Fluoroquinolone Antimicrobial Agents

David C. Hooper, M.D., and John S. Wolfson, M.D., Ph.D.,

N Engl J Med 1991; 324:384-394February 7, 1991DOI: 10.1056/NEJM199102073240606
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THE introduction of fluoroquinolone antimicrobial agents (Fig. 1Figure 1

Chemical Structures of Nalidixic Acid and Quinolones.) into clinical use

is an important recent advance.1-3 These drugs, also called quinolones, include
norfloxacin, ciprofloxacin, ofloxacin, enoxacin, and pefloxacin. Of these, norfloxacin,
ciprofloxacin, and ofloxacin have been approved for use in the United States. Quinolones
are orally absorbed, are potent in vitro against a broad spectrum of bacterial species, and
have favorable pharmacokinetic properties. We shall evaluate here the current status of
the quinolones, considering mechanisms of action and resistance, activity in vitro,
pharmacokinetics, clinical efficacy, adverse effects, and clinical uses. A discussion of the
structure-activity relations of the quinolones is beyond the scope of this article, and this
topic has recently been reviewed elsewhere.4,5

Mechanisms of Action and Resistance

Uniquely among antimicrobial agents in clinical use, the primary bacterial target of
quinolones is DNA gyrase (bacterial topoisomerase II),6-9 an enzyme that introduces
negative supertwists into DNA and separates interlocked DNA molecules. Quinolones
antagonize these enzymatic activities, interfering with DNA replication, segregation of
bacterial chromosomes, transcription, and other cellular processes and damaging DNA.
Recently, binding to gyrase-DNA complexes has been reported.10
Spontaneous single-step mutation to quinolone resistance tends to be infrequent (1:<109),
and when it occurs the resistance is of a low level for many bacterial species. High-level
resistance can be selected by serial exposure of bacteria to increasing drug

concentrations. Mechanisms of bacterial resistance to quinolones include chromosomal

mutations that either alter DNA gyrase (resistance to quinolones alone) or reduce drug
accumulation in association with changes in bacterial outer-membrane proteins
(pleiotropic resistance). Destruction or modification of the drug by bacteria has not yet
been described, and plasmid-mediated resistance to fluoroquinolones has not yet been
found in clinical isolates.

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

(Branhamella) catarrhalis (Table 1Table 1

Activity of Fluoroquinolones
in Vitro.). Among the drugs listed in Table 1, ciprofloxacin is the most potent. Quinolones
are active against Pseudomonas aeruginosa but are less active against other species of
pseudomonas. They also have good activity against Staphylococcus aureus and other
staphylococci but are less active against species of streptococcus and enterococcus. They
have minimal activity against anaerobes and none against Candida albicans. Quinolones
are active against gram-negative bacilli that are resistant to multiple antibiotics,
methicillin-resistant strains of S. aureus, penicillin-resistant strains of N. gonorrhoeae,
and -lactamase-producing strains of Haemophilus influenzae and Mor. catarrhalis.
Ciprofloxacin and ofloxacin are active against Mycobacterium tuberculosis, M. kansasii,
M. fortuitum, and M. xenopi, but their activity against M. aviumintracellulare is only
fair to poor. Ciprofloxacin, ofloxacin, temafloxacin, and others are active against
Chlamydia trachomatis, mycoplasma species, and legionella species. Quinolones are also
active in vitro against species of rickettsia, Coxiella burnetii, and Plasmodium
falciparum.
Quinolones have bactericidal activity against most species of bacteria, with minimal
bactericidal concentrations typically equal to or twofold higher than the minimal
inhibitory concentrations. Although their bactericidal activity may be antagonized by
chloramphenicol or rifampin, the clinical importance of this interaction is uncertain.12
The effects of inoculum size tend to be small, with 100-fold increases in the amount of
inoculum usually causing fold to 4-fold increases in the minimal inhibitory
concentrations. Serum has a minimal effect on potency. Urine increases the minimal
inhibitory concentrations fold to 32-fold, but this effect is unlikely to be of clinical
importance because urinary drug concentrations are high. Combinations of quinolones
with a -lactam antibiotic or an aminoglycoside tend to have no interaction, to produce
additive effects, or less commonly to be synergistic against bacteria and mycobacteria,
whereas antagonism is notably rare.3

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,

lomefloxacin, and temafloxacin, however, have activity and pharmacokinetic properties

allowing their use for infections at other sites.

