SUPPLEMENT ARTICLE

The Quinolones: Past, Present, and Future

Vincent T. Andriole

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Yale University School of Medicine, New Haven, Connecticut

The quinolone class of antimicrobial agents has generated considerable interest since its discovery 140 years
ago. Substantial progress has been made in our understanding of the molecular mechanisms of the action of
quinolones against pathogenic bacteria, the induction of resistance to quinolones in these organisms, and the
potential of each quinolone compound to induce toxicity in treated patients. Here, these key discoveries are
reviewed; the present indications approved by regulatory agencies are described in detail, with comments on
adverse events caused by quinolones in treated patients; and speculation about the future of the quinolones
is proffered, even though their future is difficult to predict, because many factors may affect their clinical
usefulness. However, the emergence of bacterial resistance to the quinolones is a major factor that will determine
the future clinical effectiveness of these agents, so that intense investigation of mechanisms to either prevent
or curtail resistance to quinolones is of prime importance to their future.

PAST (SARs) of the quinolones, with respect to their relative

susceptibilities to the development of bacterial resis-
Unlike some of the first antibiotics discovered during
tance and their potential for causing adverse events in
the past century, the quinolone class of antimicrobial
treated patients [3, 4].
agents was not isolated from living organisms but,
Molecular mechanisms of action. Bacteria face a
rather, was synthesized by chemists. The prolific de-
major topological problem, because each bacterium
velopment of the quinolones began in 1962, when
contains a chromosome that is composed of double-
Lesher et al. [1] made the accidental discovery of nal- stranded DNA, which is 1300 mm long, but the average
idixic acid as a by-product of the synthesis of the an- bacterium is only 2 mm long and 1 mm wide. In 1974,
timalarial compound chloroquine. This discovery led a study by Worcel [5] helped to explain how the chro-
to the development of a library of quinolone com- mosome was packed in Escherichia coli. Worcel ob-
pounds, especially the newer quinolones in clinical use served that the chromosome is subdivided into ∼65
at the present time [2]. Other discoveries followed, but regions, which he called “domains,” each of which is
only a few were of signal importance because they pro- ∼20 mm long and is attached to an RNA core. The size
vided us with (1) a better understanding of the mech- of each domain is reduced by “negative supertwist-
anisms of action of the quinolones; (2) the ability to ing”—that is, supertwisting that occurs against the nor-
modify the quinolone nucleus to improve potency and mal direction of the helical state of DNA in its linear
the spectrum of antibacterial activity; (3) the oppor- form [6, 7]. In 1976, Crumplin and Smith [8] discov-
tunity to prolong the elimination half-life and to im- ered that the quinolone nalidixic acid caused abnormal
prove the pharmacokinetic and pharmacodynamic accumulation of single-stranded DNA precursors and
properties of quinolones, resulting in effective once- that, when each chromosomal domain was supercoiled,
daily dosing; and (4) a clearer understanding of the it was also transiently nicked. Furthermore, when su-
importance of the structure-activity relationships percoiling was completed, the single-stranded DNA
state was abolished by the sealing action of an enzyme
that was specifically inhibited by the quinolone. These
Reprints or correspondence: Dr. Vincent T. Andriole, Yale University School of observations helped to explain the mechanism of action
Medicine, 333 Cedar St., New Haven, CT 06520-8022 (vincent.andriole@yale.edu).
of the quinolones against bacteria [7–9]. Subsequently,
Clinical Infectious Diseases 2005; 41:S113–9
 2005 by the Infectious Diseases Society of America. All rights reserved.
Gellert et al. [10] identified this enzyme that nicks dou-
1058-4838/2005/4102S2-0002$15.00 ble-stranded chromosomal DNA, introduces negative

Overview of Quinolone Development • CID 2005:41 (Suppl 2) • S113

supercoils, and then seals the nicked DNA, and they called it activity could be enhanced by simply adding a fluorine or a
“DNA gyrase” (or “topoisomerase II”) [11, 12]. These obser- chlorine at C-8 to compounds with a cyclopropyl group at N-
vations provided a molecular basis for the potent antibacterial 1 [19]. The most recent key modification was the observation
effects of the newer quinolones. Subsequently, 4 DNA topoiso- that the addition of a methoxy group, instead of a halide, at
merases were identified in bacteria [4, 13]. Topoisomerases I and the C-8 position specifically targets both topoisomerase II and
III are not very susceptible to inhibition by the quinolones, IV, which also may decrease the possibility of the development
whereas topoisomerases II and IV are the 2 major targets of of resistance to quinolones [18, 20]. Of the currently available
quinolones. Both topoisomerases II and IV are tetrameric struc- agents, only gatifloxacin and moxifloxacin have a C-8 methoxy
tures and are composed of 2 subunit pairs. There are 4 subunits group in their chemical structure.
Effect on antimicrobial activity. Differences in the in vitro

