbial and and a feared complication of the procedures that we use for treatment.
human worlds is important to the understanding of the derangements As effective methods of eradicating microorganisms using anti-
that occur during sepsis. microbial agents, or of eliminating foci of invasive infection using
source control measures, have evolved, it has become apparent that
■■Host–microbial interactions the morbidity of sepsis arises from more than simply the cytopathic
consequences of sustained uncontrolled microbial proliferation.
in evolution At the same time, advances in our understanding of the biology of
Multicellular organisms have an evolutionarily ancient and biologi- host–microbial interactions have shown that the response of the host
cally complex relationship with the microbial world. Bacteria and against infection is also the vector of the illness that we have come
viruses are not simply a ubiquitous feature of our environment, they to call sepsis.
are also a fundamental part of whom we are. More than a billion
years ago, simple unicellular organisms were parasitized by primi-
tive protobacteria and, as a result, acquired the ability to generate
■■Evolving concepts of sepsis
energy. This development enabled cellular specialization and the The word “sepsis” is attributed to Hippocrates (460–370 bce) who
emergence of multicellular species. These protobacteria became believed that living tissues broke down through one of two distinct
the mitochondria of cells of the animal world and the chloroplasts processes (Majno 1991). “Sepsis” was the term used to describe tissue
of the plant world. Over time, genetic material has been transferred breakdown in a manner that was unpleasant, foul smelling, and induc-
between the mitochondrion and the host cell nucleus, and only ing of disease; examples of the Hippocratic concept of sepsis included
13 protein-coding genes remain in human mitochondrial DNA, the festering of wounds, the rotting of plants, and the vapors arising
whereas 22% of nuclear genes share a bacterial origin. Thus the from the bad air of swamps which gave rise to the word “malaria.”
276 SEPSIS: SYSTEMIC INFLAMMATION AND ORGAN DYSFUNCTION

In contrast, “pepsis” was tissue breakdown in a manner that supported to sterile tissue injury or ischemia, or other processes that result in
life and health, and was exemplified by the digestion of food (hence inflammatory mediator release, the term “systemic inflammatory
the origins of the word “peptic”) or the fermentation of grapes to pro- response syndrome” (SIRS) was coined to describe the response,
duce wine. His ideas were articulated more than two millennia before independent of its cause. The interrelationship of infection, sepsis,
the identification of microorganisms, yet are remarkably prescient in and SIRS is represented graphically in Figure 25.1. It is important
their recognition that these processes could be both beneficial and to recognize that SIRS is a concept, not a disease. The SIRS criteria
harmful to the host. have been widely criticized as being too non-specific to inform man-
Bacteria were first visualized in the seventeenth century by Antony agement decisions (Vincent 1997), yet the concept that a clinical
van Leeuwenhoek, the inventor of the microscope; however, it was syndrome of systemic inflammation, independent of cause, can be
not until the work of Louis Pasteur in the nineteenth century that the recognized marks an important advance in an evolving understanding
role of bacteria in the pathogenesis of infection was established, and of a complex biological process.
the germ theory of disease born. With this evolving model of infection
as a product of bacterial invasion, the word “sepsis” was seconded Box 25.1 Definitions of infection, sepsis, SIRS and septic shock.
to denote the process, and the words sepsis and infection were used
interchangeably, although sepsis generally denoted a more severe Infection: The invasion of normally sterile tissues by viable mi-
form of infection. Indeed as recently as 40 years ago, a major medical croorganisms
dictionary defined sepsis as “the presence of pus-forming organisms Sepsis: The maladaptive host response to infection
within the bloodstream” (Sweet and Williams 1972). By implication, Systemic inflammatory response syndrome (SIRS): The character-
the equation of infection with the clinical syndrome suggested that istic maladaptive host response, independent of cause
sepsis was a direct consequence of the proliferation of microorganisms Severe sepsis: Sepsis in association with organ dysfunction
or the release of their toxins within the host. Septic shock: Sepsis in association with an inability to provide
This model, however, proved inadequate. Although bacteria or bac- adequate oxygen delivery to tissues
terial products such as endotoxin can trigger clinical manifestations
characteristic of sepsis in both humans and experimental animals,
multiple lines of evidence over the past half century have shown that More recently, recognition that patients with sepsis represent a
the syndrome arises indirectly – through the release of inflammatory highly heterogeneous population has stimulated interest in the con-
mediators by the host – rather than through any direct toxic effects cept that more sophisticated descriptive staging systems are needed.
of the microorganism. One of the more compelling experiments that Adjuvant therapy in oncology is guided by the use of staging systems
established this concept involved studies in which endotoxin from that stratify cancers, not only on the basis of their site of origin and
Gram-negative bacteria was administered to inbred mice (Michalek histological type, but also on the degree of local and regional spread,
et al. 1980). Two otherwise genetically identical strains of mice – the and, increasingly, on the basis of expression of specific tumor markers.
C3h HeN and C3h HeJ strains – differ by a point mutation in a single By analogy to oncology, the PIRO model (predisposition, insult, re-
gene. That mutation, which developed spontaneously decades ago, sponse, organ dysfunction – Table 25.1) has been proposed as a model
resulted in differential susceptibility to bacterial endotoxin: Although that may be applicable to patients with acute illness (Levy et al. 2003).
mice of the C3h HeN parent strain became ill after endotoxin injec- The PIRO model is still a concept, and an evolving work in progress,
tion, mice of the C3h HeJ strain could tolerate otherwise lethal doses but may provide a means of resolving the enormous heterogeneity
with no apparent ill effects. When investigators created chimeric
mice by irradiating mice of each strain to eliminate their own bone
marrow, and repopulating the irradiated mice with bone marrow
of the opposite strain, it was found that susceptibility to endotoxin
could be transferred. In other words, the effects of endotoxin did not
result from a direct toxic effect of the bacterial product on the host,
but rather occurred indirectly, through products released from bone
marrow cells in response to endotoxin exposure. Trauma
This subtle shift in concept – from sepsis as a direct consequence Infection Sepsis
of bacteria to sepsis as an indirect consequence of the response of Burns
the host – has profound clinical implications which are discussed in SIRS
greater detail throughout this chapter. One of the most important is
Pancreatitis
that the host response itself is a legitimate target for intervention in
the treatment of sepsis.
Terminology has changed with this shift in scientific concept, Systemic inflammatory
although contemporary conventions still fail to fully embody the nu- response syndrome
ances of a complex biological process (Box 25.1). Infection denotes
a microbial phenomenon – the presence of viable microorganisms Figure 25.1  The conceptual interrelationship of sepsis and infection (Bone
invading normally sterile host tissues – whereas sepsis describes the et al. 1992). Infection is a microbial process – the invasion of normally sterile
response of the host to that process of microbial invasion. As a host host tissues – that evokes a response in the host that can be both protective
response is appropriate and essential for survival, the maladaptive and injurious. The response is not specific to infection, but can be elicited by
sterile inflammatory stimuli such as burns, trauma, and acute pancreatitis; it
consequences of the septic response are called severe sepsis when the
has been termed the systemic inflammatory response syndrome (SIRS). Thus
response results in organ dysfunction and septic shock when it leads sepsis is present when infection elicits SIRS (and, perhaps more accurately, an
to cardiovascular instability. Moreover, as the response of the host is injurious response characterized by organ dysfunction). It is apparent as well
not specific to an infectious etiology, but can occur also in response that infection may occur in the absence of a systemic response.
 The biology of the inflammatory response 277

Table 25.1 The PIRO (predisposition, insult, response, organ dysfunction) model (from Levy et al 2003).
Domain Present Future
Predisposition Premorbid illness with reduced probability of short term servival. Genetic polymorphisms in components of inflammatory response
Cultural or relisious beliefs, age, sex (e.g., TIR, TNF, IL-1, CD14); enhanced understanding of specific
interactions between pathogens and host diseases
Insult infection Culture and sensitivity of infecting pathogens; detection of disease Assay of microbial products (LPS, mannan, bacterial DNA); gene
amenable to source control transcript profiles
Response SIRS, other signs of sepsis, shock, CRP Nonspecific markers of activated inflammation (e.g., PCT or IL-6) or
impaired host responsiveness (e.g., HLA-DR); specific detection of
target of therapy (e.g., protein C, TNF, PAF)
Organ dysfuntion Organ dysfunction as number of failing organs or composite score Dynamic measures of cellular response to insult – apoptosis,
(e.g., MODS, SOFA, LODS, PEMOD, PELOD) cytopathic hypoxia, cell stress
CRP, C-reactive protein; IL, interleukin; LODS, Logistic Organ Dysfunction; LPS, lipopolysaccharide; MODS, multiple-organ dysfunction syndrome; PAF, platelet-activating factor; PCT,
procalcitonin; PELOD, Pediatric Logistic Organ Dysfunction; PEMOD, PEdiatric Multiple Organ Dysfunction; SIRS, systemic inflammatory response syndrome; SOFA, Sequential Organ
Failure Assessment; TIR, toll/interleukin-1 receptor; TNF, tumor necrosis factor.

of patients with acute inflammatory disorders so that more focused prevalence of sepsis difficult. Nevertheless, it is evident that sepsis
studies of appropriate therapy can be undertaken. is a leading cause of global mortality and disability, and a common
complication of a disparate group of common diseases including
■■From sepsis to organ dysfunction cancer, trauma, and cardiovascular disease.
Four of the top ten causes of death on the World Health Organiza-
The development of clinically important physiological organ system tion’s list are infectious diseases – lower respiratory tract infections,
insufficiency is the hallmark of the entity of severe sepsis; conversely, diarrheal diseases, tuberculosis, and HIV/AIDS – and infection is a
organ dysfunction in the acutely ill patient invariably follows a clinical common morbid complication of others including trauma, prema-
insult characterized by inflammation and tissue injury. The cardinal turity, and stroke. Thus it is reasonable to conclude that sepsis is one
signs of local inflammation described by Galen and Celsus two mil- of the leading, if not the leading, causes of death.
lennia in the past have their counterpart in the systemic inflammatory Estimates of its incidence derive from large population-based stud-
disorder that is so common in the contemporary intensive care unit ies using administrative data. Martin and colleagues estimated the
(ICU): Organ dysfunction – functio laesa – is one of the core elements. incidence of sepsis in the USA to be 240 cases per 100 000, a threefold
The process has come to be one of the defining syndromes, and has increase over two decades (Figure 25.2). Rates were significantly higher
been given many names – multiple organ failure, remote organ dys- in men than women, and in non-white than in white individuals (Mar-
function, or, addressing specific affected systems, acute respiratory tin et al. 2003). Using a different methodological approach, Angus and
distress syndrome (ARDS), acute kidney injury (AKI), or disseminated co-workers came up with the surprisingly similar estimate that there are
intravascular coagulation (DIC). Most prefer the designation the approximately 750 000 cases of severe sepsis annually in the USA, and
multiple organ dysfunction syndrome (MODS), to underline the fact that more than 200 000 deaths a year are attributable to sepsis (Angus
that the process is a systemic one, of variable severity, and potentially et al. 2001). Similar estimates have been derived from studies from
reversible (Bone et al. 1992). Unlike the local impairment of func- Europe (Brun-Buisson et al. 2004) and Australia (Finfer et al. 2004a).
tion that accompanies local inflammation (impaired mobility of an Although the incidence of sepsis is increasing, its mortality ap-
acutely arthritic joint, for example), the MODS is largely an iatrogenic pears to be on the decline. Data from the Surviving Sepsis Campaign
byproduct of the successes of intensive care (Marshall 2010). The based on more than 15  000 patients around the world reveal an
early evolution of ARDS, for example, reflects the leakage of resuscita- overall in-hospital mortality rate of 31% (Levy et al. 2010), and data
tion fluids into the lung parenchyma because of increased capillary from recent randomized controlled trials of novel therapies suggest a
permeability, and becomes clinically manifest only because patients contemporary 28-day mortality rate of approximately 25%, compared
are kept alive through the intervention of intubation and mechanical with a mortality rate of ³40% in the 1990s. The extent to which these
ventilation. Its further evolution is at least in part shaped by further changes reflect improvements in care or differences in case ascertain-
injury to the inflamed lung resulting from the effects of positive pres- ment is not known.
sure mechanical ventilation. From a surgical perspective, sepsis and MODS arise in two discrete
An inability to maintain oxygenation of the blood, perfusion of the contexts. First they may be a manifestation of a community-acquired
tissues, or removal of by products of metabolism is rapidly lethal. As illness such as peritonitis secondary to perforated diverticulitis or an
a consequence, organ dysfunction is both the final pathway to death acute necrotizing soft-tissue infection. Second, they may develop as
during sepsis and systemic inflammation, and the raison d’être of the a complication of an elective or emergency surgical procedure; in the
contemporary ICU. latter case, new-onset organ dysfunction is often the initial harbinger
of a clinically occult complication.
■■EPIDEMIOLOGY OF SEPSIS,
SIRS, AND MODS ■■THE BIOLOGY OF THE
INFLAMMATORY RESPONSE
Unlike cancer, sepsis lacks a defined pathological phenotype and, un-
like heart disease or stroke, there is no single characteristic anatomic The biological response to infection of injury is enormously complex,
abnormality. These vagaries of description render estimates of the having evolved over the course of half a billion years as multicellular
278 SEPSIS: SYSTEMIC INFLAMMATION AND ORGAN DYSFUNCTION

Figure 25.2  The epidemiology of sepsis in the

USA (Martin et al. 2003). Rates of sepsis tripled
300 Men over the last two decades of the twentieth century;
Women men were consistently more likely to be affected
than women.
Population-adjusted incidence of sepsis

200
(no./100,000)

100

0
1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001

organisms emerged. The immune system is conveniently, though TLRs in humans comprise a family of 11 structurally similar pro-
imperfectly, stratified into the innate immune system and the adaptive teins that are expressed as transmembrane receptors. Their name
immune system. Innate mechanisms are those that are encoded in the derives from their similarity to toll – a fruit fly gene that was originally
germline and can be rapidly mobilized in response to a threat. The identified as necessary for dorsoventral patterning during embryonic
innate immune system is potent but non-specific, and so bystander development (this role was considered to be very cool by the German
injury is a consequence of its activation. Its cellular elements include scientists who found the gene, so they called it toll – the German word
neutrophils, monocytes, and macrophages. The adaptive immune for ‘neat’ or ‘cool’). Individual TLRs bind specific DAMPs (Box 25.2),
system develops in response to exposure to a specific antigen; its providing a measure of specificity to the response, although the sub-
responses are highly specific, but dependent on prior exposure. Its sequent signaling cascades evoke similar gene expression patterns.
cellular elements include lymphocytes and dendritic cells. The two TLR4 is the receptor for endotoxin, but also for a variety of host-derived
arms of the immune system interact at multiple levels, and so the DAMPs, whereas TLR2 binds products of Gram-positive bacteria, and
distinction is somewhat arbitrary. Our primary focus here will be the TLR3, -7, and -8 recognize molecular patterns characteristic of viruses.
innate immune system, both because it provides an immediate and
potent response to an acute threat and because its activation contrib-
utes to the organ injury of MODS. Box 25.2 Toll-like receptors (TLRs) and their ligands.