Urinary Tract Infections

For the treatment of uncomplicated urinary tract infections,19-22 norfloxacin,23
ciprofloxacin,24 and ofloxacin25 have been highly effective (92 to 100 percent) and
comparable to trimethoprimsulfamethoxazole in double-blind studies in which patients
were treated for 3 to 1 14 days21 and in unblinded studies. Treatment of acute cystitis
with single oral doses of ciprofloxacin, ofloxacin, or fleroxacin has resulted in the
eradication of bacteriuria in 86 to 93 percent of patients, but ofloxacin was less effective
than trimethoprimsulfamethoxazole in one study.26 The emergence of bacterial
resistance during treatment of acute cystitis is uncommon, but reduced eradication of S.
saprophyticus has been reported with three or fewer days of therapy.27
In the only double-blind, placebo-controlled study of quinolones for prophylaxis against
recurrent urinary tract infections, norfloxacin given at bedtime for one year completely
prevented recurrences in a small number of women.28 For patients with pyelonephritis
with no known urinary tract abnormalities, treatment with norfloxacin or ofloxacin for 7
to 10 days was comparable to trimethoprimsulfamethoxazole therapy in prospective,
unblinded studies, with elimination of bacteriuria in 78 to 91 percent of patients.22
For complicated urinary tract infections, treatment with quinolones, usually for to 10
days, was similar or in several instances superior to treatment with trimethoprim
sulfamethoxazole, -lactam antibiotics, or other drugs, including parenteral agents, in
their ability to eliminate bacteriuria. In most studies, complicated urinary tract infections
were defined as those in patients with structural or functional abnormalities of the urinary
tract. Recurrences (relapses and reinfections) are common in patients with such
infections. In one study,29 the bacteriologic efficacy of ciprofloxacin was greater than
that of trimethoprimsulfamethoxazole five to nine days after therapy, but rates of
recurrence were similar at follow-up four to six weeks later.
Quinolones have been effective for the treatment of complicated urinary tract infections
caused by P. aeruginosa and other bacteria resistant to multiple agents. In collected open
studies, P. aeruginosa was eradicated in 70 percent of patients treated with
ciprofloxacin.3 The development of bacterial resistance, however, has been well
documented, occurring in 9.5 percent of urinary isolates of P. aeruginosa in 12 studies
with ciprofloxacin.3

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

Sexually Transmitted Diseases

For gonococcal infections, single oral doses of a quinolone are highly effective in curing
uncomplicated urethritis and cervicitis. In two randomized studies comparing the efficacy
of norfloxacin and spectinomycin32 and of ofloxacin and a combination of amoxicillin
and probenecid, the drugs were found to have similarly high rates of efficacy (96 to
percent).33 Efficacies of 91 to 100 percent have been reported in other studies that
included patients infected with strains of penicillinase-producing N. gonorrhoeae and a
comparison with ceftriaxone.34,35 Rectal infections32-34 have been cured in 99 percent
of patients given quinolones, and 88 percent of patients with pharyngeal infections have
been cured. Quinolone-resistant isolates of N. gonorrhoeae (with a 60-fold increase in the
minimal inhibitory concentration in one case) have been recovered from a patient who
relapsed after treatment with enoxacin.36 The efficacy of oral quinolones in gonococcal
salpingitis or disseminated gonococcal infections is not known.
For chlamydial infections, single doses of all quinolones studied to date have been
ineffective in eradicating Chl. trachomatis. When given for 5 to 10 days, ofloxacin in two
of three small studies eradicated urethral and cervical infections at rates somewhat lower
than those for doxycycline, the currently recommended agent.37,38 In patients with
urethritis, similar courses of therapy with norfloxacin39 were ineffective, ciprofloxacin40
was less effective than doxycycline, and the results with fleroxacin were
conflicting.41,42
In the only comparative studies of patients with chancroid treated with quinolones,
ciprofloxacin given as a single dose or for three days43 and enoxacin given for three
doses44 both eradicated H. ducreyi from genital ulcers in 93 percent of patients. These
results were equivalent to those obtained with trimethoprimsulfamethoxazole given for
three days43 or as a single dose.44 Fleroxacin given as a single dose had similar efficacy
in African men with chancroid who had no antibodies to human immunodeficiency virus,
but it was less effective in men who were seropositive for the virus.45
Comparisons of quinolones with regimens currently recommended for the treatment of
pelvic inflammatory disease have not yet been reported, but in two randomized
comparisons in which the disease was diagnosed by laparoscopy46 or clinical criteria,47
intravenous followed by oral ciprofloxacin for a total of 14 days cured 94 percent of
patients and was equivalent to combinations of doxycycline and metronidazole46 and of
clindamycin and gentamicin.47 Facultative or anaerobic bacteria, chlamydia, and
gonococci were the predominant pathogens. No studies of quinolone therapy in patients
with syphilis have been reported, but ofloxacin was not effective in experimental
infections in rabbits.48