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in topoisomerase II: 2 A monomers and 2 B monomers, which
are known as “Gyr A” and “Gyr B,” to denote DNA gyrase [14, activity of the fluoroquinolones primarily form the basis of
15]. Topoisomerase IV also has A and B subunits that are encoded their classification, as shown in table 1. The antimicrobial ac-
by the parC and parE genes. Topoisomerase IV is involved with tivity of the early, first-generation quinolones (i.e., nalidixic
decatenation of the linked DNA molecules in the bacterial cell acid, oxolinic acid, cinoxacin, piromidic acid, pipemidic acid,
[13]. Thus, topoisomerases II and IV are the lethal targets of the and flumequine) was excellent against aerobic, gram-negative
quinolones. Their identification has led to the development of bacteria. However, first-generation quinolones were not very
new quinolones that have increased activity against topoisomer- active against aerobic, gram-positive bacteria or anaerobic bac-
ases II and IV [4, 13, 16]. teria. In 1980, the second-generation quinolones were intro-
Modifications to the quinolone nucleus. A new key finding duced when norfloxacin was synthesized by adding a fluorine
in the evolution of quinolones was modification of the quin- at C-6 and a cyclic diamine piperazine at C-7 [13]. These
olone nucleus through the addition of different substituents at changes added antimicrobial activity against aerobic gram-pos-
the N-1, C-6, C-7, and C-8 positions [4, 13] (see also figure 1 itive bacteria and improved activity against gram-negative bac-
in Owens and Ambrose [17]). These modifications altered the teria, compared with the first-generation compounds, but the
antimicrobial activity, pharmacokinetics, and metabolic prop- second-generation quinolones still lacked activity against an-
erties of the quinolones and provided a better understanding aerobic bacteria. Norfloxacin was the first of the “fluoroquin-
of the SARs in quinolone compounds. The addition of specif- olones,” a name resulting from the addition of a fluorine at
ically selected substituents at these key positions on the quin-
olone nucleus made it possible to target specific groups of Table 1. Classification of quinolone anti-
bacteria and to improve the pharmacokinetics of the earlier microbials: selected examples.
quinolone compounds [18–20]. Some of the key changes in-
First generation
cluded the addition of a fluorine atom at position C-6, which
Nalidixic acid
increased DNA gyrase inhibitory activity, facilitated penetration
Cinoxacin
into the bacterial cell, and provided activity against staphylo-
Second generation
cocci. The addition of a second fluorine group at position C-
Norfloxacin
8 resulted in increased absorption and a longer elimination
Ciprofloxacina
half-life but also increased phototoxicity. The addition of a
Lomefloxacin
piperazine group at position C-7 provided the greatest activity
Ofloxacin
against aerobic gram-negative bacteria and increased the activ-
Levofloxacin
ity against both staphylococci and Pseudomonas species. Al-
Third generationb
kylation of the C-7 ring improved the activity against aerobic
Sparfloxacin
gram-positive bacteria and increased the elimination half-life
Gatifloxacin
of quinolone compounds. The addition of a methyl group to
Grepafloxacin
the distal nitrogen of the C-7 piperazine ring also increased the
Fourth generationc
elimination half-life and improved bioavailability. Finally, the Trovafloxacin
addition of a cyclopropyl group at position N-1 yielded cip- Moxifloxacin
rofloxacin, which has increased antibacterial activity against Gemifloxacin
aerobic gram-positive and gram-negative pathogens. In addi- a
Most potent agent against Pseudomonas
tion, increased activity against Mycoplasma and Chlamydia spe- aeruginosa.
b
cies was achieved by adding an amino group at C-5 and a More potent against Streptococcus pneumoniae
and anaerobes, compared with earlier agents.
fluorine group at C-8 to quinolone compounds that possessed c
Most potent against S. pneumoniae and
a cyclopropyl group at N-1 [3]. Similarly, overall antibacterial anaerobes.