■■Recognition of danger TLR1: Triacyl lipopeptides

TLR2: Lipoteichoic acid, bacterial lipoprotein, heat-specific pro-
The primary role of the innate immune system is the recognition tein HSP70
of danger, and the expression of an immediate response to that TLR3: Double-stranded RNA
danger. The recognition of danger in the environment of the cell is TLR4: Endotoxin, elastase, heparan, HSP60, oxidized phospho-
accomplished through the activation of cell surface proteins that are lipids
collectively known as pattern recognition receptors (PRRs). At least TLR5: Flagellin
four classes of such receptors exist – the toll-like receptors (TLRs), the TLR6: Mycoplasma lipopeptide
NOD (nucleotide oligomerization domain)-like receptors (NLRs), the TLR7: Imiquod, single-stranded RNA
retinoic acid-inducible gene I (RIG) receptors, and the C-type lectin TLR8: Viral DNA, single-stranded RNA
receptors. Each recognizes conserved patterns that communicate TLR9: Bacterial DNA CpG motifs
potential danger, and are collectively known as danger-associated
molecular patterns, or DAMPs. DAMPs include viruses, bacterial
products such as endotoxins, and bacterial proteins such as flagel-
lin, but also include an array of substances normally found within
■■Modulation of gene expression
the cell, the presence of which in the extracellular environment after receptor engagement
indicates local cell damage; these include oxidized phospholipids, The engagement of a TLR results in receptor clustering, and attracts
heat shock proteins (HSPs), uric acid, and elastase. The binding of a series of adapter molecules to the intracellular tail of the receptor
a DAMP results in the association of an array of signaling proteins (Figure 25.3). These protein–protein interactions are facilitated by
to the receptor, leading to the expression of inflammatory gene enzymes that add a phosphate group (kinases) or remove a phos-
products. We focus here on the biology of the best characterized of phate group (phosphatases) to the amino acids tyrosine, serine, and
these, the TLRs. threonine in the adapter proteins. This process of protein–protein
 The biology of the inflammatory response 279

Apoptosis occurs through the activity of a family of enzymes called

caspases which cleave target proteins at specific peptide sequences
Ligand adjacent to an aspartic acid residue. The result is the degradation of
Receptor an intact cell into membrane-bound vesicles that are phagocytosed by
macrophages, and so fail to evoke an inflammatory response.
Depending on the cell population evaluated, apoptosis can be
Adapter molecules shown to be both excessive and impaired in sepsis. Increased apop-
+ PO4 A tosis of lymphocytes contributes to the characteristic lymphopenia,
kinase and prevention of this in animal models results in improved survival.
Intestinal epithelial cell apoptosis is also increased after multiple
B trauma and sepsis. On the other hand, neutrophils are constitutively
apoptotic cells that normally survive only hours in the circulation. In
– PO4 trauma and sepsis, inflammatory stimuli activate survival pathways
C Phosphatase within the neutrophil which enables longer survival in an activated
state.

■■Early mediators of inflammation

X

Figure 25.3  Signal transduction after engagement of a receptor. Gene

Prominent among the genes whose expression is initially induced
transcription in response to a stimulus from the extracellular environment
occurs through a process called signal transduction. The engagement of a after activation of PPR are interleukin-1 IL-1) and tumor necrosis
cell surface receptor by its ligand results in receptor clustering, and in the factor (TNF), two key proinflammatory cytokines. Each exerts varied
recruitment of adapter proteins to the intracellular tail of the receptor. This and sometimes overlapping effects, but the importance of both is
process, in turn, results in recruitment of additional intracellular proteins, and underlined by the fact that their manipulation in a variety of animal
the activation of transcription factors – proteins that pass into the nucleus models has striking effects on subsequent mortality.
of the cell and regulate gene expression. These protein–protein interactions
IL-1 is produced by a variety of cells, particularly monocytes
depend on transient changes in protein structure, one of the most common
being phosphorylation of an amino acid (typically tyrosine, serine, or and macrophages. Signaling through PRR leads to activation of an
threonine) using a phosphate group derived from ATP. An enzyme that adds intracellular signaling complex called the inflammasome, which is
a phosphate group to its target protein is called a kinase, whereas one that necessary for the activation of IL-1. Once released from the cell, IL-1
removes a phosphate group is known as a phosphatase. exerts a variety of activities, acting on the hypothalamus to increase
core temperature, on lymphocytes to promote their activation, and
on neutrophils to prolong their survival by inhibition of apoptosis.
interaction enables a signal to be transferred from the cell membrane IL-1 is actually a member of a family of related proteins, including
to the interior of the cell, ultimately activating transcription factors IL-1 variants, IL-18, and IL-33. One of these – the IL-1 receptor an-
such as NF-kB which, on activation, are able to translocate from the tagonist (IL-1Ra) – is also synthesized in response to the same stimuli
cytoplasm into the nucleus. Within the nucleus they bind the promoter that trigger IL-1 release. IL-1Ra binds to the IL-1 receptor on target
region of target genes, stimulating or suppressing the transcription of cells, but this binding does not result in intracellular signaling, so
genes, the expression of which is altered during inflammation. Studies IL-1Ra serves as a competitive antagonist of IL-1 activity. Intrigu-
in healthy volunteers given a single bolus of endotoxin have revealed ingly, the IL-1 receptor is a member of the TLR family, although IL-1
that the transcription of >3700 genes is influenced by this single signal activation from its precursor form requires the activity of caspase-1,
(Calvano et al. 2005). an enzyme initially identified in apoptosis. Increased understand-
ing has made it clear that apparently disparate processes such as
■■Apoptosis in sepsis and inflammation, anti-inflammation, coagulation, and cell death are
intimately interrelated.
systemic inflammation TNF is synthesized as a protein that is expressed on the cell mem-
Apoptosis, or programmed cell death, is a physiological mode of brane, and released into the cellular environment when it is cleaved
cell death that enables the body to remove cells without evoking by TNF-converting enzyme. TNF interacts with cells through the
an inflammatory response. It plays a fundamental role in normal CD95 family of death receptors, the engagement of which can result
growth and development, facilitating, for example, the deletion of in apoptosis. Binding of TNF to its receptor can paradoxically cause
cells in the web space of the palm to create fingers, or enabling the either cell activation and new gene expression or apoptosis, depending
turnover of cells such as blood or epithelial cells. Apoptosis plays on other associated cell signals. With inflammation, the role of TNF
a role as well in the controlled removal of transformed or virally in activating gene transcription predominates; however, it was first
infected cells. Both excessive and inadequate apoptosis can play a identified as a protein that could kill tumor cells. The TNF receptor
role in the pathogenesis of disease. AIDS and Clostridium difficile can also be cleaved from the cell surface and binds circulating TNF.
colitis are examples of illnesses caused by excessive apoptosis of The list of inflammatory mediators that are activated and released
CD4+ lymphocytes and colonic epithelial cells, respectively. Im- after engagement of a pattern recognition receptor is long, and
paired apoptosis contributes to the pathogenesis of cancer and to includes a variety of protein cytokines (e.g., IL-6, IL-8, IL-10, and
keloid formation. macrophage migration inhibitory factor [MIF]) as well as lipid me-
Apoptosis is a complex and tightly regulated process. It can be diators such as prostaglandins, leukotrienes, and platelet-activating
initiated in response to both extracellular stimuli that result in ligation factor (PAF). How these interact to create the phenotype of systemic
of cell death receptors of the Fas or CD95 family, and stimuli such as inflammation is poorly understood, but several important features
ionizing radiation that produce increased mitochondrial permeability. are well recognized.
280 SEPSIS: SYSTEMIC INFLAMMATION AND ORGAN DYSFUNCTION

■■Late mediators of inflammation

The initial activation of innate immune cells results in the release
of a number of early mediators that act on target cells to enhance 80%
or modify the resulting response. A coherent grand scheme of this • Reduced resistance
process has yet to be articulated; however, it is instructive to consider • Increased permeability
a few key processes. • Tissue edema
Inducible nitric oxide synthase (iNOS) is a gene expressed in a va- • Increased diffusion distance
• Increased rate of transit
riety of cells, in particular endothelial cells; the enzyme NOS catalyzes • Shunts
the conversion of the amino acid citrulline to the amino acid arginine,
and in the process releases nitric oxide (NO). NO is a short-lived but
potent inhibitor of vascular smooth muscle contraction. Its release
100%
results in vasodilation, a property that underlies the therapeutic use
of NO donors such as nitroglycerin, nitrates, and sodium nitroprus-
side. Local release of NO results in locally increased blood flow – the
rubor of a local inflammatory response. A disseminated increase in
NO release secondary to upregulation of the activity of iNOS produces Figure 25.4  Vascular alterations in sepsis. Resuscitated sepsis is typically
the systemic vasodilatory state characteristic of sepsis. characterized by mixed venous oxygen saturation levels that are higher than
Inflammatory stimuli can also trigger the expression of tissue factor the normal value of 70%. Multiple factors contribute to this. Reduced resistance
on the surface of innate immune cells or endothelium; tissue factor results in higher rates of flow, providing less time for oxygen to diffuse from red
cells in the microvasculature. Increased capillary permeability results in tissue
interacts with factor VIIa, resulting in the activation of factor X and
edema, increasing the distance that oxygen must diffuse, and so reducing the
leading to local coagulation. Local induction of coagulation is respon- gradient. Moreover shunting through the microvasculature leads to stasis in
sible for the formation of the fibrin capsule that encloses an abscess, or some capillaries and very rapid flow in others.
for the adhesions that follow peritoneal injury. Intravascular activation
of coagulation results in DIC.
A variety of early inflammatory mediators, including both IL-1 function, and even by increasing transcellular fluid flow. The
and TNF, acting on neutrophils can activate survival pathways, avoid combination of reduced small vessel resistance and increased
apoptosis, and permit survival in an activated state – a process that permeability results in an extracellular redistribution of the normal
prolongs neutrophil antibacterial activity, but also contributes to intravascular fluids, and a relative reduction in the functional intra-
the bystander injury that accompanies neutrophil activation; it is an vascular volume. This reduction results in a fall in blood pressure,
important factor in the early pathogenesis of the ARDS. a reflex increase in heart rate, and hypoperfusion or shock. As fluid
Other late-acting mediators of inflammation include IL-10, which resuscitation proceeds, these two physiological derangements cre-
exerts anti-inflammatory activity, and transforming growth factor β ate the characteristic features of resuscitated sepsis, in particular
(TGF-β), which plays an important role in fibrosis and tissue repair. the elevated mixed venous oxygen saturation seen in septic shock.
High mobility group box 1 (HMGB1) is another late-released proin- The diffusion of oxygen from the red blood cell to cells in the mi-
flammatory mediator that exerts its activities, in part, by binding and croenvironment of the capillary bed is a passive process, driven by the
activating TLR4, thus prolonging the expression of an inflammatory concentration difference between oxygen in the red cell and oxygen in
response. the tissues. In health, the saturation of oxygen in the red cells leaving
the lung is 100%. As the cells traverse through the microcirculation,
■■THE CLINICAL PHENOTYPE OF THE approximately 25–30% of that oxygen diffuses from the red cell into
the adjacent tissues, so that the oxygen saturation of venous blood
INFLAMMATORY RESPONSE returning to the heart (denoted SVO2) is about 70%. In hypovolemic
shock, or early during unresuscitated septic shock, the SVO2 is lower,
Activation of the cellular and biochemical processes above as part reflecting the fact that tissue hypoxia has created a greater oxygen gra-
of a systemic inflammatory response results in characteristic abnor- dient. In resuscitated distributive or septic shock, however, the SVO2
malities of cardiovascular, metabolic, and immunological homeostasis is increased, often up to 80% or more. Multiple factors contribute to
which create a characteristic clinical syndrome. this. First, fluid resuscitation in the face of increased capillary perme-
ability creates a greater distance between the red cell and the tissues,
■■Cardiovascular alterations rendering the diffusion gradient less steep. Second, alterations in flow
at the microvascular level result in the creation of functional shunts,
Abnormalities of cardiovascular homeostasis are particularly promi- with some capillaries occluded, and others wide open. Finally, reduced
nent during a septic response (Dellinger 2003). They define the most tone at the postcapillary venule results in reduced resistance to flow
severe form of the syndrome – septic shock – and contribute signifi- through the microvasculature, with the result that the time available
cantly to its morbidity and mortality by impairing oxygen delivery to for unloading of oxygen is reduced.
the tissues. Increased and patchy microvascular thrombosis, secondary to
Two key early alterations shape the vascular response – vasodila- the activation of coagulation, is another cardiovascular manifesta-
tion and increased capillary permeability (Figure 25.4). As discussed tion of systemic inflammation. Moreover studies of red cells and
above, vasodilation results from increased local generation of NO. A leukocytes have demonstrated reduced cellular deformability of
single cause of increased capillary permeability has not been iden- both cell types, with the result that capillaries become occluded with
tified (Goldenberg et al. 2011). Multiple inflammatory mediators these more rigid cells and microthrombi secondary to the activation
can reproduce the phenomenon by impeding intracellular barrier of coagulation.
 The multiple organ dysfunction syndrome 281

