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Fluoroquinolone Antimicrobial Agents
Fluoroquinolone Antimicrobial Agents
Fluoroquinolone Antimicrobial Agents
Activity in Vitro
In general, quinolones have excellent potency in vitro3,11 against most
Enterobacteriaceae, fastidious gram-negative bacilli including species of haemophilus,
and gram-negative cocci, such as Neisseria gonorrhoeae, N. meningitidis, and Moraxella
Pharmacokinetic Properties
The pharmacokinetics3,13-18 of quinolones given orally to healthy subjects are shown in
Table 2Table 2
Pharmacokinetic Properties of a Single 400-mg Oral
Dose of Quinolone Administered to Normal Subjects.. Absolute oral bioavailability
exceeds 50 percent and is greatest (>95 percent) for ofloxacin and pefloxacin. The
terminal half-lives of elimination are relatively long, allowing doses to be given twice or
once daily. The areas under the curve of serum concentrations plotted against time differ,
tending to be lower for ciprofloxacin, in part offsetting the greater potency of this agent
in vitro. Binding to serum proteins is 14 to 25 percent, except for enoxacin, for which
binding is 18 to 54 percent. The volumes of distribution exceed total body water content,
in a manner consistent with the concentration of quinolones in many tissues. The drug
concentrations are very high in urine, high in kidney and prostate tissue, but lower in
prostatic fluid. Concentrations in feces are very high, resulting in a marked reduction in
species of Enterobacteriaceae, variable reductions of enterococci, and minimal effects on
anaerobic bacteria. Peak drug concentrations in saliva and bronchial secretions tend to be
lower than those in serum, but concentrations in lung tissue substantially exceed serum
concentrations. Their ability to penetrate into cerebrospinal fluid is low except for
pefloxacin (40 percent of serum) and ofloxacin (90 percent of serum). Quinolones are
concentrated in macrophages and polymorphonuclear leukocytes.
Elimination is both renal and nonrenal for norfloxacin, ciprofloxacin, enoxacin,
fleroxacin, and lomefloxacin; primarily renal for ofloxacin; and primarily nonrenal for
pefloxacin. With the exception of pefloxacin, less than 20 percent of the drug is
eliminated by conversion to less active metabolites. Norfloxacin, the chief metabolite of
pefloxacin, has activity equivalent to pefloxacin.
The terminal half-lives of elimination in patients with poor renal function or none are
increased about 2-fold for norfloxacin, ciprofloxacin, enoxacin, and fleroxacin and 4.5fold for ofloxacin, and are unchanged for pefloxacin but not its metabolite, norfloxacin.
Hemodialysis and peritoneal dialysis contribute 14 percent or less to the elimination of
norfloxacin, ciprofloxacin, ofloxacin, and enoxacin. In elderly patients, peak serum
concentrations may be 1.3-fold to 3.0-fold higher than in younger patients, reflecting
increased oral absorption, reduced renal elimination, or both.
Clinical Efficacy
Unless stated otherwise, quinolones were given orally in the studies described.
Norfloxacin has been effective for infections of the genitourinary and gastrointestinal
tracts, although in the United States susceptibility criteria have been developed only for
infections of the urinary tract. Ciprofloxacin, ofloxacin, enoxacin, pefloxacin, fleroxacin,
Bacterial Prostatitis
In a small comparative study that included cultures of expressed prostatic secretions
(most often yielding Escherichia coli), treatment with norfloxacin for four to six weeks
produced bacteriologic cures in 92 percent of patients one month after treatment, as
compared with 67 percent of those treated with trimethoprimsulfamethoxazole.30 In
open studies with other quinolones given for 4 weeks or longer, 65 to 91 percent of
patients were cured at follow-up 1 to 13 months later.22 With two weeks of ciprofloxacin
therapy and longer follow-up, however, the rates of cure were lower and included
treatment failures with Enterococcus faecalis.31
Currently, the use of quinolones as primary therapy for sexually transmitted diseases
seems limited by the need to exclude patients with syphilis and those who are pregnant
(see below).