S114 • CID 2005:41 (Suppl 2) • Andriole

the C-6 position. Other second-generation quinolones include various quinolones, but it also is different among the various
ciprofloxacin, ofloxacin, levofloxacin, enoxacin, fleroxacin, species of bacteria [13, 19, 28–31].
lomefloxacin, pefloxacin, and rufloxacin [4]. Newer fluoro- The incidence of adverse events observed in association with
quinolones (i.e., third-generation fluoroquinolones, including the early-generation quinolones was low; adverse events fre-
grepafloxacin, gatifloxacin, sparfloxacin, temafloxacin, tosu- quently appeared within the first several days of treatment and
floxacin, and pazufloxacin) were subsequently developed and occurred with similar frequencies in both young and elderly
had greater potency against gram-positive bacteria, particularly patients, except that CNS adverse events occurred more fre-
pneumococci; they also had good activity against anaerobic quently in elderly patients [32, 33]. The rate of adverse events
bacteria. The final group of compounds (i.e., trovafloxacin, associated with both oral and intravenous fluoroquinolones
appears to be dose related, with an increasing incidence of

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clinafloxacin, sitafloxacin, moxifloxacin, and gemifloxacin) was
termed “fourth-generation fluoroquinolones,” because they adverse events associated with increasing doses and duration
had potent activity against anaerobes and increased activity of therapy [32, 33]. In any event, fluoroquinolones are con-
against pneumococci [4, 13]. Although there are a number of sidered to be relatively safe, compared with other classes of
ways to categorize quinolones (i.e., by chemical structure, by commonly used antimicrobial agents [4, 18, 32, 33]. Gastro-
SARs, by in vitro spectrum of antimicrobial activity, or by intestinal disturbances have been reported most frequently, fol-
clinical efficacy), these classifications clearly are arbitrary. The lowed by CNS adverse effects, hypersensitivity reactions, and,
aforementioned classification system—first to fourth genera- quite rarely, hypotension, tachycardia, crystalluria, thrombo-
tion—is based on the newest spectrum of antibacterial activity cytopenia, leukopenia, and anemia. Some of the early quino-
and potency against pneumococci and anaerobic organisms and lones interacted with theophylline and caffeine and other quin-
provides a practical classification system for clinical use [4]. olone compounds (i.e., those that have a fluorine in the C-8
Effect on pharmacokinetics. In early studies, the quino- position) and produced moderate-to-severe phototoxicity, be-
lones were observed to have excellent oral absorption, good cause they accumulated in high concentrations in skin. Pho-
distribution in tissue, with excellent interstitial fluid levels, entry totoxicity is more common and more severe in association with
into phagocytic cells, and urinary concentrations that exceeded the use of lomefloxacin, fleroxacin, and sparfloxacin and is
the MICs for many common pathogens [21]. Key structural much rarer in association with the use of (in descending order)
modifications resulted in improved pharmacokinetics (e.g., a grepafloxacin, ofloxacin, ciprofloxacin, levofloxacin, and tro-
longer elimination half-life, which permitted once-daily dosing vafloxacin. Phototoxicity reactions have not been reported in
and better tissue penetration) of some of the newest quinolones, association with moxifloxacin and gatifloxacin [4, 32, 33]. For-
tunately, phototoxicity is not a problem associated with the
including gatifloxacin, gemifloxacin, grepafloxacin, moxiflox-
fluoroquinolones currently in common use. Three adverse
acin, sitafloxacin, sparfloxacin, and trovafloxacin [18, 19, 21–
events associated with quinolones—cardiotoxicity (e.g., pro-
23]. Specific modifications included alkylation of the quino-
longation of the corrected QT interval), hepatotoxicity, and
lones, which improved elimination half-life and penetration
hypoglycemia—currently command the most attention [4, 32,
into tissue; the addition of 2 methyl groups to the C-7 piper-
33]. The naphthyridone quinolones (i.e., nalidixic acid, pirom-
azine ring, which increased oral efficacy; the addition of an
idic and pipemidic acid, enoxacin, tosufloxacin, trovafloxacin,
amino group at C-5, which increased lipophilicity; and the
and gemifloxacin) have 2 nitrogens in their basic nuclei—a
addition of a halogen at position C-8, which improved in vivo
traditional nitrogen in the 1 position and a second nitrogen in
activity [4, 13, 19].
the 8 position. Some of the naphthyridone quinolones are as-
Effect on resistance and adverse events. Progress in our
sociated with higher incidences of and a greater number of
understanding of the role of SARs, along with the application
serious adverse events, compared with quinolones without a
of current research techniques, has indicated that bacterial re-
nitrogen in the 8 position.
sistance to quinolones occurs either with the induction of
amino acid changes in specific areas of the parC and parE genes
PRESENT
of topoisomerase IV, particularly in pneumococci, and in the
gyrA gene of topoisomerase II, in staphylococci, or with amino A number of infectious diseases are successfully treated with
acid changes in both topoisomerases II and IV in many bacterial quinolones administered orally or intravenously. Clinical effi-
species [24–28]. The specific areas of these genes are known as cacy has been demonstrated for respiratory tract infections,
“quinolone resistance–determining regions” (QRDRs). Mod- including acute bacterial exacerbations of chronic bronchitis,
erate resistance can also occur because of increased efflux of community-acquired pneumonia, nosocomial pneumonia, and
the quinolone out of the bacterial cell, which reduces intra- bacterial sinusitis. Quinolones also have documented effective-
cellular concentrations of the drug. Key observations have dem- ness for treating uncomplicated (and some complicated) uri-
onstrated that, not only is the level of resistance different among nary tract infections, bacterial prostatitis, skin and other soft-