Depression of myocardial contractility has also been described in Although efforts have been made to describe this process as either
sepsis, and attributed to a still poorly characterized myocardial de- an excessive or an inadequate response, or to suggest that an initial
pressant factor. Right heart dysfunction is particularly prominent. On state of enhanced inflammation is followed by a state of immune sup-
the other hand, the cardiac output is usually elevated. Cardiac output pression (the so-called compensatory anti-inflammatory response
(denoted Q) is the product of the heart rate and the stroke volume. syndrome or CARS), the reality is that evidence of both augmented
The heart rate is elevated for a variety of reasons, including reduced and impaired immune responsiveness coexists.
peripheral vascular resistance, fever, and increased sympathetic Cells of the innate immune system – neutrophils, monocytes,
activity. The stroke volume is also increased because of the reduced and macrophages – typically show evidence of basal activation, ac-
peripheral vascular resistance. companied by an impaired ability to respond further after exposure
to inflammatory stimuli, e.g., basal production of reactive oxygen
■■Metabolic alterations intermediates by the neutrophil and release of TNF by circulating
monocytes are enhanced, but only a modest enhancement of these
Metabolic processes are dramatically altered in association with the processes occurs when cells are exposed to inflammatory stimuli
activation of a systemic inflammatory response. Patterns of protein ex vivo, and activity is ultimately less than that seen in healthy cells
synthesis by the liver are altered as part of the acute phase response exposed to the same stimuli. Expression of TLRs is increased. The
(Gabay and Kushner 1999). Acute phase reactants such as C-reactive phagocytosis and killing of bacteria are altered only minimally or not
protein (CRP), a1-antitrypsin, complement proteins, and serum at all. Neutrophil survival is markedly increased as a consequence of
amyloid A protein are increased, whereas other proteins – notably the activation of an endogenous survival program (Jimenez et al. 1997).
albumin – are suppressed. Hepatic synthesis of the anticoagulant, On the other hand, the adaptive immune system shows extensive
protein C, is also inhibited, contributing to a net procoagulant state. evidence of downregulation. Delayed-type hypersensitivity respon-
The net consequence of this change in patterns of protein synthesis siveness is reduced, resulting in a state of anergy (Christou et al.
is enhanced antimicrobial activity and augmentation of host defense 1995), and lymphocyte proliferation in response to mitogenic stimuli
capacity. CRP binds to phosphocholine, a DAMP associated with is decreased. Antibody responses are variably affected: Production
bacterial cells and injured tissue. Lipopolysaccharide-binding protein of antibody to a protein antigen such as tetanus toxoid is reduced,
binds endotoxin, and a1-antitrypsin provides local protection against whereas antibody production in response to pneumococcal capsular
proteases such as elastase released during inflammation. Reduced polysaccharide, a polysaccharide antigen, is normal or increased.
synthesis of iron-binding proteins such as transferring reduces the Lymphocyte apoptosis is also increased (Hotchkiss and Karl 2003).
availability of iron – an essential cofactor for bacteria. The hallmark of immune dysfunction in systemic inflammation
Multiple endocrine disorders have been described (Vanhorebeek et is an increased susceptibility to nosocomial infection with a char-
al. 2006); in general, anabolism is reduced while catabolism is increased. acteristic group of largely endogenous pathogens. These are not the
Insulin resistance is characteristic, and results in elevated serum glu- typical infecting organisms of classic immunodeficiency disorders,
cose levels (Andersen et al. 2004), and a worse clinical prognosis. It is and susceptibility to them reflects the spectrum of derangements in
unclear whether increased morbidity results from reduced insulin avail- host defense mechanisms that occur in the critically ill patient. The
ability or responsiveness, or from the direct effects of hyperglycemia. upper gastrointestinal tract becomes colonized with organisms such
It is, however, apparent that judicious control of hyperglycemia using as staphylococci, enterococci, Escherichia coli, and Pseudomonas and
exogenous insulin can improve clinical outcomes (Van den Berghe et Candida spp. – the same spectrum of organisms that predominate
al. 2001), although strict glycemic control to maintain normoglycemia in ICU-acquired infections (Marshall et al. 1993). These organisms
is associated with a poorer outcome, perhaps because of the adverse share a number of features that favor their emergence and infectiv-
effects of hypoglycemia (Brunkhorst et al. 2008, Finfer et al. 2009). ity. They form biofilms, and so can grow on surfaces such as vascular
Impaired adrenocortical function and reduced vasopressin release and urinary catheters or endotracheal or nasogastric tubes. They
have been implicated in the pathogenesis of the cardiovascular al- also tend to be relatively resistant to first-line antibiotics, and so are
terations of systemic inflammation. Varying degrees of acute adrenal selected out under antibiotic pressure. They are also able to translocate
insufficiency have been documented in critical illness in both adults across an intact gut mucosa, likely accounting for the development
(Annane et al. 2000) and children (Menon et al. 2010), and the provi- of occult bacteremia with organisms such as enterococci, and for the
sion of exogenous glucocorticoids improves hemodynamic function, development of infected peripancreatic necrosis. Finally organisms
although the impact on mortality is less clear (Annane 2002, Sprung such as Pseudomonas spp. can increase their virulence in response to
et al. 2008). Reduced pituitary synthesis of adrenocorticotropic hor- stress in the host. Although alteration in innate and adaptive immune
mone (ACTH) has been observed, and may account for the changes function may predispose to nosocomial infection, the disruption of
in adrenocortical function (Polito et al. 2011). Vasopressin levels are physical barriers such as the skin by vascular lines, of anatomic de-
reduced in sepsis, and treatment of septic shock with exogenous fenses such as the upper airway by endotracheal tubes, of chemical
vasopressin results in improved outcomes, particularly for patients barriers such as gastric acidity, and of the microbial barriers created
with lesser degrees of shock (Russell et al. 2008). by the indigenous flora are likely to play a much more important role
Muscle atrophy – a result of increased proteolysis and reduced in the pathogenesis of these infections.
myofibrillar synthesis – is common in acute illness (Derde et al. 2012),
and plays a significant role in delayed weaning from mechanical
ventilation and in return to normal activities after ICU and hospital
■■THE MULTIPLE ORGAN
discharge (Herridge et al. 2011). DYSFUNCTION SYNDROME
■■Immunological alterations Organ dysfunction of varying degrees of severity is a common mani-
festation of a systemic inflammatory response. The process has been
Immunological homeostasis is equally altered in the patient with called MODS, although the concept is sufficiently complex and of such
sepsis and the patient with organ dysfunction (Marshall et al. 2008). importance to the optimal management of the critically ill patient that
282 SEPSIS: SYSTEMIC INFLAMMATION AND ORGAN DYSFUNCTION

its origins and implications merit further consideration. MODS is at the term the “acute respiratory distress syndrome,” and defined it as
once a cardinal manifestation of an activated inflammatory response, arterial hypoxemia, in association with diffuse bilateral pulmonary
a reflection of the successes of ICU care, and a consequence of the infiltrates on chest radiograph in the absence of pulmonary edema.
sequelae of that care. This somewhat arbitrary definition has been refined several times,
MODS evolves only because patients who otherwise would have and its vagaries underline the fact that variable degrees of measur-
died of lethal physiological organ insufficiency can be kept alive us- able physiological alterations and lung injury are a common feature
ing a spectrum of organ support technologies. The development of of systemic inflammation.
dialysis, positive pressure mechanical ventilation, and techniques for Increased capillary permeability with interstitial edema is the
central monitoring of cardiovascular function after the Second World earliest abnormality in ARDS. Widening of the alveolar wall results
War created the preconditions for the first ICUs in the late 1950s. The in reduced diffusion of oxygen from the alveolus into the adjacent
development of ICUs created a spectrum of disorders that developed capillary, whereas diffusion of carbon dioxide is unaffected. As a result,
only because the patient could be kept alive on life support – ARDS, an early manifestation is arterial hypoxemia with a normal or even
AKI, septic shock, DIC, and acute stress ulceration of the stomach. reduced carbon dioxide tension. The influx of activated neutrophils
The late Arthur Baue (1975) suggested that these were not separate into the lung causes a further increase in local capillary permeability,
processes, but rather the specific organ system manifestations of a increasing the resultant hypoxemia (Figure 25.5a).
common process that he termed “multiple or progressive systems However, these initial physiological responses to an activated
failure.” Other terms such as multiple organ failure or remote organ systemic inflammatory response represent only a part of the pheno-
dysfunction have been used, but the current preferred terminology type of ARDS. Hypoxemia leads the treating clinician to intubate the
is the MODS, emphasizing that the process can involve any organ, patient and initiate positive pressure ventilation. This intervention
is variable in its severity, and is potentially reversible. Baue further can attenuate hypoxemia, but the exogenous distending pressure
emphasized that the challenge is not the failure of any single system, results in further injury to the lung from inflammation (Figure 25.5b).
but rather the interactions between systems, and perhaps, most im- Ultimately the pathophysiology of acute lung injury reflects a combi-
portantly, emphasized that MODS is a process to be prevented, rather nation of processes – increased capillary permeability and enhanced
than a disease to be treated. neutrophil influx as early events, further injury from positive pressure
For the surgeon, the prevention of MODS encompasses the entire ventilation and over-distension of alveolar units, and subsequently
spectrum of judgment and management decisions that comprise the reparative processes including vascular thrombosis and activation
optimal care of a vulnerable critically ill patient. Our focus below, of local fibrosis.
therefore, is on the ICU management strategies that are associated Lung injury can be minimized by prophylactic measures to prevent
with the lowest risk of additional iatrogenic injury, and so with the ventilator-associated pneumonia (VAP), including elevation of the
best clinical outcomes. head of the bed, and the use of the orotracheal route for intubation,
closed endotracheal suction systems (Dodek et al. 2004), and lung
■■Respiratory dysfunction protective methods of ventilatory support. These last include the use
of non-invasive ventilation where feasible (Ferrer et al. 2009) and
Impaired gas exchange in the lung, with reduced levels of oxygen in the pressure-limited ventilatory approaches during mechanical ventila-
blood, is the functional manifestation of the respiratory dysfunction of tion (Brower et al. 2000, Meade et al. 2008). Limiting the amount of
MODS. Following early descriptions of acute respiratory failure devel- fluids administered after ICU admission (National Heart, Lung, and
oping in association with peritonitis, Ashbaugh et al. (1967) proposed Blood Institute Acute Respiratory Distress Syndrome [ARDS] Clinical

a b

Figure 25.5  The lung in acute respiratory distress syndrome (ARDS). (a) A photomicrograph of the lung of a patient who died of ARDS reveals massive
pulmonary infiltration by neutrophils, edema of the alveolar walls, intravascular thrombosis, and fibrin deposition in the alveoli; all of these contribute to impaired
gas exchange. (b) A CT scan of a patient with ARDS reveals the further iatrogenic nature of the lung injury, showing consolidation in the dependent posterior lung
zones, and cystic changes in the anterior anti-dependent areas resulting from over-distension of the lung.
 The multiple organ dysfunction syndrome 283

Trials Network 2006), or active diuresis with diuretics and albumin The pathological findings in sepsis-induced AKI are minimal, and
(Martin et al. 2005), can shorten the duration of ventilator dependency. the pathogenesis of injury is incompletely understood (Bougle and
Duranteau 2011). Reduced renal blood flow – either global or regional
■■Cardiovascular dysfunction – with resulting cellular hypoxia likely contributes to injury and kidney
dysfunction. However, the classic concept of acute tubular necrosis
The cardiovascular derangements of systemic inflammation have does not reliably reflect the histological findings, and mounting evi-
been described earlier, and consist primarily of reduced peripheral dence suggests that renal epithelial cell apoptosis plays an important
vascular resistance and increased capillary permeability. Once again, role (Havasi and Borkan 2011). Remote tissue injury, such as occurs
the process of resuscitation and support can result in further injury. during ventilator-induced lung injury, has been shown to induce renal
Intravenous fluids increase preload, but, in the setting of altered capil- apoptosis (Imai et al. 2003).
lary permeability, they increase tissue edema, resulting in impaired Support of the dysfunctional kidney is accomplished through
pulmonary gas exchange, reduced myocardial contractility, reduced renal replacement therapy. In contrast to chronic renal failure, the
abdominal wall compliance and the abdominal compartment syn- indication for institution of dialysis therapy for AKI is less frequently
drome, and impairment of gut, brain, and renal function (Prowle et hyperkalemia or acidosis, and more frequently for regulation of
al. 2010). Moreover vasopressors such as norepinephrine, dopamine, volume status. Continuous dialysis techniques such as continuous
and epinephrine can compromise blood flow, increasing the risk of venovenous hemofiltration (CVVH) or slow low-efficiency dialysis
complications such as anastomotic leaks (Zakrison et al. 2007), and (SLED) that enables fluid removal without resulting hemodynamic
the use of large doses of inotropes to augment cardiac output has been instability are widely used.
found to increase mortality (Hayes et al. 1994). For reasons that are
not at all clear, and despite the increase in myocardial work associated
with the response to critical illness, myocardial infarction is a relatively
■■Gastrointestinal dysfunction
uncommon complication; atrial dysrhythmias, on the other hand, Multiple abnormalities of gastrointestinal function are apparent in
occur relatively frequently (Goodman et al. 2008). the patient with MODS; however, these are often clinically occult and
Support of the cardiovascular system after ICU admission hinges difficult to quantify. Striking changes occur in patterns of microbial
on supporting preload through the administration of fluids, afterload colonization of the small bowel and colon, with overgrowth of the small
through the judicious use of vasopressor agents, and myocardial con- bowel by organisms commonly isolated from ICU-acquired infections
tractility through the use of inotropic agents. Optimal strategies are (Marshall et al. 1993), and a reduction in the complexity of the colonic
not well defined. There is no convincing evidence that goal-directed flora with a particular reduction in the density of anaerobic bacteria
strategies targeting either mixed venous oxygen saturation or cardiac (Shimizu et al. 2006). These changes, together with alterations in gut
index improve survival (Gattinoni et al. 1995). Both albumin and saline epithelial barrier function, predispose to translocation of viable bac-
are equally efficacious as replacement fluids (Finfer et al. 2004b), and teria and bacterial products such as endotoxin into the host, although
the tolerance of moderate degrees of anemia is preferable to more the mechanisms through which these changes lead to systemic disease
liberal transfusion strategies (Hebert et al. 1999). are complex and poorly understood (Alverdy et al. 2003). Ileus and
intolerance of enteral feeding are a common manifestation of gut
■■Renal dysfunction dysfunction. Acute upper gastrointestinal tract bleeding as a result
of so-called “stress ulceration” was common in the early years of
The renal dysfunction of MODS is characterized primarily by an in- intensive care, but has become uncommon today (Cook et al. 1998).
ability to clear creatinine and other solutes from the blood. The term Hyperbilirubinemia is the classic manifestation of liver dysfunction
AKI has become the preferred term to describe the process, and, in sepsis, although, similar to stress ulceration, its prevalence appears
recognizing that graded degrees of dysfunction occur, the RIFLE cri- to be decreasing. Although patterns of protein synthesis are altered as
teria have been developed to describe these, reflecting risk, injury, part of the acute phase response described earlier, clinically significant
failure, loss, and end-stage disease (Box 25.3) (Bellomo et al. 2004). derangements of hepatic synthetic or secretory function are extremely
rare in the absence of primary liver pathology.
Enteral feeding is a key intervention in minimizing gastrointestinal
dysfunction in the septic patient. Feeding stimulates gastrointestinal
Box 25.3 The RIFLE criteria for acute kidney injury. peristalsis, attenuating stasis and bacterial overgrowth, stimulates the
release of gastrointestinal hormones, and maintains the integrity of
Risk: Glomerular filtration rate (GFR) decreased >25%, serum the gut mucosa. Conversely, total parenteral nutrition is associated
creatinine increased 1.5 times or urine production of <0.5 ml/kg with an increased risk of cholestasis, particularly when administered
per h for 6 h early during the ICU stay (Casaer et al. 2011).
Injury: GFR decreased >50%, doubling of creatinine or urine pro-
duction <0.5 ml/kg per h for 12 h
Failure: GFR decreased >75%, tripling of creatinine or creatinine
■■Neuromuscular dysfunction
>355 μmol/l (with a rise of >44) (>4 mg/dl) OR urine output <0.3 ml/ Altered levels of consciousness manifested as delirium or somno-
kg per h for 24 h lence and profound acquired neuromuscular weakness are common
Loss: Persistent acute kidney infection or complete loss of kidney manifestations of the neuromuscular derangements of sepsis and
function for >4 weeks critical illness. Multiple factors are implicated including disruption
End-stage renal disease: Complete loss of kidney function for >3 of day–night sleeping cycles, tissue edema, and circulating mediators
months of inflammation; however, the iatrogenic effects of commonly used
284 SEPSIS: SYSTEMIC INFLAMMATION AND ORGAN DYSFUNCTION

