Bacterial uropathogenic factors.

A limited number of E. coli serotypes cause most UTIs. Bacteria that cause infection have increased
adhesion, colonization and tissue invasiveness relative to nonpathogenic bacteria. The mediators of
these pathogenic features include pili, substances that increase resistance to bacteriocidal activity and
mediators of invasiveness. Pili control bacterial adherence. Specifically, Type 1 pili adhere to mannose in
the urinary epithelial mucopolysaccharide lining, and also to polymorphonuclear leukocytes (PMNs); they
are often associated with cystitis (bladder infection). P pili are mannose resistant and adhere to renal
glycolipid receptors. They do not bind PMNs and are therefore relatively resistant to phagocytosis and
clearing by PMNs. They are most often associated with kidney infections (pyelonephritis). One
characteristic of E. coli that allows it to ascend to the kidney is the phasic variation of Type 1 pili; because
of this, PMN binding is minimized and phagocytosis is less effective. One of the significant factors in
resistance to bactericidal activity involves the expression of K antigen (capsular polysaccharide) on
bacteria. Another mediator, hemolysin, produced by certain bacteria, can augment tissue invasiveness
and predispose to infection.

Host defenses
There are several factors relating to host defenses that determine susceptibility to UTIs. Mechanical
issues such as urethral length (female shorter than male), completeness of bladder emptying (leading to
residual urine in the bladder) and the integrity of the natural uretervesical junction "valve" (leading to
vesicoureteral reflux) are important anatomic issues that predipose to UTIs. Biochemical properties are
normally important in making bacterial survival difficult in urine: acid pH, high urea content, and high
osmolality. In addition, mucosal mucopolysaccharide within the lining of the urinary tract as well as
systemic and local antibody production may be protective for UTIs. Finally, it is clear that there may be a
genetic predisposition to UTIs, as certain HLA and Lewis blood group (non-secretor status) factors may
put patients at higher risk due to increased colonization ability or increased adherence by bacteria to the
urinary tract epithelium.

Natural Defenses of Urinary Tract

1. Periurethral and Urethral Region: Normal flora in these regions contain: lactobacilli, coagulase negative
staph, corynebacterium and streptococci that form barriers against colonization. Changes in estrogen, low
vaginal pH and cervical IgA affect colonization by normal flora
2. Urine: high osmolality, high urea concentration, low pH, high organic acid conc are protective. Glucose in
urine may facilitate infections. Tamm Horsfall proteins may be protective.
3. Bladder: Epithelium expresses Toll-like receptors (TLRs) that recognize bacteria and initiate
immune/inflammatory response (PMNs, Neutrophils, Macrophages, Eos, NK cells, Mast cells and
dendritic cells). Adaptive immune response then takes over (T and B lymphocytes). Induced exfoliation of
cells also occurs to allow excretion of infection.
4. Kidney: local immunoglobulin/ antibody synthesis in the kidney occurs in response to infections (IgG,
SIgA).

Alterations in Host Defense Mechanisms

 Obstruction: key factor in increasing susceptibility to UTI but does not necessarily always predispose to
infection.
 VUR: Hodson and Edwards (1960) described association of VUR, UTI, renal scarring and clubbing.
 Underlying Disease: DM, SCD, Nephrocalcinosis, Gout, Analgesic abuse, aging, hyperphosphatemia,
hypokalemia.
o DM: Glycosuria may contribute to severity. Majority of infections (80%) are in the upper tracts.
o Papillary necrosis: due to DM, Pyelo, obstruction, Analgesics, SCD, transplant rejections, Cirrhosis,
Dehydration, Contrast media, renal vein thrombosis. Some patients have chronic sloughing of papillae.
Retained necrotic papilla may calcify and act as nidus for further infection
o HIV: UTIs 5x more prevalent in this population and they recur more frequently.
 Pregnancy: Bacteriuria in pregnancy = 4-7% and incidence of acute clinical pyelo = 25-35% in untreated
patients.
 Spinal Cord injury with High Pressure bladder: high morbidity and mortality from bacteriuria

Table 1. Potentially Infective Pathogens in the Urinary Tract

Common Causative pathogens in Adult UTIs
E. Coli (80% of outpatient UTIs)
Klebsiella; Enterobacter
Proteus
Pseudomonas
Staphylococcus saprophyticus (5 - 15%)
Enterococcus
Candida
Adenovirus type 11

Normal perineal flora:

Lactobacillus
Corynebacteria
Staphylococcus
Streptococcus
Anaerobes

DIAGNOSIS OF UTI
Clinical symptoms. Symptoms are very helpful in the diagnosis of a UTI, but do not help to accurately
localize the infection within the urinary tract is difficult. In many cases, however, UTIs can be
asymptomatic. The most common form of UTI is cystitis (bladder infection) characterized by irritative
symptoms such as urinary urgency, frequency, dysuria, as well as hematuria, foul-smelling urine, and
suprapubic pain. These symptoms are also typical for urethritis and prostatitis in addition to cystitis. An
associated epididymis, diagnosed reliably by physical examination in men, is an easily localizable
variation of UTI. Symptoms associated with "upper urinary tract" infections, exemplified by pyelonephritis,
may include those typical of cystitis, as well as fever, rigors, flank or abdominal pain, and nausea and
vomiting.