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

immunodeficiency syndrome, have also been treated successfully with quinolones,

although prolonged therapy was required and relapses occurred.62 Chronic fecal carriage
of Sal. typhi, often present for years and refractory to conventional therapy, has been
eliminated by therapy with norfloxacin, ciprofloxacin, or ofloxacin. In a double-blind
study,63 most patients receiving norfloxacin for one month, including some with
cholelithiasis, had negative stool cultures, but several late relapses occurred.
Helicobacter pylori, which is associated with antral gastritis and peptic ulcer disease, is
susceptible to quinolones in vitro. In vivo, quinolones, in some instances in combination
with an H2-receptor antagonist or bismuth subsalicylate, have not eliminated Hel. pylori
consistently, however, and failures were associated with the emergence of resistance.3
Quinolones achieve favorable concentrations in bile and hepatic tissue, but data on the
treatment of hepatobiliary infections are limited.64 The few studies with quinolones
suggest potential for the treatment of peritonitis caused by gram-positive or gramnegative bacteria in patients receiving long-term ambulatory peritoneal dialysis.65,66

Respiratory Tract Infections

In comparative trials, one with a double-blind, crossover design,67 of patients with acute
exacerbations of chronic bronchitis, ciprofloxacin67 and enoxacin68 were either better
than ampicillin67 or comparable to amoxicillin68 in eradicating pathogens from sputum.
H. influenzae was consistently eradicated by ciprofloxacin69,70 and ofloxacin71 in these
and in noncomparative studies. Delayed clinical responses and a failure to eradicate
pathogens from sputum have, however, been reported in some patients with Str.
pneumoniae and P. aeruginosa infections,67,69,71 with some failures associated with the
development of resistance.69
Intravenous followed by oral ciprofloxacin was compared with intravenous ceftazidime
for the treatment of community-acquired and nosocomial pneumonias without associated
bacteremia.72 The predominant organisms isolated from sputum were H. influenzae (22
percent), P. aeruginosa (15 percent), S. aureus (13 percent), Klebsiella pneumoniae (7
percent), and Str. pneumoniae (7 percent). The rates of clinical and bacteriologic cure for
patients treated with ciprofloxacin were 91 percent (42 of 46) and 93 percent (43 of 46),
respectively, and were comparable to those for patients treated with ceftazidime. One
noncomparative study reported cure of all patients with pneumococcal pneumonia (1 with
bacteremia) who were treated with sequential intravenous and oral ciprofloxacin,64 but
pneumococcal bacteremia has occurred in some patients during treatment with oral
ciprofloxacin.73 In open studies of community-acquired pneumonias, H. influenzae and
Mor. catarrhalis were consistently eradicated from sputum by treatment with
ciprofloxacin, as were P. aeruginosa and members of Enterobacteriaceae in one study.70
Clinical responses have occurred despite the persistence of P. aeruginosa organisms in
the sputum of some patients, but several clinical failures have also been reported.74
Combination therapy may be needed in these infections. Currently, the quinolones are not
the therapy of choice for community-acquired pneumonias.

Quinolone treatment of patients with cystic fibrosis and recurrent respiratory

exacerbations associated with P. aeruginosa in the sputum has been evaluated in several
trials. Orally administered ciprofloxacin75,76 and ofloxacin76 have been compared with
parenteral combinations of an antipseudomonal -lactam antibiotic and tobramycin and
with each other. In efficacy these quinolones were comparable to, better than,75 or in
patients with more severely impaired lung function, inferior to76 conventional parenteral
therapies and equivalent to each other.76 Eradication of P. aeruginosa from the sputum
occurred in few patients in any treatment group; in some studies, resistant organisms
appeared in the sputum, but their appearance was not always associated with clinical
failure.75 Resistance to ciprofloxacin in isolates from sputum did not persist after therapy
in some but not all studies.
The use of quinolones for the treatment of pulmonary tuberculosis has been limited. In
patients with infections due to strains of M. tuberculosis that are resistant to multiple
agents, ofloxacin in combination regimens was only partially effective.77 Resistance to
most of the other components of the multidrug regimens was frequent, however, and
resistance to ofloxacin also occurred. The use of ciprofloxacin alone for M. fortuitum
infections at other sites has also been limited by the development of resistance.78