ICU medications and prolonged bed rest play a particularly important

role (Vasilevskis et al. 2010). Corticosteroids, for example, have been
■■Measuring the severity of
shown to be a risk factor for prolonged weakness in survivors of ARDS organ dysfunction
(Herridge et al. 2003), whereas benzodiazepines are associated with A number of scoring systems have been developed to measure the
an increased risk of delirium when compared with dexmedetomidine severity of MODS, including the Multiple Organ Dysfunction (MOD)
(Riker et al. 2009). Score (Table 25.2) (Marshall et al. 1995), the Sequential Organ Failure
Sedation vacations, accomplished by daily interruption of seda- Assessment (SOFA) score (Vincent et al. 1996), and the Logistic Organ
tion (Kress et al. 2000) and more active programs of physiotherapy Dysfunction (LOD) score (Le Gall et al. 1996). All are similar in the
(Schweickert et al. 2009), can enhance neuromuscular recovery and systems that they incorporate, and in the equal weighting given to
accelerate weaning from mechanical ventilation. each system; they differ in relatively minor ways in the variables used
to define dysfunction.
■■Hematological dysfunction The MOD score uses a single physiological variable to characterize
dysfunction in each system, selected on the basis of specific criteria
Although mild anemia is a common feature of systemic inflammation, as being the optimal indicator of dysfunction in the specific system
the most striking abnormalities are those involving the coagulation (Marshall 1993). By analogy to the PO2/FiO2 ratio used to quantify
system (Marshall 2001). Thrombocytopenia either present on admis- pulmonary dysfunction, which corrects the oxygen tension by con-
sion or developing over the ICU stay occurs in up to 40% patients, and sideration of the concentration of inspired oxygen needed to achieve
is associated with an increased risk of death (Hui et al. 2011). Throm- that value, the MOD score uses a variable called the pressure-adjusted
bocytopenia often signals the presence of intravascular activation rate (PAR) to describe cardiovascular failure. The PAR is calculated as
of coagulation, or DIC, characterized by consumption of coagulant the product of the heart rate (HR) and central venous pressure (CVP),
proteins resulting in an increased prothromin time and increased divided by the mean arterial pressure (MAP):
levels of fibrin degradation products. Enhanced expression of tissue PAR = HR × CVP/MAP.
factor on endothelial cells contributes to activation of intravascular Increasing abnormality is reflected in increasing values, and the
coagulation, whereas the synthesis and activation of anticoagulant PAR reflects the impact of fluid challenge on pressure; in the absence
proteins such as protein C, tissue factor pathway inhibitor, and anti- of a CVP measurement, a normal value of 8 is imputed for the CVP.
thrombin are impaired (van der Poll et al. 2011). Variables in the MOD score are calibrated so that, within any system, a
Although coagulopathy is associated with adverse outcome in score of 0 reflects normal function, whereas a score of 4 reflects mark-
sepsis, and plausibly plays a pathogenic role in the evolution of edly abnormal function and a risk of death of at least 50%.
MODS, effective treatment strategies are not available. Recombi- Organ dysfunction scores can serve several purposes. Calculated on
nant activated protein C (drotrecogin alpha activated or Xigris) was the day of admission, the admission score serves as a severity measure.
reported to improve survival in severe sepsis, particularly in those Measured on a daily basis, the daily score can reflect net improvement
patients with septic shock or DIC (Bernard et al. 2001). However, a or deterioration in an individual patient. Calculated over a period of
recent randomized trial of 1696 patients failed to replicate the ben- time (e.g., the ICU stay) by recording the worst value in each system,
eficial results of the original study, and the drug has been withdrawn independent of the day it occurred, the aggregate score measures the
from the market. Similar promising early results with antithrombin overall severity of organ dysfunction. By subtracting the admission
or tissue factor pathway inhibitor have likewise not withstood the score from the aggregate score, it is possible to calculate a delta score
rigors of subsequent trials. that quantifies new, and potentially preventable, organ dysfunction

Table 25.2 The Multiple Organ Dysfunction (MOD) score (from Marshall et al. 1995).
Organ system 0 1 2 3 4
Respiratorya (PO2/FiO2 ratio) >300 226–300 151–225 76–150 <75
Renalb (serum creatinine) <100 101–200 201–350 351–500 >500
Hepaticc (serum bilirubin) <20 21–60 61–120 121–240 >240
Cardiovasculard (PAR) <10.0 10.1–15.0 15.1–20.0 20.1–30.0 >30.0
Hematologicale (platelet count) >120 81–120 51–80 21–50 ≤20
Neurologicalf (Glasgow Coma Scale) 15 13–14 10–12 7–9 ≤6
aThe PO2/FiO2 ratio is calculated without reference to the use or mode of mechanical ventilation, and without reference to the use or level of positive end-expiratory pressure.
bThe serum creatinine level is measured in μmol/l, without reference to the use of dialysis.
cThe serum bilirubin level is measured in μmol/l.
dThe pressure-adjusted heart rate (PAR) is calculated as the product of the heart rate and right atrial (central venous) pressure (RAP), divided by the mean arterial pressure (MAP):
PAR = Heart rate × RAP/MAP.
eThe platelet count is measured in platelets ´ 103/ml.
fTheGlasgow Coma Scale score is preferably calculated by the patient’s nurse, and is scored conservatively (for the patient receiving sedation or muscle relaxants, normal function is
assumed unless there is evidence of intrinsically altered mental status).
 Management of sepsis 285

that has arisen over the ICU stay. Finally, a combined mortality and be initiated using a crystalloid such as 0.9% saline or Ringer lactate,
morbidity measure can be created by recording the aggregate score with an initial rapid infusion of 30 ml/kg. Subgroup analyses of the
for survivors and the aggregate score plus 1 for non-survivors. 7000 patient Australia/New Zealand SAFE Trial that showed no overall
Organ dysfunction scores have been most frequently used in mortality difference when patients received either saline or albumin,
research to compare baseline severity, and describe clinical course; because the resuscitative fluid suggested the possibility that albumin
their use as tools in the ICU management of critically ill patients has might be superior to saline in the management of sepsis, but harmful
not been extensively evaluated. in the setting of head injury (Finfer et al. 2004b). On the other hand,
the use of synthetic colloids has been associated with increased rates
■■The iatrogenic roots of MODS of AKI (Brunkhorst et al. 2008). Several large international trials cur-
rently under way should help to clarify the role of synthetic colloids
Early descriptions of MODS emphasized its association with infec- as acute resuscitative fluids.
tion (Fry et al. 1980, Bell et al. 1983), even suggesting that new onset Fluid resuscitation should be administered to target specific
of organ dysfunction can be a valid sign of occult infection and an physiological endpoints, although which is the best measure of the
indication for exploratory laparotomy (Polk and Shields 1977). In the adequacy of resuscitation is also a matter of debate. A reduction in
early postoperative period, the development of organ dysfunction heart rate and an increase in blood pressure suggest a therapeutic
– particularly respiratory insufficiency, renal dysfunction, atrial ar- response to fluids, although they are relatively insensitive markers of
rhythmias, or confusion – is not uncommonly a harbinger of a major resuscitation adequacy, and impacted by other factors such as pain
surgical complication. However, improvements in diagnostic imaging and anxiety. Urine output can be an effective and dynamic marker of
have essentially obviated the need for blind surgical exploration, and, the adequacy of intravascular fluid volumes, and has the added ad-
for the patient in the ICU, the etiology of new organ dysfunction more vantage of reflecting both renal flow and renal function. Either acute
frequently reflects the iatrogenic consequences of ICU support than or chronic renal impairment may render urine output unreliable.
a missed diagnosis of infection. Indeed MODS is by definition an iat- Measures of cardiac preload such as CVP, or of oxygen extraction such
rogenic process, because it arises only in survivors of otherwise lethal as central venous O2 saturation (ScvO2) also provide useful information
illness, and ongoing ICU supportive care contributes to its evolution. on the adequacy of fluid resuscitation.
If the conceptual importance of MODS in the twentieth century was If perfusion remains compromised despite apparently adequate
as sign of occult infection, its importance in the twenty-first century is filling pressures (e.g., if blood pressure or urine output remains low
as a reminder of the inadvertent consequences of ICU support (Mar- despite a normal or elevated CVP), then vasopressor agents are used to
shall 2010): The clinical challenge is to support physiological function increase blood pressure. Norepinephrine, epinephrine, and dopamine
while minimizing the harm associated with that support. all exert vasopressor activity; norepinephrine is the most commonly
used agent in North America and Europe, a practice supported by a
■■MANAGEMENT OF SEPSIS meta-analysis suggesting improved survival when norepinephrine is
used rather than dopamine (De et al. 2012).
The core principles in the management of the septic patient include Finally, if tissue perfusion remains compromised despite adequate
the following: filling volumes and vasoactive drug therapy, augmentation of cardiac
⦁⦁ Resuscitate the patient to ensure adequate tissue perfusion output with an inotropic agent such as dobutamine, or of oxygen-
⦁⦁ Identify and treat a focus of infection with appropriate antibiotics carrying capacity through blood transfusion, may provide additional
and source control measures benefit.
⦁⦁ Provide the necessary support for failing organ systems while A defined protocol for initial resuscitation has been popularized
minimizing further iatrogenic injury. by Rivers et al. (2001) who proposed the concept of multimodal, early,
These have recently been synthesized into evidence-based man- goal-directed therapy in the management of severe sepsis. The Riv-
agement guidelines developed by the Surviving Sepsis Campaign ers protocol calls for the placement of a central venous catheter for
(Dellinger et al. 2008). Although the focus is the patient with sepsis monitoring, and the rapid administration of crystalloids targeting a
(i.e., new-onset organ dysfunction as a consequence of infection), it CVP of 8 mmHg. If the mean arterial pressure remains low despite this
is often unclear in the early stages of patient management whether initial fluid challenge, norepinephrine is added, targeting a MAP of
infection is the trigger for physiological instability, and the principles 65 mmHg. A ScvO2 is measured, and if the value is <70%, dobutamine
apply equally to patients whose illness arises from an acute sterile and/or transfusion is administered (Figure 25.6). Using such a proto-
inflammatory process such as pancreatitis. col in the emergency department of a single urban hospital, Rivers et
al. demonstrated a mortality reduction from 46% to 30% for patients
■■Resuscitation of the septic patient presenting with septic shock. Several large studies are currently in
progress to validate the concept and to assess the relative importance
A relative or absolute intravascular volume deficit is common in unre- of the differing elements of the protocol.
suscitated septic shock, occurring because of ongoing losses, reduced
intake, peripheral vasodilation, and increased capillary permeability.
Reduced oxygen delivery to the tissues results in anaerobic metabo-
■■Diagnosis and
lism; measurement of serum lactate can provide information on the treatment of infection
severity of the energy deficit, and so lactate assay is recommended as Although a distributive shock state may result from a variety of non-
a diagnostic tool in the early resuscitation of the septic patient. infectious causes, infection is both a common and a readily treatable
The initial step in resuscitation is the administration of intravenous cause of the physiological derangement, and so its early detection and
fluids to optimize circulatory function. The optimal resuscitative fluid management are critical to a favorable outcome.
remains controversial; however, in the absence of compelling evi- The specific site of an inciting infection is often readily apparent
dence for the superiority of any particular fluid, resuscitation should based on the pattern of signs and symptoms at clinical presentation.
286 SEPSIS: SYSTEMIC INFLAMMATION AND ORGAN DYSFUNCTION

Figure 25.6  Early goal-directed therapy for

Supplemental oxygen ± sepsis and septic shock (Rivers et al. 2001). The
endotracheal intubation and strategy popularized by Rivers and colleagues begins
mechanical ventilation in the emergency department with measurement of
central venous pressure (CVP), and infusion of fluids
to raise the CVP to ≥8 mmHg Vasopressors are added
if this fails to increase the mean arterial pressure to
at least 65 mmHg, and transfusion and inotropes
Central venous and administered as needed to increase the central
arterial catheterization
venous oxygen saturation to at least 70%.

Sedation, paralysis
(if intubated),
or both

Crystalloid
<8 mm Hg
CVP
Colloid
8-12 mm Hg

<65 mm Hg
MAP Vasoactive agents
>90 mm Hg

>65 and <90 mm Hg

>70%
<70% Transfusion of red cells
Scv02 <70%
until hematocrit >30%

>70%

Inotropic agents
Goals
achieved
No

Yes

Hospital admission

Documentation of the site of infection is based on the history and eradicate a focus of infection. In general, source control removes foci
physical findings combined with appropriate imaging of chest radio- of microbial growth, and drainage converts a closed space infection to
graph, ultrasonography, and computed tomography (CT). Additional a controlled sinus or fistula. In selecting a method of achieving source
investigations such as lumbar puncture are dictated based on clinical control, the optimal approach accomplishes the anatomic objective
presentation. A microbiological diagnosis should also be sought before with the least degree of physiological and anatomic disruption; thus
anti-infective therapy is started, by obtaining two sets of blood cultures, percutaneous and minimally invasive approaches have emerged as
along with cultures guided by the presumptive anatomic diagnosis. the preferred initial intervention in feasible circumstances. (Marshall
Broad-spectrum empirical antibiotic therapy, based on the as- et al. 2004b).
sumed anatomic focus and presumptive spectrum of pathogens,
should be started as soon as cultures have been obtained, and ideally
within an hour of initial presentation. Observational studies show that
■■Support of the septic patient
mortality increases strikingly with every hour of delay in initiating ap- Beyond the initial resuscitation and treatment of infection, support-
propriate antibiotic therapy (Kumar et al. 2006). Antibiotic selection ive care of impaired organ function while minimizing the adverse
is discussed in Chapter 2. sequelae of the support-related interventions is paramount. For
Early source control is a key element of initial management for the intubated patient, a ventilatory mode that minimizes further
many infections. Source control measures are those that use physical ventilator-induced lung injury should be used. The best-studied
interventions such as drainage (for infected fluids such as those found approach is that popularized by ARDSNet in the USA (Brower et al.
in an abscess), debridement (for infected or necrotic solid tissue), or 2000), which limits tidal volumes to 6 ml/kg, using sedation and pa-
device removal (for colonized foreign bodies and medical devices) to ralysis as needed. Newer strategies such as high-frequency oscillation
 Targeting the mediators of systemic inflammation 287