Gastrointestinal Infections
The bacterial pathogens49,50 often implicated in diarrhea in travelers to areas of poor
sanitation are strains of enterotoxigenic E. coli and species of shigella. In a double-blind
study of patients with traveler's diarrhea, a three-day course of norfloxacin begun within
24 hours of the onset of symptoms was more effective than placebo in eradicating
pathogens (74 vs. 38 percent) and shortening the duration of diarrhea (3.2 vs. 4.4
days).51 As compared with placebo, ciprofloxacin begun within 72 hours of the onset of
symptoms) also shortened the duration of diarrhea (from 81 to 29 hours), a result similar
to that observed with trimethoprimsulfamethoxazole (from 81 to 20 hours).52 For
prevention of traveler's diarrhea, both norfloxacin53-55 (protection rates of 68 to 92
percent) and ciprofloxacin56 (protection rate of percent) were effective when compared
with placebo in double-blind studies, but antimicrobial agents are not routinely
recommended for this use.
Quinolones have also been evaluated for the treatment of bacterial gastroenteritis in
nontravelers in several double-blind comparative studies. In a study from Thailand in
which vibrio species, Pleisomonas shigelloides, and species of aeromonas were the
predominant pathogens, a three-day course of norfloxacin was more effective than
placebo (97 vs. 40 percent) in eradicating pathogens from stool, but there were no
differences in the time required for the resolution of diarrhea.57 In two other blinded
comparative studies in which species of campylobacter, salmonella, and shigella
predominated, ciprofloxacin was better than placebo58,59 and trimethoprim
sulfamethoxazole59 in shortening the duration of fever and diarrhea as well as
eradicating stool pathogens. In one of these studies,58 the duration of diarrhea in the
subgroup with salmonella infections was also significantly shortened from 3.4 days to 1.9
days, but in 25 percent of the patients receiving ciprofloxacin, salmonellae were
reisolated from the stools within three weeks after the completion of therapy. In
unblinded comparative studies of shigellosis, norfloxacin and enoxacin were equal in
efficacy to trimethoprim sulfamethoxazole, even when norfloxacin was administered in
a single dose.60 The limited data on the treatment of Camp. jejuni infections suggest that
ciprofloxacin may shorten symptoms.58,59 Treatment failures associated with the
emergence of quinolone-resistant strains of Camp. jejuni have been documented,
however.59 Small numbers of patients with infections with Yersinia enterocolitica
responded to therapy with quinolones. Despite the increasing use of quinolones, the
development of diarrhea associated with the presence of the Clostridium difficile toxin in
stools has been documented only rarely.61
Quinolones are effective therapy for typhoid fever and rapidly eliminate Salmonella typhi
from the stool without the development of a carrier state, but direct comparisons of
quinolones with chloramphenicol have not yet been reported. Nontyphoidal salmonella
infections in immunocompromised patients, including those with the acquired
Only a few patients with septic arthritis (caused by N. gonorrhoeae, Str. pneumoniae, or
E. coli) have been treated with ciprofloxacin.9,82 Failures have been associated with the
presence of prosthetic joints82 and the development of resistance in strains of S. aureus
and P. aeruginosa.
Other Uses
For the initial empirical therapy of episodes of fever in patients with neutropenia,
intravenous ciprofloxacin in combination with aminoglycosides or -lactam antibiotics
has been compared with combinations of -lactam antibiotics and aminoglycosides.92-94
The patients had similar degrees and durations of neutropenia, frequencies of
defervescence within 72 hours of beginning therapy (56 to 66 percent), and eradication of
microbiologically documented infections, but often it was not possible to determine
whether later modification of therapy was required. In one study, patients with grampositive bacteremias responded to a combination of ciprofloxacin and netilmicin less well
than did those with gram-negative bacteremias.92
The treatment of patients with other bacteremic infections with quinolones has thus far
been reported principally in noncomparative studies. For the treatment of right-sided
endocarditis due to S. aureus in intravenous drug users,95 intravenous (one week)
followed by oral three weeks) ciprofloxacin combined with oral rifampin (four weeks)
resulted in an apparent cure one month after therapy in all 10 of the patients who
complied with the regimen. Ciprofloxacin therapy alone, however, has been unsuccessful
in some cases of P. aeruginosa and S. aureus endocarditis.96
Data on the treatment of bacterial meningitis with quinolones are limited. Intravenous
pefloxacin cured the gram-negative bacillary meningitis in 9 of 11 neurosurgical patients
(82 percent), many of whom had failed to respond to therapy with -lactam antibiotics.97
Cases caused by P. aeruginosa and other gram-negative bacilli were among those cured,
but S. aureus persisted in one mixed infection and klebsiella in another. Intravenous
ciprofloxacin also cured the gram- negative bacillary meningitis in 18 of 20 patients in
another study.98 One patient with an infection due to Enterobacter cloacae and one of
the two patients with infections due to P. aeruginosa did not respond to ciprofloxacin
therapy.