Collection method. Analysis of the urine is critical in determining the likelihood of infection. The method of
urine collection is important to distinguish between contamination and true infection. There are 3
commonly used methods of collection: a) clean catch midstream voided urine, b) catheterized urine and
c) suprapubically aspirated urine. The most variable of these three is the midstream voided urine,
especially in females, where contamination of urine by vaginal or perineal organisms is common during
collection. Voided urines that are sterile or contain high colony counts (>100,000) of a single bacteria
correlate well with urine obtained by other methods.
 Urinalysis. A positive chemical (dipstick) leukocyte esterase is 64 - 90% specific and has a similar level of
sensitivity for UTI. The finding of nitrite positivity on urine dipstick, indicating the conversion of nitrate to
nitrite by gram negative bacteria (not gram positive), is very specific but only about 50% sensitive for a
urinary tract infection. The finding of elevated white blood cells in the urine (pyuria) is the most reliable
indicator of infection (>10 WBC/hpf on spun specimen) is 95% sensitive but much less specific for a UTI.

Quantitative urine culture. In general, > 100K colonies/mL on urine culture is diagnostic for UTI. However,
the probability of a UTI does depends on the method of collection. In general, lower colony counts
obtained by sterile urethral catheterization or by suprapubic aspiration can represent true infection, but
clean catch, mid-stream urine that harbors < 100K colonies/mL in a female requires further verification or
repeat sampling to confirm a UTI.

Methods to localize infection. Used mainly to diagnose prostatitis, several localization methods have been
described, but are otherwise uncommonly used. Upper urinary tract infections may be isolated using the
Stamey test in which the bladder urine is cultured after catheterization, both before and after a thorough
saline wash. If the second, post-wash bladder culture is positive, this may indicate upper tract bacteria
entering the bladder. Combining bladder washing with selective ureteral catherization is a more precise
way to localize the laterality of the upper tract infection. To diagnose chronic prostatitis, a "four glass"
quantitative culture test can be used. With this method, urine is collected in four separate containers: 1)
an initial voided urine that reflects bacterial activity within the urethra (urethral pathogens), 2) a
subsequent, mid-stream urine to evaluate bacteria within the bladder. 3) the collection of expressed
prostatic secretions, captured from the penile urethra while messaging the prostate with a rectal exam,
and 4) a post-massage voided urine collection that may reflect prostatic bacteria. Significantly increased
bacterial colony counts in the third (expressed prostatic secretion) and fourth (post-prostatic secretion)
cultures are diagnostic of chronic prostatitis.

Correctable GU abnormalities that cause bacterial persistence:

 Infected stones
 Chronic bacterial prostatitis
 Unilateral infected atrophic kidneys
 Ureteral duplication and ectopic ureters
 Foreign bodies (ie retained ureteral stent)
 Urethral diverticula
 Unilateral medullary sponge kidneys
 Non-refluxing normal appearing, infected ureteral stumps after nephrectomy
 Infected urachal cyst
 Infected communicating cysts of renal calyces
 Papillary necrosis
 Perivesical abscess with fistula to the bladder

INDICATIONS FOR RADIOLOGIC IMAGING WITH UTI

Patients with uncomplicated cystitis or uncomplicated pyelonephritis generally do not benefit from imaging
studies to look for anatomic abnormalities. In patients who do not respond to treatment, or in patients with
predisposing factors, imaging with kidney and bladder ultrasound, or a non-contrast CT scan of the
abdomen and pelvis may be useful. Cystoscopic or ureteroscopic evaluation of the urinary tract is not
typically performed with uncomplicated UTI or pyelonephritis.
DIFFERENTIAL DIAGNOSIS:
Other pathogens, processes and conditions that can cause symptoms that mimic UTI include:
Herpes genitalis (HSV)
Urethritis
N. Gonorrhoeae
Chlamydia
Trichomonas
Vaginitis
Prostatitis
Nephrolithiasis
Trauma
GU tuberculosis
GU neoplasm
Intra-abdominal abscess
Sepsis - source other than GU system

Management of UTI
The combination of clinical findings and urine evaluation are used to diagnose UTI. Treatment is based
upon pathogen identification and the type and degree of clinical illness, and presence or absence of other
predisposing host factors. In general, the treatment consists of hydration, relief of urinary tract
obstruction, removal of foreign body or catheter if feasible, and judicious use of antibiotics.

The type and duration of antibiotic treatment is dependent on site of infection (if known), host factors and
severity of illness. Most antibiotics are highly concentrated in the urine and therefore are very effective at
clearing bacteria from the urinary tract.

Highest mean urine concentration (from highest to lowest):

Cabrenicillin > Cephalexin > Ampicillin > TMP/SMX > Cipro > Nitrofurantoin

However, in cases of pyelonephritis, prostatitis or epididymitis, proper tissue antibiotic concentrations are
important.