may well play an increasingly important role in the future (Sud et al. sepsis. Unfortunately this promise has been agonizingly difficult to
2010). realize. Upwards of 100 phase 2 and 3 clinical trials have been con-
Although aggressive fluid resuscitation contributes to survival when ducted, evaluating a spectrum of interventions (Figure 25.7). Despite
used early during the course of sepsis, there is some evidence that a some inconsistent evidence of clinical benefit, the net result of this
persistently positive fluid balance is harmful in the period after ICU enormous body of work is that there are currently no novel mediator-
admission (Boyd et al. 2011), and that conservative fluid management directed treatments available. Lack of convincing evidence of efficacy,
strategies result in improved clinical outcomes. Similarly, there is no however, does not equate to convincing evidence of lack of efficacy,
evidence that normalization of hemoglobin levels through transfu- and a strategy aimed at a variety of targets may yet find a clinical role.
sion improves outcome, but rather a suggestion that indiscriminate
transfusion may be harmful (Hebert et al. 1999).
Although broad-spectrum empirical therapy is appropriate in the
■■Endotoxin
initial management of the septic patient, once the results of culture Endotoxin is the prototypical microbial trigger of innate immunity,
and sensitivity testing become available, the antibiotic spectrum and evokes the clinical manifestations of sepsis and lethality in both
should be narrowed and, if cultures are negative, antibiotics should animals and humans. Endotoxemia is also common in critically ill
be stopped altogether. patients, although importantly its presence does not necessarily signal
Evidence-based strategies should be implemented to prevent the presence of Gram-negative infection, and levels may be elevated
nosocomial complications, including pharmacological prophylaxis even without infection, suggesting the gut as a source of circulating
against deep venous thrombosis, and interventions to prevent VAP and endotoxins (Marshall et al. 2004a). A variety of strategies to neutralize
central venous catheter infections. Data from randomized controlled endotoxin have been evaluated, including monoclonal antibodies,
trials and systematic reviews indicate that the risk of nosocomial endogenous neutralizing proteins such as bactericidal permeability
ICU-acquired infection and even mortality can be reduced through increasing protein, high-density lipoprotein, soluble CD14, and in-
the use of selective decontamination of the digestive tract (SDD), testinal alkaline phosphatase, and synthetic antagonists including a
particularly in surgical patients (Nathens and Marshall 1999). SDD non-toxic lipid that binds TLR4 without inducing activation, a lipid
is an antibiotic-based prophylactic regimen that uses topical agents emulsion, and the antibiotic polymyxin B. Recent studies, using an
active against Gram-negative bacteria (tobramycin and polymyxin B) extracorporeal polymyxin B column, have shown improved survival in
and fungi (amphotericin B), leaving the Gram-positive and anaerobic severe peritonitis. Its utility is the focus of an ongoing North American
flora intact. For reasons that are unclear, SDD has not been widely clinical trial.
adopted outside Europe. Finally maintenance of blood glucose lev-
els in the near normal range appears to improve outcome, although
targeting strict normoglycemia has been found to increase mortality
■■Tumor necrosis factor
(Finfer et al. 2009). The neutralization of TNF using either specific neutralizing antibodies
or soluble receptor constructs has been evaluated in a dozen clinical
■■TARGETING THE MEDIATORS OF trials. In aggregate, data derived from more than 7000 patients en-
rolled in these studies reveal a statistically significant, albeit small,
SYSTEMIC INFLAMMATION benefit in 28-day survival (see Figure 25.7). None of these studies
was individually compelling enough to lead to regulatory approval of
Contemporary understanding of the biological mechanisms that anti-TNF therapies, although they have emerged as mainstays in the
result in organ injury has raised the prospect that therapies targeting management of other inflammatory disorders, notably arthritis and
host-derived mediators of inflammation might improve outcomes in inflammatory bowel disease.

Figure 25.7  Mediator-targeted therapy in sepsis

Anti-endotoxin therapy
(Marshall 2008). Pooled data from studies of agents
9 trials; 3057 patients that neutralize endotoxin, tumor necrosis factor, or
interleukin-1, provide exogenous immunoglobulin,
Anti- TNF antibodies or administer the endogenous anticoagulant,
10 trial; 6821 patients activated protein C, show a small but consistent
signal for benefit, although for none of these has
IL-1ra the effect been sufficiently robust that a commercial
3 trials; 1688 patients therapy is available for use.

Intravenous immuneglobulin
20 trials; 2621 patients

Activated protein C; all patients

2 trials 4303 patients

Activated protein C; patients with MOF

2 trials; 2133 patients

0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3

Experimental agent better Placebo better
288 SEPSIS: SYSTEMIC INFLAMMATION AND ORGAN DYSFUNCTION

■■Interleukin-1 the interaction of PAF with its receptor or accelerate its degradation;
recombinant lactoferrin; inhibitors of NOS; and ibuprofen. Each has
The activity of interleukin-1 is regulated through the release of a natural shown promise in pre-clinical models, but failed in sepsis trials. The
occurring inhibitor, the IL-1Ra, a protein that shares homology with reasons for this ongoing lack of connection are many (Marshall 2008).
IL-1, and binds to the IL-1 receptor without inducing its activation. The entry criteria for sepsis trials have been the so-called sepsis
Recombinant IL-1Ra has been evaluated in three clinical trials which, syndrome or a variant, first developed almost 30 years ago for the
in aggregate, show a 5% improvement in survival. As in the case of first large trial of methylprednisolone in sepsis. The criteria are non-
anti-TNF therapies, the signal was insufficient to support therapeutic specific, and identify a highly heterogeneous population of patients
approval as a therapy for sepsis, although recombinant IL-1Ra has who do not share common sites, bacteriology, or patterns of circulating
found a role in other inflammatory disorders. endogenous mediators. The same criteria are used despite the fact that
the targets are biologically diverse; studies are conducted without con-
■■Activated protein C firming that the target of intervention is present, or that intervention
alters target levels or improves physiological parameters. The dose and
Protein C is a naturally occurring anticoagulant protein synthesized duration of therapy are typically established in an arbitrary manner,
by the liver, activated through its interactions with endothelial cell rather than titrated to a response, and some of the agents tested have
thrombomodulin. Once activated it functions as an anticoagulant ultimately proven to be biologically inactive. A fundamental rethink
by binding the endothelial cell protein C receptor, and exerting anti- of the approach to sepsis research is needed, and this may lead to a
inflammatory activity. Recombinant activated protein C (drotrecogin re-evaluation of strategies that have previously failed.
alpha activated) was licensed for use in severe sepsis and septic shock
in 2001 on the basis of findings from the PROWESS trial which showed
a significant 6.1% mortality reduction in septic patients (Bernard et al.
■■CONCLUSIONS
2001). Observational studies supported the conclusions of the PROW- Sepsis is an enormously complex process both biologically and
ESS trial; however randomized trials in children and less ill adults conceptually. The inflammatory response is effected though the
failed to replicate the earlier evidence of benefit. As a result, European coordinated interaction of literally hundreds of distinct host-derived
regulatory authorities mandated a further placebo-controlled trial molecules. These are expressed at low levels, and exert their most
of drotrecogin alpha activated in septic shock. The trial – PROWESS potent activities locally in the microenvironment of a contained insult.
Shock – showed no benefit to patients receiving the agent, and the Moreover their activities are redundant. Remarkably, manipulation
drug has been withdrawn from the market. of any of more than three dozen of these before challenge will protect
a mouse against a lethal endotoxin challenge (Box 25.4) (Marshall
■■Corticosteroids 2003); conversely, it would seem implausible that neutralization of
any single mediator after challenge might alter outcome. Moreover it
As pharmacological agents with broad anti-inflammatory activity, cor- is unclear when these mediator responses are a host adaptation and
ticosteroids have a long history of use in the management of sepsis, but therefore when they are beneficial and not an independent threat.
an inconsistent evidentiary base. The first contemporary sepsis stud- The conceptual challenges of sepsis rival the biological challenges.
ies evaluated high-dose methylprednisolone in sepsis, and failed to Microorganisms normally colonize the multicellular host, and contrib-
show benefit. However, observational studies suggesting that relative ute symbiotically to health. Although the endogenous flora can cause
adrenal insufficiency was common in critically ill patients prompted
evaluation of low-dose hydrocortisone, and an influential French study
suggested that the use of pharmacological doses of hydrocortisone
together with fludrocortisone improved survival. A subsequent trial Box 25.4 Mediators, the manipulation of which improves survival
reported that steroid use could hasten the resolution of shock without in murine endotoxemia (adapted from Marshall 2003).
altering survival, and the role of corticosteroids remains controversial.
Systematic reviews of the available data do show benefit, and our Cytokines
approach is to consider the use of hydrocortisone in the treatment ⦁⦁ Neutralization of: IL-1, IL-12, IL-18, IL-31, IL-33, TNF, IFNα,
of vasopressor-dependent hypotension, continuing treatment if the TGFβ, LIF, MIF, G-CSF, HMGB-1, MIP-1α, MFP-14, LBP, PTH-RP
shock resolves, but terminating it if there is no apparent effect. ⦁⦁ Administration of: IL-1Ra, IL-4, IL-10, IL-13, IFNα, HGF, LIF,
CRP, MCP-1, BPI, CAP18, TSG-14, VLDL, VIP, C3, C4, melatonin
■■Intravenous immunoglobulin Receptors
⦁⦁ Inhibition of: TNF receptor, p55, IL-1R, PAF receptor, LECAM-1,
A number of small clinical trials of intravenous immunoglobulin have TREM-1, LDL receptor, CD11a, CD14
suggested efficacy in treating sepsis and, when these are aggregated ⦁⦁ Activation of: VIP receptor, adenosine A3 receptor
in a meta-analysis, the signal for benefit is strong. The quality of these Non-proteins
studies is variable, and the evaluation of intravenous immunoglobulin ⦁⦁ Neutralization of: PAF, PLA2
in large and well-designed trials is needed. ⦁⦁ Administration of: Vitamin B12, vitamin D3
Signal transduction
■■Other approaches and the ⦁⦁ Inhibition of: hck, COX-2, p38, jnk, NF-kB, iNOS, caspase-3
⦁⦁ Activation of: Stat4, Stat6, IκB, HSP70, hemoxygenase
failure of sepsis trials Coagulation factors
A variety of other strategies has been evaluated including: Recom- ⦁⦁ Inhibition of: PAI-1, tissue factor
binant anticoagulant proteins such as antithrombin, tissue factor ⦁⦁ Administration of: TFPI, APC
pathway inhibitor, and soluble thrombomodulin; agents that block
 References 289

infection, indiscriminate eradication of this flora can predispose to sarily result in improved clinical outcomes. Clearly, advanced staging
bacterial translocation, superinfection, and antimicrobial resistance. systems of sepsis and MODS are necessary.
Endotoxin may be better considered an endogenous hormone than an These challenges notwithstanding, however, results from the Sur-
exogenous toxin (Marshall 2005). Moreover endotoxin is commonly viving Sepsis Campaign have shown that adequate resuscitation, early
present in patients who do not meet conventional criteria for sepsis, treatment with antibiotics, appropriate source control, and optimal
and absent in those who do. Finally, the clinical syndrome is driven ICU support can improve survival by up to 6% (Levy et al. 2010). At-
not only by host–microbial interactions, but also by the consequences tention to basic principles of surgery and infection control remains
of clinical intervention. Normalization of physiology does not neces- the mainstay of management.

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program targeting severe sepsis. Crit Care Med 2010;38:367–74. Prowle JR, Echeverri JE, Ligabo EV, et al. Fluid balance and acute kidney injury.
Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping Nat Rev Nephrol 2010;6:107–15.
microbial diversity in the human intestine. Cell 2006;124:837–48. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for
Majno G. The ancient riddle of (Sepsis). J Infect Dis 1991;163:937–45. sedation of critically ill patients: a randomized trial. JAMA 2009;301:489–99.
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(MODS). In: Sepsis: Current perspectives in pathophysiology and therapy. Berlin: of severe sepsis and septic shock. N Engl J Med 2001;345:1368–77.
Springer-Verlag, 1993: 38–49. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion
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organ dysfunction syndrome. Crit Care Med 2001;29(suppl):S106. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and
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2008;83:471–82. septic shock. N Engl J Med 2008;358:111–24.
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 Index
Note: Page numbers in bold or italic refer to tables or figures respectively.