Ciprofloxacin has been used successfully for the treatment of patients with invasive
external otitis caused by P. aeruginosa. In the largest report,99 21 of 23 patients were
found to be free of infection 9 to 25 months after surgical dbridement and a 6-week
course of oral ciprofloxacin. In a subgroup of patients with diabetes mellitus and positive
bone scans, 8 of 10 were cured and 1 died of progressive infection. Similar results were
reported for ciprofloxacin plus rifampin at a one-year follow-up in patients with bone
destruction.100
In addition to their prophylactic use in urinary tract infections and traveler's diarrhea,
quinolones have been used prophylactically to prevent infections in patients with
neutropenia and eradicate nasopharyngeal carriage of N. meningitidis.101,102 In
randomized trials in adults with neutropenia, oral norfloxacin, ciprofloxacin, and
ofloxacin were uniformly more effective than oral placebo, trimethoprim
sulfamethoxazole, or vancomycinpolymyxin B sulfate in preventing gram-negative
bacteremias, with no differences in the incidence of fungal infections or overall
mortality.3,103-105 Norfloxacin, however, was less effective than trimethoprim
Adverse Effects
Clinical Findings
The quinolones are well tolerated, although with increasing use less common toxic effects
may be identified. In randomized, double-blind comparative trials involving norfloxacin
(3 studies), ciprofloxacin (11 studies), ofloxacin (3 studies), and enoxacin (1 study), the
incidence of adverse effects was similar to or significantly lower23,24 than that observed
with more commonly used agents.3 The prolonged use of norfloxacin, however, was
associated with significantly more adverse effects than occurred with placebo in one
study. The frequency of reactions may also increase with the drug dose.34 In general,
quinolone therapy was discontinued in only about 2 percent of patients because of
adverse reactions.
Gastrointestinal symptoms have been reported most often (3 to 6 percent) and have
included, in declining order, nausea, abdominal discomfort, vomiting, and diarrhea.3,106
Colitis associated with Cl. difficile has been reported infrequently after quinolone
therapy.61 Symptoms referable to the central nervous system have been the next most
common effect (1 to 4 percent) and have included headache, dizziness, agitation, and
sleep disturbance.3 Seizures, delirium, and hallucinations have been reported rarely.
Seizures have been associated with underlying brain lesions and concurrent use of
enoxacin with theophylline and fenbufen, a nonsteroidal antiinflammatory drug (see the
section on drug interactions).107 Allergic reactions have been infrequent (0.5 to 2
percent) and most often manifest as rash or pruritus3; photosensitivity eruptions have
been reported with pefloxacin and fleroxacin.108 Fever, urticaria, angioedema,
anaphylactoid reactions, and hypersensitivity vasculitis have been rare.107,109 For
intravenously administered ciprofloxacin, local reactions at the site of the infusion were
more frequent in the small veins on the dorsum of the hand.110
Because of cartilage erosions in the weight-bearing joints of young animals given
quinolones, routine use of these agents in children or pregnant or nursing patients is not
recommended.8 Small numbers of children have, however, generally tolerated
ciprofloxacin well, with uncommon joint symptoms reported.111 In adults, reports of
reversible arthritis and tendonitis have also been rare.8,111
Laboratory Findings
Transient elevations of serum aminotransferase levels (2 to 3 percent), transient mild
leukopenia (0.2 to 3 percent), and eosinophilia (0.2 to 2 percent) occur infrequently
during quinolone therapy and seldom require its cessation.3 Rare cases of hematuria,
interstitial nephritis, and acute renal failure have been reported.112 Crystalluria may
occur in patients with alkaline urine who are given large doses of quinolones, but it has
not been associated with renal toxicity.3
Tests for mutagenicity and carcinogenicity in vitro have been negative with many but not
all quinolone congeners.8,113 The mammalian homologue of bacterial DNA gyrase,
topoisomerase II, is at least 100-fold less sensitive to the current group of quinolones than
its bacterial counterpart.113,114 Dose-related skeletal abnormalities have been seen in
animal fetuses exposed to ofloxacin in utero.115 Fetal wastage was found in animals
given high doses of norfloxacin or ciprofloxacin, but not teratogenic effects.3 For these
reasons, none of the quinolones are currently recommended for use during pregnancy.