Overview of Quinolone Development • CID 2005:41 (Suppl 2) • S115

tissue infections, bone and joint infections, gastrointestinal It is also worth noting that, although a quinolone may be
infections caused by toxigenic E. coli or Salmonella species (in- approved to treat a specific infection, consideration must be
cluding typhoid and paratyphoid fevers and the chronic Sal- given to the susceptibility of the infecting organism. In this
monella carrier state), and infection with Shigella, Cam- context, all quinolones are not equal and should not be used
pylobacter, Aeromonas, and Vibrio species and Plesiomonas interchangeably [34]. To use them most effectively, clinicians
shigelloides. The quinolones have also been effective in treating should be familiar with the specific properties and clinical in-
sexually transmitted diseases, such as gonococcal and chla- dications of each quinolone. For example, ciprofloxacin con-
mydial infections, chancroid, and pelvic infections. Some quin- tinues to be an excellent choice for treating infections caused
olones have also been very useful in treating immunocom- by aerobic gram-negative bacilli, including those caused by
drug-susceptible P. aeruginosa.

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promised patients with febrile neutropenia [34–41]. It should
be noted that not all fluoroquinolones have been approved for In contrast to other classes of antimicrobial agents, the ap-
use in the treatment of all of the aforementioned infections. propriate use of the quinolones—in particular for the treatment
The use of all fluoroquinolones interchangeably, especially for of respiratory tract infections—continues to generate much dis-
unapproved indications, is discouraged. cussion among clinical investigators [42–45]. One issue is the
At present in the United States, the most frequently prescribed emergence of resistance to quinolones, particularly among S.
fluoroquinolones are ciprofloxacin, levofloxacin, gatifloxacin, pneumoniae [44, 45] and, more recently, among Haemophilus
and moxifloxacin [34]. Gemifloxacin became available for gen- influenzae [46]. Although the overall incidence of resistance to
eral use in 2004. Ciprofloxacin is approved for use for both quinolones among pneumococci is currently relatively low
uncomplicated and complicated urinary tract infections, includ- (!5%), the incidence is increasing, and the justifiable concern
ing cystitis, pyelonephritis, and chronic bacterial prostatitis; un- is that it will continue to increase [45]. Importantly, resistance
complicated urogenital and rectal gonorrhea; skin and other soft- to quinolones among pneumococci has been observed to occur
tissue infections; bone and joint infections; infectious diarrhea in association with those quinolones that have modest in vitro
and typhoid fever; intra-abdominal infections (when used with activity against pneumococci [47–52]. Therefore, the possibility
metronidazole); sinusitis; nosocomial pneumonia. Cirpofloxacin exists that the use of those quinolones with the most potent
is also approved for use as empirical therapy for patients with in vitro activity against pneumococci may delay the emergence
febrile neutropenia, as prophylaxis and treatment for anthrax, of resistance in these pathogens. However, future studies are
and for lower respiratory tract infections, including acute bac- required to answer this question.
terial exacerbations of chronic bronchitis, pneumonia (other than Another issue of concern is whether in vitro resistance to
pneumococcal pneumonia), hospital-acquired pneumonia, and antimicrobial agents affects clinical outcomes, particularly in
infection with Legionella species (table 2) [34]. Levofloxacin is pathogens responsible for serious respiratory tract infections.
approved for use in treating both uncomplicated and complicated Recent reports suggest that in vitro resistance to b-lactams and
urinary tract infections (including pyelonephritis and chronic macrolides does not correlate with either therapeutic failure or
bacterial prostatitis), skin and skin structure infections, acute increased mortality among patients with pneumococcal pneu-
maxillary sinusitis, acute bacterial exacerbations of chronic bron- monia [53, 54]. If these observations are correct, then they are
chitis, community-acquired pneumonia (including that due to unique, compared with our earlier experiences with the resis-
penicillin-resistant Streptococcus pneumoniae [PRSP] and mul- tance and clinical outcomes associated with infections caused
tidrug-resistant S. pneumoniae [MDRSP]), and nosocomial by other pathogens. For instance, clinical failure was observed
pneumonia (table 2) [34]. Gatifloxacin is approved for use in after the appearance of resistance to b-lactams among staph-
treating both uncomplicated and complicated urinary tract in- ylococci, resistance to vancomycin and aminoglycoside among
fections (including pyelonephritis), uncomplicated urogenital enterococci, multidrug resistance among Mycobacterium tuber-
gonorrhea, uncomplicated skin and skin-structure infections, culosis, and antiretroviral resistance among HIV. Recently, an
acute sinusitis, and acute bacterial exacerbations of chronic bron- alternative concept has been proffered that may help to explain
chitis and community-acquired pneumonia (including that due the lack of correlation between therapeutic failure and resis-
to PRSP and MDRSP) (table 2) [34]. Moxifloxacin is approved tance to b-lactams and macrolides among pneumococci [55].
for use in treating acute bacterial sinusitis, uncomplicated skin Specifically, the problem may involve the methods used to iden-
and skin-structure infections, and acute bacterial exacerbations tify pneumococci, so that misidentification results in a falsely
of chronic bronchitis and community-acquired pneumonia (in- elevated prevalence of resistance [55]. Misidentification obvi-
cluding that due to PRSP and MDRSP) (table 2) [34]. Gemi- ously would also affect clinical evaluations. Clearly, correct
floxacin is approved for use in treating acute bacterial exacer- identification of pneumococci in additional surveillance stud-
bations of chronic bronchitis and community-acquired ies, as well as proper clinical investigation of outcomes, is
pneumonia of mild-to-moderate severity (table 2). needed to resolve the perplexing issue of the in vitro resistance