A Antimicrobial therapy 11 Azithromycin 13, 254

Abacavir, HIV infection 157 agents Azole antifungal drugs 151–152
Abdominal aortic aneurysm (AAA) 205 aminoglycosides 18–19 Aztreonam 13, 17
Abdominal pain, crampy 125 β-lactam antibiotics 14 Azurophilic granules 37
Abdominal ultrasonography 212 carbapenems 17, 17–18, 18
Abscesses 226, 226–227 cephalosporins 15, 15–17 B
bartholin gland 226–227 colistin 18 Bacillus anthracis, and anthrax infection 251
intra-abdominal 75, 82 daptomycin 20–21 Bacillus Calmette–Guérin (BCG) 212
labial 226 linezolid 19–20 Bacillus cereus 72
perirectal 89–93 Bacitracin 13
monobactams 17
pilonidal 93, 93–94, 95 Bacteremia 196, 197, 203, 243
penicillins 14–15
Skene gland 228 Bacteria 1, 49
pharmacokinetics and pharmacodynamics
Acinetobacter baumannii, ventilator-associated air-borne 55
 14
pneumonia (VAP) by 98 cell structure 1-2, 1, 2
Acne inversa see Hidradenitis suppurativa quinolones 19 gram-negative 1, 1–2, 2, 4
Acticoat A.B. Dressing 141 telavancin 21–22 gram-positive 1, 1, 4
Activated protein C 288 tigecycline 21 inoculum of, and infection 49–50, 50
Acute eosinophilic pneumonia (AEP), vancomycin 19 mutation 6
daptomycin-induced 21 burn wound infections 137 resistance mechanisms to antibiotics 12–14, 14
Acute kidney injury (AKI) 277 cellulitis 65 alterations of target 12–13
RIFLE criteria 283 Clostridium difficile infections 126–127 antibiotic modification 12
Acute parotitis (AP) 195, 196 erysipelas 65 bypassing drug’s action 14
Acute respiratory distress syndrome (ARDS) 38, human and animal bite infections 66 efflux pumps 13
261, 263, 277, 282, 282 hydradenitis suppurative 66
entry prevention 13–14
Adefovir, hepatitis B virus (HBV) infection 158 inoculum effect 6
Bacterial formylated peptides (fMLP) 37
Adhesive drapes 55 for intra-abdominal infections (IAIs) 83–85
Bacterial translocation 261
Aeromonas hydrophila 72 mechanisms of action 11–12, 12
and gut-origin sepsis 261, 262, 262–264, 264
Air-handling systems 55 necrotizing soft-tissue infection 69
Bacteroides fragilis 57, 78–79
Alanine aminotransferase (ALT) 156 post-antibiotic effect 6
capsular polysaccharide 4
Alar fascia 190 resistance mechanisms 12–14, 14
superoxide dismutase 5
Alarmins 28 sensitivity 5–6
Bactroban see Mupirocin
ALT see Alanine aminotransferase (ALT) spectrum of action 11, 11
Bartholin gland abscess 226–227, 227
Alveolar osteitis 199 for surgical site infections (SSIs) prevention
Basophils 38
American College of Surgeons’, wound 56–58, 57
B cells, activation 45
classification 49 target receptor 5–6
BCG see Bacillus Calmette–Guérin (BCG)
clean-contaminated operations 49–50 urinary tract infection (UTI) 111
Benzylpenicillin 13
clean operations 49 for ventilator-associated pneumonia (VAP)
β-Lactamase inhibitor
contaminated operations 50 103–104
spectrum of activity 11
dirty operations 50 in wound management 61
β-Lactamases 7, 7
Aminoglycoside 6, 7, 13, 18–19, 206, 209, 212, APACHE II (Acute Physiology and Chronic Health
β-Lactams 6–7, 14
219 Evaluation II) score 80, 98
resistance mechanism 7, 7
resistance mechanism 7–8 Apoptosis 27, 27
spectrum of activity 11
Aminopenicillins 15 Appendicitis 76–77
Betadine 249
Amoxicillin 13, 209 acute 75, 77
Biofilms 5
Amphotericin B deoxycholate 150–151, 151 diagnosis 80
Bioterrorism
Amphotericin colloidal suspension 151 gangrenous 77
recognition 258
Amphotericin lipid complex 151 perforated 75, 77
threats 251
Ampicillin 13, 231 source control for 81–82
Bladder ultrasonography, prostatitis 212
Anal carcinoma 162 see also Human Arachidonic acid 27
Blastomycosis 146–147
papillomavirus (HPV) ARDS see Acute respiratory distress syndrome
Blood–brain barrier (BBB) 243
Anal glands, infection in see Perirectal (ARDS)
Blood urea nitrogen (BUN) 226
abscesses Argentine hemorrhagic fever 257
Boceprevir 159
Anidulafungin 151 Arterial graft infections, surgical management
Boerhaave syndrome 180
Animal bites 66 206
Bolivian hemorrhagic fever 257
Anthrax 251, 251–252 Aspartate aminotransferase (AST) 156
Bone and joint infections
cutaneous 252, 252 Aspergillus fumigatus 148–149, 149
diagnosis 216
gastrointestinal 252 Atazanavir, HIV infection 157
pathogenesis
inhalational 252 Augmentin 13

291
292 INDEX

local and systemic host factors 215 Carbapenems 13, 17–18, 18, 199 fourth-generation 16
microorganism factors 215 spectrum of activity 11 hypersensitivity reactions 16
Bone flap infections 246 Carbenicillin, mechanism of action 12 second-generation 16
Bone scintigraphy 216 Carbuncles 65, 226 spectrum of activity 11
Botulinum toxin 251, 257–258 antibiotics 226 third-generation 16
Bowen disease 163 Carotid artery aneurysm 190, 193 Cephalothin 13
Brain abscess 246, 246–247 Carotid endarterectomy 205 Cephamycins 15
Brazilian hemorrhagic fever 257 CARS see Compensatory anti-inflammatory Cerebral spinal fluid (CSF) 243
Brevibacterium spp., skin colonization 64 response syndrome (CARS) Cervical carcinoma 161, 161 see also Human
Bronchoalveolar lavage (BAL), bronchoscopic Caspases 279 papillomavirus (HPV)
100–102 Caspofungin 151 Cervical crepitus 177
Brucella melitensis 254 Catalase 5 Cervical dysplasia see Cervical intraepithelial
Brucellosis 251, 254 Catheter-associated urinary tract infection (CAUTI) neoplasia (CIN)
Bubonic plague 251 109, 109 see also Urinary tract infection (UTI) Cervical intraepithelial neoplasia (CIN) 161
Budesonide 194 Catheter-related bloodstream infections (CRBSIs) Cervical necrotizing fasciitis 199
Bullous impetigo 196–197 115, 116 Cervical space infection (CSI) 199
BUN see Blood urea nitrogen (BUN) causes 115 anatomy
Burkholderia mallei 255 epidemiology 115 entire length-of-neck spaces 190, 190–191
Burkholderia pseudomallei 255 febrile patient management 118, 119 infrahyoid space 191
Burn wound 133 local infection vs. catheter colonization 115 superficial and deep cervical fascial planes 189,
burn wound cultures, use of 133–134 meticillin-resistant S. aureus (MRSA) and 115  189–190, 190
colonization 135, 135–136 microbiology 115–116 suprahyoid spaces 190
diagnosis 133–134 prevention complications 192–193
erythema 134, 135 catheters and sites selection 116–117 diagnosis 191
impetigo 135, 135 education and training 116 imaging studies 191
infectious vs. non-infectious complications 134 hand hygiene and aseptic technique 118 microbiology 191–192
invasive infection 136 reduction of, in intensive care unit (ICU) 116 risk factors 191
pathobiology 133 Catheters, intravascular 116–117, 117 see also surgical management of 192
toxic shock syndrome 136 Catheter-related bloodstream infections (CRBSIs) treatment 192
Burn wound infections 133 see also Burn wound Cat-scratch infection 66 Chitin 2
anaerobes 138 CAUTI see Catheter-associated urinary tract infection Chloramphenicol 12, 13
fungi 138 (CAUTI) Chlorhexidine 54
gram-negative organisms 137 Cavernous sinus thrombosis 198 hand washes 126
gram-positive organisms 136–137 CBC see Complete blood count (CBC) Cholecystitis, acute 77
infection control best practice 141 CDC see Centers for Disease Control and Prevention Cholera 254–255
management 139–140 (CDC) Cierny–Mader classification system, osteomyelitis
acticoat A.B. Dressing 141 Cefipime 16 221, 221
bacitracin/polymyxin 141 Cefoxitin 196 CIN see Cervical intraepithelial neoplasia (CIN)
gentamicin sulfate 141 Ceftaroline 16 Ciprofloxacin 12, 13, 252
mafenide acetate 140 Ceftazidime 16 Clavulanic acid 13
mupirocin 141 Ceftobiprole 16–17 Clindamycin 8, 192, 196, 199, 231, 252
nitrofurantoin 141 Ceftriaxone 16, 192, 227 carbuncles 226
nystatin 141 Cell-mediated immunity (CMI) 43, 45 cellulitis 65
povidone–iodine 140–141 Cellulitis 64–65, 225 resistance 8
silver nitrate 140 buccal 197 Clinical Pulmonary Infection Score (CPIS) 100
midfacial 196 Clostridium botulinum 257
silver sulfadiazine 140
complications 197–198 Clostridium difficile 123, 123, 124
sodium hypochlorite 140
tetanus prophylaxis 139 primary 196–197 infections (CDIs) 59, 123
viral 138 secondary 197 community-acquired 129–130
chickenpox 139 treatment 197 diagnosis 125–126
cytomegalovirus (CMV) infection 138–139 orbital 195, 195 fulminant 130
pelvic 232 incidence 124, 125f
herpes simplex virus 139
Centers for Disease Control and Prevention (CDC) pathogenesis 123–124
207, 256 prevention 126–127
C
on prevention of catheter-related bloodstream recurrent 128–129, 129
CABG see Coronary artery bypass graft (CABG)
infections (CRBSIs) 116–118 risk factors 124–125
CA-CDIs see Clostridium difficile CA-MRSA see
surgical site infection (SSI) definition by 51, 52, surgical management 130
meticillin-resistant S. aureus (MRSA)
53
Candida infections 143 see also Fungal infections treatment 127, 127–128
urinary tract infection (UTI) definitions 109
clinical aspects 145 Clostridium myonecrosis 69
Centers for Disease National Nosocomial Infections
epidemiology 143, 144 Clostridium perfringens, necrotizing soft-tissue
Surveillance System 203
management infection 68
Central nervous system (CNS) infection 243
candidemia 145–146 Clostridium spp, exotoxins 5
epidural infections and osteomyelitis 246–248
intra-abdominal abscess 146 Coagulase activity 5
brain abscess 246, 246–247 Coccidioidomycosis 147
peritonitis 146
shunt infections 247–248 Colistin 18
suppurative thrombophlebitis 146 postoperative spine infections 248–250 Collagenase 5
urinary tract infection 146 risk factors 243–244, 244
microbiology 143 Community-acquired pneumonia (CAP) 16
Central venous catheters 117 see also Catheter-related Compensatory anti-inflammatory response
prophylaxis 145 bloodstream infections (CRBSIs)
virulence factors 144, 144 syndrome (CARS) 281
Cephalosporin 6, 15, 15–16, 196, 199, 219 Complement cascade 28, 30
Candida spp. 2, 2–3 see also Candida infections first-generation 16 Complement receptors (CRs) 37
 INDEX 293

Complete blood count (CBC) 209 Delavirdine, HIV infection 157 Erythromycin 8, 13
Complicated skin and skin structure infections Dendritic cells 28–29, 31, 33 mechanisms of action 12
(cSSSIs) 16 classic 33 resistance 8
Computed tomography (CT) function and regulation 33–35 ESBLs see Extended-spectrum β-lactamases (ESBLs)
acute respiratory distress syndrome (ARDS) 282 plasmacytoid 33 Escherichia coli 5, 56, 204, 209
appendicitis 80 Dengue fever 257 intra-abdominal infections 78
bone and joint infections 216 Depilatory creams 54 Esophageal perforation 176–180, 177
brain abscess 246 Descending necrotizing mediastinitis (DNM) 175, ESRD see End-stage renal disease (ESRD)
catheter-related bloodstream infections (CRBSIs) 175–176 Ethmoid sinusitis 197
118 Diabetes mellitus and cervical space infection 191 Etravirine, HIV infection 157
cervical space infection 190, 191 Diarrhea, Clostridium difficile infection (CDI) and European linezolid surveillance network 20
Clostridium difficile infection (CDI) 125 125 Exotoxins 5, 68
after coronary artery bypass graft 174 DIC see Disseminated intravascular coagulation Expressed prostatic secretions (EPS) 213
descending necrotizing mediastinitis, 175, 175 (DIC) Extended-spectrum β-lactamases (ESBLs) 16
emphysematous pyelonephritis 211 Dicloxacillin, carbuncles 226
empyema 169 Didanosine, HIV infection 157 F
esophageal perforation 177 Disseminated intravascular coagulation (DIC) 277 Facial erysipelas 196
intra-abdominals infection 79, 80 DNM see Descending necrotizing mediastinitis Femoropopliteal vein (FPV) 207
necrotizing fasciitis 213 (DNM) Fiberoptic nasotracheal intubation 192
nosocomial sinusitis 194, 195 Doripenem 13, 17, 17, 18 Fidaxomicin, Clostridium difficile infections 127, 128
odontogenic infections 199 Doxycycline 13, 213, 252, 255 FIP see Focal intestinal perforation (FIP)
parotitis 196 carbuncles 226 Fistulography 91
postoperative spine infection 249 DSWI see Deep sternal wound infection (DSWI) Fistulotomy, delayed 91
pyelonephritis 209 Dual specificity phosphatases (DUSPs) 33 Fluconazole 151, 152
renal abscess 210 Dysuria 213 5-Fluorocytosine 151, 151
subdural empyema 245 Fluorodeoxyglucose (FDG) 173, 222
thoracic empyema 169 E Fluoroquinolone 13, 200, 206, 209, 213
vascular surgical site infection (SSI) 205 Echinocandins 152 Focal intestinal perforation (FIP) 237
Conjugation 6 Ecthyma gangrenosum 137, 137 Foley catheter 233
Continuous venovenous hemofiltration (CVVH) 283 EEV see Equine encephalitis virus (EEV) Foreign bodies, and infection 51
Coronary artery bypass graft (CABG) 49, 172 Efavirenz, HIV infection 157 Fosamprenavir, HIV infection 157
Corticosteroids 288 Efflux pumps 13 Foscarnet 165
Corynebacterium spp., skin colonization 64 Electric clippers 54 Fosfomycin 9
Coxielia burnetii 255 ELISA see Enzyme-linked immunosorbent assay Fournier gangrene 213–214, 214
Craniotomy 244, 244, 245 (ELISA) FPV see Femoropopliteal vein (FPV)
CRBSIs see Catheter-related bloodstream infections Emphysematous pyelonephritis 210–211 Francisella tularensis and tularemia infection 253
(CRBSIs) Empyema 169 Fungal infections 143
C-reactive protein (CRP) 216, 236, 245 Emtricitabine antifungal agents 150–152, 151
Crepitus 213 hepatitis B virus (HBV) infection 158 in burned patients 138
Cricothyrotomy 192 HIV infection 157 Candida infections 143–146
Crimean–Congo hemorrhagic fever 257 Endotoxin 2, 4, 287 community-acquired pathogens 146–146
Crohn disease 77 Endotracheal aspirate (EA) 101 non-Candida 148–150
with perirectal abscesses 93 Endotracheal intubation 192 Fungi 1 see also Fungal infections
Cryptococcal infections 147–148 Endovascular stent graft 203 cell structure
CSF see Cerebral spinal fluid (CSF) End-stage renal disease (ESRD) 204 cell wall 2
CSI see Cervical space infection (CSI) Enfuvirtide, HIV infection 157 genetic material 2
cSSSIs see Complicated skin and skin structure Entecavir, hepatitis B virus (HBV) infection 158 dimorphic character 2, 2–3
infections (cSSSIs) Enterobacteriaceae 6, 18 infection mechanism 3
Cubicin Outcomes Registry and Experience 2004 carbapenem breakpoints 18, 18 Furacin see Nitrofurantoin
(CORE) Registry 21 spontaneous bacterial peritonitis 75 Furuncles 65, 225–226
Cutaneous colonization 49 Enterococcus faecium, healthcare-associated IAIs 78 Furunculosis 197
CVVH see Continuous venovenous hemofiltration Enzyme-linked immunosorbent assay (ELISA) 155, Fusidic acid, mechanisms of action 12
(CVVH) 257
Cystitis see Urinary tract infection (UTI) Eosinophils 38 G
Cytokines 27–28, 29 Epidermal growth factor (EGF) 238 GALT see Gut-associated lymphoid tissue (GALT)
Cytomegalovirus (CMV) 165 Epidermodysplasia verruciformis (EV) 163 Ganciclovir 165
burn wound infections 138–139 Epididymitis 212 Garamycin see Gentamicin sulfate
Epididymo-orchitis 212 Gas gangrene 67
D Epidural infections and osteomyelitis Gastroduodenal perforations 77
Dalbavancin 9, 22 brain abscess 246, 246–247 GCS see Glasgow Coma Scale (GCS)
Damage control laparotomy 82 shunt infections 247–248 Gelatinase granules 37
Danger-associated molecular patterns (DAMPs) 27, Episiotomy infections 232 Genital herpes 164 see also Human herpesvirus
28 Epstein–Barr virus (EBV) 164–165, 196 (HHV)
Daptomycin 9, 206, 208 Equine encephalitis virus (EEV) 256 Genital warts 162, 162–163 see also Human
carbuncles 226 Eastern 256 papillomavirus (HPV)
cSSSIs treatment 20–21 Venezuelan 256 Gentamicin 13, 231, 254
Darunavir, HIV infection 157 Western 256 Gentamicin sulfate 141
Dead tissue, and infection 51 5 Ergyphilus 269 Gingivitis 198
Deep cervical fascia 189, 189 Ertapenem 13, 18 Glanders 251, 255
Deep sternal wound infection (DSWI) 172, 172 Erysipelas 65, 196, 225 Glasgow Coma Scale (GCS) 194
De-escalation 100 Erythrocyte sedimentation rate (ESR) 216 Glycemic control, and infection prevention 60
294 INDEX