Drug Interactions
Multivalent cations, including aluminum, magnesium, and calcium, found in
antacids,116-119 and ferrous sulfate120 reduce the absorption of orally administered
quinolones, possibly by the formation of nonabsorbable chelates. Sucralfate, which
contains aluminum, also diminishes the absorption of norfloxacin and ciprofloxacin.118
Cimetidine and ranitidine, in contrast, delay but do not affect the completeness of
quinolone absorption.117
The clearance of theophylline and caffeine is inhibited by enoxacin, to a lesser extent by
ciprofloxacin and pefloxacin, and minimally by norfloxacin, ofloxacin, and
lomefloxacin.3,121,122 Theophylline-induced toxicity has been reported in patients
receiving theophylline concurrently with either enoxacin or ciprofloxacin, indicating the
need to monitor serum levels of theophylline in such patients. Rifampin does not alter the
pharmacokinetics of ciprofloxacin,100 and ciprofloxacin does not alter the
pharmacokinetics of cyclosporine.123
Interaction between quinolones and nonsteroidal antiinflammatory drugs has been
suggested by the occurrence of seizures in patients receiving both enoxacin and
fenbufen.107 Although the clinical importance of this interaction is as yet uncertain,
patients receiving both a quinolone and a nonsteroidal antiinflammatory drug, in
particular, should be cautioned about and monitored for central nervous system
symptoms.
Cost
The current wholesale cost (to the pharmacy) of one week of oral therapy is about $30for
norfloxacin (400 mg twice daily) and $25 to $50 for ciprofloxacin (250 to 750 mg twice
daily).3 Many generic oral antibiotics cost less and many parenteral nongeneric
antibiotics cost more than these quinolones, making the cost advantage of the quinolones
greatest when they replace parenteral therapies. This advantage is augmented if quinolone
therapy obviates the need for hospitalization or allows earlier discharge.
(Table 3Table 3
Role of Quinolones in the Treatment of Specific Infections.).
First, for complicated urinary tract infections, in particular those caused by P. aeruginosa
or resistant gram-negative pathogens, few other oral agents are effective. Second, for
suspected bacterial gastroenteritis in patients sufficiently ill for the consideration of
specific therapy before the results of cultures are known, the quinolones are the only
agents available in the United States that have activity against all known bacterial
pathogens. Third, chronic carriage of Sal. typhi in the stool is difficult to eradicate, and
quinolones appear to be reasonably effective in this application. Fourth, in patients with
cystic fibrosis and mild respiratory exacerbations associated with P. aeruginosa in the
sputum, the quinolones offer the opportunity to avoid at least some of the many courses
of parenteral therapy to which these patients are subjected. Fifth, although ciprofloxacin
has not been compared directly with preferred parenteral agents for the therapy of
invasive external otitis caused by P. aeruginosa, the preliminary results are sufficiently
encouraging that this quinolone may be considered as an initial drug regimen in
conjunction with surgical dbridement. Finally, because prolonged parenteral therapies,
often with toxic effects, have been required for the treatment of chronic gram-negative
bacillary osteomyelitis, the apparent efficacy of the oral quinolones makes them
candidates for initial therapy. Until further comparative data emerge, one conservative
strategy (as yet untested) for the treatment of osteomyelitis might consist of initial
conventional parenteral therapy for two weeks, during which time bacteriologic data are
gathered and dbridement is completed, followed by four or more weeks of therapy with
an oral quinolone.
The usefulness and convenience of the quinolones for the treatment of a broad range of
infections have already resulted in their extensive use. Such use, however, carries the risk
of additional pressure for the selection of resistant organisms. Resistance among strains
of P. aeruginosa has increased in Germany since the introduction of norfloxacin and
ofloxacin,124 and the prevalence of strains of S. aureus resistant to both quinolones and
methicillin has increased to high levels in some hospitals since the introduction of
ciprofloxacin.88,89 In Japan, resistance may also be increasing in other gram-negative
bacteria such as Ser. marcescens.125
The use of the quinolones should, in our view, focus on infections in which there is a
differential benefit over conventional agents in terms of efficacy, safety, or cost or on
infections for which few alternative treatments exist. Such focused application and
possibly the use of drug combinations in circumstances in which the development of
resistance is most likely may reduce the possibility that resistance will compromise the
usefulness of these drugs. These considerations emphasize the importance of further
comparative clinical trials, including those using combinations of quinolones with other
drugs in high-risk settings.