When considering treatment, first determine whether the UTI is complicated or uncomplicated in nature.
Uncomplicated infections include acute cystitis in a non-pregnant, premenopausal female, and acute
pyelonephritis in an otherwise healthy patient. Young post-pubertal females are susceptible to
uncomplicated UTIs because of sexual intercourse in combination with delayed post-coital bladder
emptying and the use of diaphragm and spermicidal contraceptives, that alter the normal vaginal flora and
may allow colonization by pathogenic E. coli.

Complicated UTIs are those that occur when certain predisposing factors are present. These factors
include: Obstructed urinary flow due to congenital causes, prostatic obstruction or urinary stones;
incomplete bladder emptying due to anatomic (prostatic or urethral) or neurogenic (congenital or aquired
spinal cord abnormalities) reasons; vesicoureteral reflux, foreign bodies in the urinary tract (instruments,
catheters, drainage tubes); systemic illness such as diabetes; pregnancy and males participating in anal
intercourse.
 Uncomplicated UTI (cystitis, some pyelonephritis):

 3 day course of oral TMP/SMX is 95% effective; 7 days is no more effective.

 If TMP/SMX resistance is > 10 - 20% (U.S. West coast, Europe), use fluoroquinolones.
 Higher percentages of resistance to TMP/SMX also implies possible resistance to ampicillin,
cephalosporins, tetracycline.

Other uncomplicated UTI:

 A full 7 - 10 day antibiotic course should be used in patients with: diabetes, symptom duration before
treatment of > 7 days, pregnancy, age >65 years, or past history of pyelonephritis or UTI with resistant
organisms

Complicated UTI (acute pyelonephritis):

 Empiric parenteral treatment after culture with:

Ampicillin plus aminoglycoside or Ampicillin/ Vancomycin (for beta-lactam allergy) plus aminoglycoside or
third-generation cephalosporin (if no enterococcus)
 Adjust antibiotics according to culture results
 Blood cultures positive in 20 - 40% of patients
 Switch from parenteral to oral therapy at 48 hours after clinically well
 Treat for 14 days.

Acute pyelonephritis with intrarenal, perirenal or pararenal abscess

 Treatment for complicated UTI and add appropriate drainage.

Epididymitis

 TMP/SMX or fluoroquinolones for at least 3 weeks to obtain adequate tissue levels.

Acute bacterial prostatitis

 TMP/SMX or fluoroquinolones for at least 4 weeks to obtain adequate tissue levels

Chronic bacterial prostatitis

 TMP/SMX or fluoroquinolones for 6 - 12 weeks.

Re-infection

 A test of cure should be undertaken by repeat culture in pregnancy, pyelonephritis, and complicated or
relapsing UTI.
 Re-infection is the relatively rapid recurrence of a UTI with the same or different organism after cure has
been documented.
 Each infectious episode should be treated separately.
 Consider 6 - 12 months of antibiotic prophylaxis (once a day oral intake of TMP/SMX or nitrofurantoin at
1/3 to ½ of a daily treatment dose
 For patients with recurrent cystitis related to coitus, consider self-administered single-dose antibiotics
post-coital treatment.

Relapsing infection

 Failure to clear or completely eradicate the pathogen despite a reasonable treatment course
 Should trigger a urologic investigation that includes imaging to define possible anatomical causes and
prolonged therapy in the meantime.

Asymptomatic bacteriuria

 Generally, does not need treatment, except in pregnancy.

 Treatment is not indicated in the elderly (20 - 40% incidence) and patients on catheterization (90%
incidence).

Summary

1. Urinary tract infection are both prevalent and costly.

2. Bacterial UTIs (different from urinary colonization) results from the interaction of multiple host and
bacterial factors.
3. The diagnosis of UTI is made by urine examination and a clinical picture of illness.
4. A broad differential diagnosis can exist with urinary tract symptoms that include nonbacterial pathogens,
and non-infectious conditions.
5. Effective treatment of bacterial UTI depends on the pathogen, severity and site of illness, and other
complicating patient factors.

References
Pontari, M. AUA Core Curriculum for Residents "Urinary Tract Infections"

Shoskes, D. (2011): Urinary Tract Infections Retrieved From: The American Urological Association
Educational Review Manual in Urology: 3rd Edition Chapter: 23 Page: 737-766

Smith's General Urology 16th edition 2004. Tanagho and McAninch, eds. Chapter 13. "Bacterial
Infections of the Urinary Tract" Nguyen, Hiep. pp. 203 - 227.

Stamm, WE, Norrby, SR. Urinary Tract Infections: Disease Panorama and Challenges. J Infect Dis. 2001
Mar 1; 183 Suppl 1:S1-4.

Hooten, TM, Scholes, D, Hughes, JP, et al. A Prospective Study of Risk Factors for Symptomatic Urinary
Tract Infection in Young Women. NEJM 1996; 335: 468-74