Glycopeptides 11, 13 genital warts 162, 162–163 postoperative 78

Glycylcycline 13 male genital carcinoma 162 primary peritonitis 75
Gonococcal arthritis 218 vulvovaginal carcinoma 161–162 secondary peritonitis 75
Goodsall rule, anal fistula 90–91, 91 non-genital cutaneous 163 sources 76
Gram-negative rods, skin colonization 64 Humoral immunity 43–44 appendicitis 76–77
Granulomatous disease of childhood, chronic 51 Hyaluronidase 5 biliary disease 77
Group B streptococcal (GBS) infection 197 Hydradenitis suppurative (HS) 66–67 gastroduodenal perforations 77
Guarnieri bodies 256 Hydrochloroquine 255 large/small bowel perforation 77
Guillain–Barré syndrome 257 Hyperbaric oxygen 193 pancreatic/peripancreatic infection 77
Gustilo and Anderson classification system 218, therapy 200 tertiary peritonitis 75
218–219 see also Open fractures, infection Hyperbaric oxygenation, for clostridial necrotizing uncomplicated 75
prevention soft-tissue infections (NSTIs) 68 Intracranial infections 199
Gut-associated lymphoid tissue (GALT) 265 Hyperbilirubinemia 283 Intracranial pressure (ICP) 247
Gut barrier, therapeutic options 267, 267b Intravenous drug abuse (IVDA) 180
Gut lymph hypothesis 263 I Intravenous immunoglobulin 288
IAIs see Intra-abdominal infections (IAIs) Intravenous urogram (IVU) 209
H Iclaprim 22 Investing fascia 189, 189 see also Deep cervical fascia
HAART see Highly active antiretroviral therapy Ilizarov technique 221 Involucrum 216
(HAART) Imipenem 13, 18, 196 Ischiorectal abscess 89, 89 see also Perirectal
Hair at surgical site, removal of 54 Imiquimod 162 abscesses
Hantavirus 251, 257 Immune cell necrosis 27, 27 Isopropyl alcohol 54
HB-EGF see Heparin-binding EGF (HB-EGF) Immune response 27 Isotretinoin 228
Healthcare-associated (HCA) infections 181 Immune system 27 Itraconazole 151, 152
Heat shock proteins (HSP) 28, 278 adaptive 43–45, 44 IVDA see Intravenous drug abuse (IVDA)
Hemoglobin, and microbial growth 51 cells 31
Hemolysins 5 classification 27, 27–28 J
Hemophilus influenzae 4 innate 27, 40–43, 41 JAK-STAT signaling system 33
Hemophilus influenzae type b (Hib) 197 role 27
Heparinase 5 Immunoglobulins 40 K
Heparin-binding EGF (HB-EGF) 238 Impetigo 65, 196, 225 Kaposi sarcoma (KS) 165
Hepatitis A virus (HAV) 156–158 bullous 196–197 Ketoconazole 151, 152
Hepatitis B virus (HBV) 158, 158–159 Indinavir, HIV infection 157 Keystone project 116
Hepatitis C virus (HCV) 159–160 Infective endocarditis (IE) 180–185, 184 Klebsiella pneumoniae 18, 56, 204
Hepatitis D virus (HDV) 160 definitions 180 Koch postulates 263, 264b
Hepatitis E virus (HEV) 160 diagnosis 182 Kyasanur forest disease 257
Hepatitis G virus (HGV) 160 surgical treatment 184
Hepatitis syndrome 255 Inflammation, mediators of 27 L
Herpes simplex infection 163–164 see also Human Inflammatory response Labial abscess 226
herpesvirus (HHV) biology 277–278 Lamina papyracea 193
Hidradenitis suppurativa 227–228 danger recognition 278 Lamivudine
Highly active antiretroviral therapy (HAART) 93 gene expression 278–279, 279 hepatitis B virus (HBV) infection 158
High mobility group box 1 (HMGB1) 280 clinical phenotype HIV infection 157
High-mobility group protein B1 (HMGB1) 28 cardiovascular alterations 280, 280–281 Laparoscopic appendectomy 82
Histoplasmosis 148 immunological alterations 281 Laparotomy 233, 239
HMGB1 see High-mobility group protein B1 metabolic alterations 281 Lassa fever 257
(HMGB1) Inframylohyoid infections 190 LEADER surveillance program 20
Horner syndrome 190 Intensive care unit (ICU) 20, 97–98, 102, 110, LEEP see Loop electrical excision procedure (LEEP)
Horseshoe abscess 91–92, 92 116–117, 125, 143, 193, 235 Lemierre syndrome 190, 193, 199
Hospital-acquired pneumonia (HAP) Interferon-α-2a, HBV infection 158 Leukocidins 5
see Ventilator-associated pneumonia (VAP) Interleukin-1 (IL-1) 4, 288 Leukocytosis 209
HPV see Human papillomavirus (HPV) Intersphincteric abscess 89, 89, 91 see also Leukopenia 257
HSP see Heat shock proteins (HSP) Perirectal abscesses Levofloxacin 13
Human bites 66 Intestinal barrier 264–267, 266 Lincomycins 13
Human herpesvirus (HHV) Intra-abdominal infections (IAIs) 75 Linezolid 9, 197, 206
cytomegalovirus 165 antimicrobial resistance 79 carbuncles 226
Epstein–Barr virus (EBV) 164–165 catheter-associated peritonitis 75 mechanisms of action 12
genital herpes 164 community-acquired 83, 83–84 meticillin-resistant S. aureus (MRSA) infections 19–20
herpes simplex 163–164 complicated 75 ventilator-assisted pneumonia (VAP) treatment 103
HHV-6 165 diagnosis 79–80 Lipoglycopeptides 9
HHV-7 165 healthcare-associated 79, 84–85 Liposomal amphotericin 151
HHV-8 165 intra-abdominal abscesses 75 Lister, Joseph 49
varicella-zoster 164 intra-abdominal phlegmon 76 Logistic Organ Dysfunction (LOD) score 284
Human immunodeficiency virus (HIV) 4, 155–156, management 80 Loop electrical excision procedure (LEEP) 161
156 Lopinavir, HIV infection 157
antimicrobial therapy 83–85
treatment 157 Ludwig’s angina 192, 193, 197
clinical outcomes 83–85
Human papillomavirus (HPV) 161 Lumbar puncture 197
patient risk assessment 80
aerodigestive tract 163 Lymphadenitis 253
physiological resuscitation and support 80
anogenital 161 Lymphocytes 28
source control interventions 80–83
anal carcinoma 162 B cells 39–40
microbial flora 78–79
cervical carcinoma 161, 161 T cells 38–39
pathophysiology 76
 INDEX 295

M Monocytes 28–29, 31 diagnosis 67

Macrolides 13 classic 30 microbiology 67
Macrophages 4, 28–29, 30, 31 dysfunction 28–29 polymicrobial 72, 72
function and regulation 33–35 function and regulation 33–35 risk factors 67
Mafenide acetate 140 micro-RNAs, role of 35, 35–36, 36 staphylococcal 70–71, 71
Magnetic resonance imaging (MRI) 206 intermediate 30 streptococcal 69–70
bone and joint infections 216 non-classic 30 Negative pressure-assisted closure devices 61
brain abscess, 246 release from bone marrow 30 Neisseria gonorrhoeae 218
cervical space infection 191 role in immune system activation 28 Neisseria meningitides 4
intracranial mycotic aneurysms 185 Moxifloxacin 199 Nelfinavir, HIV infection 157
meningitis, 198 M protein coat, Streptococcus pyogenes 4 Neutrophil extracellular traps (NETs) 38
postoperative spine infection 249 MR angiography (MRA) 193 Neutrophils 37
septic arthritis and osteomyelitis, 217, 218 MSCRAMMs (microbial surface components apoptosis 38
subdural empyema 245 recognizing adhesive matrix molecules) 4 function 37–38
thoracic empyema 169 Mucormycosis 149–150 migration 37
Male genital carcinoma 162 see also Human Multidrug-resistant (MDR) Staphylococcus aureus 16 phagocytosis 37–38
papillomavirus (HPV) Multiple organ dysfunction (MOD) score 284, 284 Nevirapine, HIV infection 157
Mannheim peritonitis index 80 Multiple organ dysfunction syndrome (MODS) 261, New Delhi metallo-β-lactamase 1 (NDM-1) 18
MAPK-phosphatases (MKPs) see Dual specificity 263, 277, 281–282 Nissen fundoplication 179
phosphatases (DUSPs) cardiovascular dysfunction 283 Nitrofurantoin 141
MAPKs see Mitogen-activated protein kinases epidemiology 277 Nitrofurazone catheters 111
(MAPKs) gastrointestinal dysfunction 283 NOD see Nucleotide oligomerization domain (NOD)
Maraviroc, HIV infection 157 hematological dysfunction 284 Non-bacterial thrombotic endocarditis (NBTE) 181
Mast cells 38 iatrogenic roots 285 Non-invasive positive pressure ventilation (NIPPV)
Maxillary sinusitis 199 neuromuscular dysfunction 283–284 97, 99
MBP see Mechanical bowel preparation (MBP) renal dysfunction 283 Normothermia 60
Mechanical bowel preparation (MBP) 58–59 respiratory dysfunction 282–283 Nosocomial sinusitis (NS)
Mechanical ventilation (MV), and hospital-acquired severity 284–285 anatomy 193
pneumonia 97–98 see also Ventilator-associated Mupirocin 141, 197, 205 complications 195
pneumonia (VAP) Myeloperoxidase (MPO) 37 diagnosis 194, 194
Mediastinal infections 174–180 Mylohyoid muscle 190 prevention and treatment 194–195
Mediastinitis 192 inframylohyoid 190 risk factors, pathogenesis, and bacteriology
Mediastinum 174 supramylohyoid compartment 190 193–194
Meleney’s gangrene 72 Nuclear factor-κB (NF-κB) pathway 33, 34, 36
Meningitis 198, 245 N Nucleotide oligomerization domain (NOD) 278
bacterial 245 Nafcillin, meticillin-sensitive S. aureus (MSSA) NVE see Native valve endocarditis (NVE)
sterile 245 infection 15 Nystatin 141
Meropenem 13, 18, 196 National Healthcare Safety Network (NHSN) 52, 53
Mesenteric lymph node (MLN) 263 data on catheter-associated urinary tract O
Methylmethacrylate 246 infections (CAUTIs) 110, 110 Oakley classification, mediastinitis 172
Meticillin-resistant Staphylococcus aureus (MRSA) 14, data on ventilator-associated pneumonia (VAP) 97 Obstetric and gynecological infections
69, 191, 203, 225 National Nosocomial Infection Surveillance (NNIS) postoperative infections 228–229, 229
antibiotics for treatment 19–22 52, 53 postoperative pelvic infection 232, 232–233
catheter-related bloodstream infections (CRBSIs) data on ventilator-associated pneumonia (VAP) 97 postpartum endometritis 230–232, 231
116 Native valve endocarditis (NVE) 180 surgical site infection 229–230, 230
community-associated meticillin-resistant NBTE see Non-bacterial thrombotic endocarditis (NBTE) Oculoglandular infection 253
Staphylococcus aureus (CA-MRSA) 5, 57 Necrotizing enterocolitis (NEC) Odontogenic infections 197 see also Cellulitis
skin infections by 65 Bell stages of 236 complications 199–200
pneumonia 98, 99 complications 239 diagnosis 198–199
surveillance cultures 54 diagnosis mandibular 198
Meticillin-sensitive Staphylococcus aureus (MSSA) clinical 236 maxillary 198
69, 204 differential 237 microbiology 198
Metronidazole 8, 199, 227, 231 laboratory findings 236–237 pathogenesis 198
Clostridium difficile infections (CDIs) 127, 127–128 radiographic 237 risk factors 198
resistance 8 experimental and emerging science treatment 199
Micafungin 151 epidermal growth factor (EGF) 238 Omsk hemorrhagic fever 257
Microbial colonization, skin 63–64, 64 probiotics 238 Open fractures, infection prevention 218–219
Micrococci, skin colonization 64 antibiotic therapy 219, 219–220
surgical management 238–239
Micro-RNAs 35, 35–36, 36 debridement 220
pathology 237, 237
Migration inhibitory factor (MIF) 279 fracture stabilization 221
pathophysiology
Milwaukee protocol 167 Gustilo and Anderson classification system 218,
abnormal bacterial colonization 235
Minimum inhibitory concentration (MIC) 11 218–219
enteral feeding 235
Minocycline, carbuncles 226 wound management 220–221
immature intestinal barrier 235
MiRNA-155 35, 35 Orchitis 212
Mitogen-activated protein kinases (MAPKs) 33–34, immunoglobulins 235 Oritavancin 9, 22
34, 36 inflammatory mediators and 236 Oroantral fistula 199
MLN see Mesenteric lymph node (MLN) treatment 237–238 Osteomeatal complex 193
MODS see Multiple organ dysfunction syndrome Necrotizing fasciitis 198, 213–214, 214 Osteomyelitis 199–200, 243
(MODS) Necrotizing soft-tissue infection (NSTI) 67 adult 218
Monobactams 13, 17 characteristic findings 67 pediatric 216-218
clostridial 68–69, 69
296 INDEX