S116 • CID 2005:41 (Suppl 2) • Andriole

 Table 2. Approved clinical uses for selected fluoroquinolones.

Agent Approved indications

Ciprofloxacin Acute uncomplicated cystitis in females (oral use only)
Urinary tract infections
Chronic bacterial prostatitis
Uncomplicated cervical and urethral gonorrhea
Skin and skin-structure infections
Bone and joint infections
Infectious diarrhea (oral use only)

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Typhoid fever (oral use only)
Complicated intra-abdominal infections, in combination with metronidazole
Acute sinusitis
Lower respiratory tract infections
Nosocomial pneumonia (iv use only)
Empirical therapy for patients with febrile neutropenia, in combination with piperacillin
sodium (iv use only)
Inhalational anthrax (after exposure)
Complicated urinary tract infections and pyelonephritis in pediatric patients (1–17 years old)
Levofloxacin Uncomplicated urinary tract infections (mild to moderate)
Complicated urinary tract infections (mild to moderate)
Acute pyelonephritis (mild to moderate)
Chronic bacterial prostatitis
Uncomplicated skin and skin-structure infections (mild to moderate)
Complicated skin and skin-structure infections
Acute maxillary sinusitis
Acute bacterial exacerbation of chronic bronchitis
Community-acquired pneumoniaa
Nosocomial pneumonia
Moxifloxacin Acute bacterial sinusitis
Acute bacterial exacerbation of chronic bronchitis
Community-acquired pneumoniaa
Uncomplicated skin and skin-structure infections
Gatifloxacin Uncomplicated urinary tract infections
Complicated urinary tract infections
Pyelonephritis
Uncomplicated urethral and cervical gonorrhea
Acute uncomplicated gonococcal rectal infections in women
Uncomplicated skin and skin-structure infections
Acute sinusitis
Acute bacterial exacerbation of chronic bronchitis
Community-acquired pneumoniaa
Gemifloxacin Acute bacterial exacerbation of chronic bronchitis
Community-acquired pneumonia (mild to moderate)a
a
Includes pneumonia due to multidrug-resistant Streptococcus pneumoniae.

to and clinical efficacy of quinolones used to treat respiratory of newer compounds may have (1) greater potency, particularly
tract infections. against staphylococci and enterococci; (2) better penetration into
the CNS and cerebrospinal fluid; (3) broader and more potent
FUTURE activity against anaerobic bacteria; (4) greater activity against
The future of the quinolones is difficult to predict. Nevertheless, infections caused by mycobacteria and Stenotrophomonas, Pseu-
the quinolone nucleus continues to provide opportunities for domonas, and Alcaligenes species, which currently are difficult to
future modifications that may produce more valuable com- treat; (5) decreased drug-drug interactions; and (6) better patient
pounds. As mentioned in earlier reviews [2–4], future prospects tolerability, with lower incidences of adverse reactions and serious

Overview of Quinolone Development • CID 2005:41 (Suppl 2) • S117

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