P Pilonidal abscess 93, 93–94, 95 Pyelonephritis 209–210 see also Urinary tract
PAMPs see Pathogen-associated molecular patterns excision of 93–94, 94, 95 infection (UTI)
(PAMPs) Pilonidal pits 93, 93 Q
Panendoscopy 178 PIRO (predisposition, insult, response, organ Q fever 251, 255
Paneth cells 235 dysfunction) model 276, 277 Quinolones 19, 253
Panton–Valentine leukocidin (PVL) 5, 197 PJI see Periprosthetic joint infections (PJI) resistance 8
Paracoccidioidomycosis 148 Plague infection 252–253, 253 spectrum of activity 11
Parapneumonic pleural effusion (PPE) 169 Plasmids 6
Parotitis Platelet-activating factor (PAF) 279 R
anatomy 195 PML see Progressive multifocal leukoencephalopathy Rabies 166–167
bacteria in acute 196 (PML) Raltegravir, HIV infection 157
diagnosis 196 Pneumocystis pneumonia 150, 150 Reactive oxygen species (ROS) 37–38
pathogenesis and microbiology 195–196 Polyethylene glycol solutions 59 Relapse 185
risk factors 195 Polymerase chain reaction (PCR) 126, 216, 227, Renal abscess 210, 210
treatment 196 253 Renal ultrasonography, pyelonephritis 209
Pasteur, Louis 50 Polymixins 9 Resistance
Patent ductus arteriosus (PDA) 237 Polymorphonuclear leukocytes (PMNs) 27, 27, 37 see antimicrobial 5–6
Pathogen-associated molecular patterns (PAMPs) also Neutrophils genetics of 6
27, 28 Polymyxin 13 mechanisms 6–8, 9
Pathogen recognition receptors (PRRs) 28, Polyoma viruses 165–166, 166 Retinoic acid-inducible gene I (RIG) 278
32, 33 BK polyoma infection 166 Retropharyngeal infection 190
Pattern recognition receptor (PRR) 27, 278 JC polyoma infection 166 Reverse transcriptase polymerase chain reaction
Penicillin 14–15, 200, 252 rabies 166–167 (rtPCR) 156, 158
aminopenicillins 15 Polypeptides 13 Ribavirin 159, 257
anti-pseudomonal 15 Polytetrafluoroethylene (PTFE) 207 Ricin 251, 258
anti-staphylococcal 14–15 Porins 1–2 Rifampin (rifampicin) 9, 12, 13, 207
cellulitis 65 Posaconazole 151, 152 Rifamycins 13
mechanisms of action 12 Positron emission tomography (PET) 216 Rift Valley fever 257
natural 14 thoracic empyema 169 RIG see Retinoic acid-inducible gene I (RIG)
Pepsis 276 Post-exposure prophylaxis (PEP) 167 Rilpivirine, HIV infection 157
Peptidoglycan 1 Postoperative cranial infections Ritonavir, HIV infection 157
Peptococci, skin colonization 64 meningitis 245 Roseola 165
Percutaneous drainage 82 subdural empyema 245–246
Perianal abscess 89, 89 see also Perirectal abscesses Postpartum endometritis 230–232, 231 see also S
Perinephric abscess 210 obstetric and gynecological infections Saquinavir, HIV infection 157
Peripheral catheters 116–117 see also Poststyloid compartment infections 190 SARS see Severe acute respiratory syndrome
catheter-related bloodstream infections (CRBSIs) Post-traumatic osteomyelitis 221–222 (SARS)
Peripheral graft infections, treatment 205 Cierny–Mader classification system 221, 221 Scrotal ultrasonography, epididymo-orchitis 212
Periprosthetic joint infections (PJI) 222–223 Povidone-iodine 54, 140–141 Selective decontamination of digestive tract (SDD)
Musculoskeletal Infection Society 222–223 PPE see Parapneumonic pleural effusion (PPE) 99, 269–270
Perirectal abscesses 89–93, 213 PRCT see Prospective randomized clinical trial Selective gut decontamination (SGD) 127
with Crohn disease 93 (PRCT) Selective oral decontamination (SOD) 270
diagnosis 89 Prebiotics 268–269 Sepsis 80, 81b, 133, 197, 275, 276
differential diagnosis 89–90 Pressure-adjusted rate (PAR) 284 apoptosis 279
drainage 90, 90 Prestyloid compartment infections 190 definition 276
and fistulas 90–91, 91 Probiotics 238, 268–269 epidemiology 277, 278
granulocytopenic patients and 93 Proctosigmoidoscopy 126 evolving concepts 275–277
HIV-positive patients and 93 Programmed cell death 279 host–microbial interactions 275
with leukemia 93 Progressive multifocal leukoencephalopathy (PML) inflammation, mediators 279–280
with necrotizing infection 92, 92 165 management 285–287, 286
postoperative care 92 Propionibacterium acres 66 to organ dysfunction 277
recurrent 90 Prospective randomized clinical trial (PRCT) perianal 93
symptoms 89 268 severe 276
treatment 90–92 Prostanoids 236 Sepsis Resuscitation Bundle 80
types 89, 89 Prostate abscess 212–213 Septic arthritis
Perirectal fistulas 89, 89 see also Perirectal abscesses Prostate-specific antigen (PSA) 213 adults 218
Peritonitis 75 Prostatitis 212–213 pediatric 216-218, 217
catheter-associated 75 acute bacterial 212 Septic shock 80, 81, 276
primary 75 asymptomatic 212 Sequential Organ Failure Assessment (SOFA) score
secondary 75 chronic bacterial 213 284
source control for 82–83 Prosthetic valve endocarditis (PVE) 180 Sequestration 75
tertiary 75 Protected specimen brush (PSB) 100–102 Serratia spp. 5
Peritonsillar space 190 Protein A 215 Seton 91
Phagocytosis 27 PRRs see Pathogen recognition receptors (PRRs) Severe acute respiratory syndrome (SARS) 275
and microbial killing 37–38 Pseudomonas aeruginosa 5, 16, 204 Sex pili, Gram-negative bacteria 2
Pharmacodynamics 14 pneumonia 98, 98, 99 SGD see Selective gut decontamination (SGD)
Pharmacokinetics 14 Pseudomonas spp., burn wound infections 137, Short bowel syndrome 239
Phlegmon, intra-abdominal 76 137 Shunt infections 247–248
Phosphate-containing mechanical bowel Psittacosis 251 Sialography 196
preparation (MBP) 59 PVE see Prosthetic valve endocarditis (PVE) Siderophores 5
PI3K-Akt pathway 36 Pyelitis 210–211 Silver-coated catheters 111
 INDEX 297

Silver nitrate (AgNO3) 140 Surgical Care Improvement Project (SCIP) 172, prevention 170, 170
Silver sulfadiazine 140 172 surgical treatment 171
SIRS see Systemic inflammatory response syndrome Surgical site infection (SSI) 49, 172, 203 Thrombocytopenia 257
(SIRS) Centers for Disease Control (CDC) definition 51, 52 Tigecycline 9, 13, 21
Sjögren syndrome 195 deep incisional 52 complicated skin and skin suture infections
Skene gland abscess 228 determinants 49 (cSSSIs) treatment 21
Skin antiseptics 54–55 diagnosis 51 spectrum of activity 11
Skin, skin structure, and soft-tissue infections intraoperative prevention methods Tipranavir, HIV infection 157
(SSSTIs) 63 adhesive drapes 55 Tissue injury 27
animal bites infection 66 air-handling systems 55 Tobramycin 207
cellulitis 64–65 bowel preparation 58–59 Toll-like receptors (TLR) 28, 33, 278
clostridial necrotizing soft-tissue infections (NSTIs) delayed primary closure 55 Toll-like receptor 4 (TLR-4) 33, 34
68–69 drainage systems 55 Tonsillitis 199
erysipelas 65 hair removal 54 Torqueteno (TT) virus 160
human bites infection 66 operating room traffic 55 Total parenteral nutrition (TPN) 270, 271
hydradenitis suppurative 66–67 Toxic shock syndrome (TSS) 136, 196
preventive antibiotics 56–58, 57
necrotizing soft-tissue infection 67 Tracheotomy 192
skin antiseptics 54–55
polymicrobial NSTIs 72 Transduction 6
technical considerations 55
pyogenic 65–66 Transesophageal echocardiography (TEE) 183
wound sealant 55
skin anatomy and 63, 63–64, 64 Transformation 6
management
staphylococcal NSTIs 70–71 Transient colonization, skin 64
streptococcal NSTIs 69–70 antimicrobial management 61 Transthoracic echocardiography (TTE) 183
Slow low-efficiency dialysis (SLED) 283 drainage and debridement 60–61 Trimethoprim, mechanisms of action 12
Smallpox 251, 255–256, 256, 257 foreign bodies removal 61 Trimethoprim–sulfamethoxazole 8
SOD see Selective oral decontamination (SOD) wound management 61 carbuncles 226
Sodium hypochlorite (NaOCl) 140 organ/space 52 cellulitis 65
SOFA score see Sequential Organ Failure Assessment pathophysiology resistance mechanism 8
(SOFA) score host responses 51 Tularemia 251, 253–254
Soft-tissue crepitus 67 inoculum of contamination 49–50, 50 inhalational 253
Spine infections, postoperative 248–250 surgical site environment 50–51 Tumor necrosis factor (TNF) 4, 287
Spontaneous bacterial peritonitis 75 virulence of contamination 50, 50 Typhus 251
Sporotrichosis 148–149 physiologic prevention methods
SSSTIs see Skin, skin structure, and soft-tissue glycemic control 60 U
infections (SSSTIs) normothermia 60 Ultrasonography
Staphylococcus aureus 5, 56, 191, 215, 218, 243 supplemental oxygen 59–60 appendicitis 80
burn wound infections 136 postoperative prevention methods 60 bladder 212
microbial surface components recognizing preoperative prevention methods 53 cervical space infection 191
adhesive matrix molecules (MSCRAMMs) 4, 5 nursing home patients 54 intra-abdominal infection 79
necrotizing soft-tissue infection (NSTI) 70–71 prehospitalization cleansing 53–54 necrotizing enterocolitis 237
skin colonization 64 preoperative hospitalization 54 nosocomial sinusitis 194
Staphylococcus epidermidis 37, 51, 56 prior antibiotics 54 odontogenic infections 199
skin colonization 64 parotitis 196
surveillance cultures 54
Stavudine, HIV infection 157 pyelonephritis 209
risk factors 204
Stenotrophomonas maltophilia, ventilator assisted renal abscess 210
superficial incisional 52
pneumonia (VAP) by 98 shunt infection, 248
surveillance 51–53
Stensen’s duct 195, 196 thoracic empyema 169
Surveillance cultures 54
Sternal wound infections 172–174, 174 Umbilical catheters 117 see also Catheter-related
Synbiotic 2000 FORTE 268
Streptococcal myonecrosis 68 bloodstream infections (CRBSIs)
Synbiotics 268–269
Streptococcus pneumoniae 4 Urethritis 213
Systemic inflammation, mediators 287, 287–288
Streptococcus pyogenes 5, 69, 225 Urinalysis 109–110, 209
Systemic inflammatory response syndrome (SIRS)
cellulitis 65 Urinary infection with obstruction, management
81b, 133, 252, 261, 263, 276, 277
M protein coat 4 211, 211–212
necrotizing soft-tissue infection 69–70 Urinary tract infection (UTI) 109–110, 209
T
Streptococcus viridans 191 epidemiology 110, 110
Tanofovir disoproxil fumarate, HIV infection 157
Streptomycin 12, 13 incidence 110
T cells, activation 45
Stress ulceration 283 pathophysiology 110–111
Tedizolid 22
Study of the Efficacy of Nosocomial Infection prevention 111–112
Teicoplanin 9
Control (SENIC) project 52 signs and symptoms 109
Telaprevir 159
Subdural empyema 245–246 treatment 111
Telavancin 9, 21–22
Submental space 190 Telbivudine, hepatitis B virus (HBV) infection 158
Submucosal abscess 89, 91 see also Perirectal V
Tenofovir, hepatitis B virus (HBV) infection 158
abscesses Vacuum-assisted closure (VAC) 173
Tetracyclines 8, 13
Sulfamylon see Mafenide acetate Vaginal intraepithelial neoplasia (VAIN) 162
mechanisms of action 12
Sulfonamides, mechanisms of action 12 Vaginal microflora 229
resistance mechanism 8
Superantigens 5 Valganciclovir 165
semisynthetic 13
Superficial cervical fascia 189, 189 Vancomycin 173, 192, 196, 197, 206, 208, 238
Thoracic empyema
Superoxide dismutase 5 carbuncles 226
antibiotic treatment 170
Supplemental oxygen, and SSIs 59–60 Clostridium difficile infections 127, 127–128
clinical presentation and diagnosis 169
Supralevator abscess 89, 89, 91 see also Perirectal mechanisms of action 12
intrapleural fibrinolytic therapy 171
abscesses meticillin-resistant S. aureus (MRSA) infections 19
pathogenesis and bacteriology 169–170
resistance 8
298 INDEX

Vancomycin-resistant enterococci (VREs) 20, 128, 137 Ventriculoperitoneal shunts 243 carbuncles 226
Varicella-zoster 164 see also Human herpesvirus VHR see Viral hemorrhagic fever (VHR) cellulitis 225
(HHV) Vibrio cholerae and cholera 254 furuncles 225–226
Vascular surgical site infection Video-assisted thoracoscopic surgery (VATS) hidradenitis suppurativa 227–228
antibiotic therapy 206 171 Vulvar intraepithelial neoplasia (VIN) 162
epidemiology 203–204 VIN see Vulvar intraepithelial neoplasia (VIN) Vulvovaginal carcinoma 161–162 see also Human
preventive measures 207–208 Viral hemorrhagic fever (VHR) 251, 256–257, 257 papillomavirus (HPV)
risk factors 204–205 Virulence 4
in situ graft replacement 206–207, 207 factors 4 W
treatment 205–206 resistance to antibiotic treatment 5–8, 9 Wharton’s duct 190
VAT see Ventilator-associated tracheobronchitis (VAT) secreted toxins 4–5 White blood cell (WBC) 216, 225
VATS see Video-assisted thoracoscopic surgery structural components 4 toxicity 5
(VATS) Viruses 1, 3 Word catheter 227
Venezuelan equine encephalitis virus (EEV) 256 DNA 3–4 Wound sealants 55
Venezuelan hemorrhagic fever 257 infection pattern 3–4
Ventilator-associated pneumonia (VAP) 97, 97, 97, naked 3 X
268, 282 RNA 3 Xanthogranulomatous pyelonephritis (XGP) 211,
diagnosis 100–102, 101 structural elements 3, 3 212
doripenem 17, 17 capsid 3 Xylometazoline 194
incidence 97 nuclear material 3
National Nosocomial Infections Surveillance spikes of viral protein 3 Y
(NNIS) data 97 viral envelope 3 Yellow fever 257
pathogenesis 98–99 Voriconazole 151, 152 Yersinia pestis 252
prevention 99–100 aspergillus infection 149
risk factors 97–98, 103 VREs see Vancomycin-resistant enterococci (VREs) Z
tracheostomy and 100 Vulval infections ZAAPS program see European linezolid surveillance
treatment 102–104 abscesses 226–227 network
Ventilator-associated tracheobronchitis (VAT) 102 Zidovudine, HIV infection 157