Bone and Joint Infections

Oral agents are needed for the treatment of acute and chronic osteomyelitis in adults,
particularly when caused by gram-negative bacilli. In one study comparing oral
ciprofloxacin with parenteral regimens,79 77 percent of the patients given ciprofloxacin
for a mean of 56 days and 79 percent of the patients given broad-spectrum cephalosporins
alone or an aminoglycoside in combination with nafcillin for a mean of 47 days were
cured one year after therapy. Two thirds of the infections were caused by gram-negative
bacilli. Failures of ciprofloxacin therapy occurred most often in patients with mixed
infections that included P. aeruginosa.
Larger numbers of patients with chronic osteomyelitis have been treated in
noncomparative trials with ciprofloxacin, ofloxacin, or pefloxacin.3,80,81 The duration
of therapy was often longer than six weeks, and follow-up in most studies exceeded six
months. Clinical cures after ciprofloxacin therapy (750 mg twice daily in most patients)
were reported in 75 percent of patients overall.3 Most of these infections were caused by
gram-negative bacilli, and the rates of cure for patients with P. aeruginosa and S. aureus
infections were similar to those for the group as a whole. Larger numbers of patients with
S. aureus infections have been treated with ofloxacin and pefloxacin. For ofloxacin,
clinical cure was effected in 76 of 80 patients (95 percent), but in the largest study many
patients also received other antimicrobial agents. The development of resistance in
infections caused by P. aeruginosa, S. aureus, and Serratia marcescens was associated
with failure, as were incomplete dbridement, the presence of foreign bodies, and
compromised vascular supply. Many cures must be considered provisional because late
relapses may occur in patients with chronic osteomyelitis.

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.

Skin and Soft-Tissue Infections

Infected pressure and ischemic ulcers, subcutaneous abscesses, cellulitis, and wound
infections have been treated with quinolones. In the largest double- blind, randomized
study,83 oral ciprofloxacin (750 mg twice daily for a mean of 9.3 days) was compared
with intravenous cefotaxime (2 g every eight hours for a mean of 8.9 days) in 461
patients. Patients thought to have bacteremia and infections with resistant organisms
including anaerobes were excluded. The majority of pathogens were gram-negative
bacilli (8 percent of which were P. aeruginosa) and S. aureus (25 percent). The rates of
clinical resolution (81 percent) and bacteriologic eradication (87 percent) in the
ciprofloxacin group were comparable to those in the group treated with cefotaxime. The
results of a similar smaller study comparing ofloxacin and cefotaxime were similar.84
Comparisons of quinolones with agents considered first-line therapies for infections with
P. aeruginosa and S. aureus are needed. A preliminary comparison of sequential
intravenous and oral ciprofloxacin and the antipseudomonal cephalosporin ceftazidime
reported a substantial incidence of persistence of P. aeruginosa with both regimens.85
Open studies of ciprofloxacin therapy have generally confirmed these findings.9,81
Failures have been seen in infections with P. aeruginosa (11 percent), streptococci (6
percent), and S. aureus (5 percent)9 and have been associated with the development of
resistance in strains of P. aeruginosa and S. aureus. 86,87 Infections in the lower
extremities of patients with diabetes have been associated with the development of
resistance and with a rate of cure of only 50 percent.81
Although ciprofloxacin has moderate efficacy against skin and soft-tissue infections
caused by aerobic gram-negative bacilli, the most common organisms causing cellulitis
and wound infections are streptococci and staphylococci. Quinolones have reduced
activity against these organisms, and comparisons with first-line agents have not been
reported.
Quinolones such as ciprofloxacin and ofloxacin are active against methicillin-resistant
strains of S. aureus. Particular caution must be exercised in using these drugs in patients
with such infections, however, because in some centers the prevalence of resistance to
ciprofloxacin among methicillin-resistant strains of S. aureus has increased sharply to
levels over percent since its introduction into clinical use.88,89 Attempts to eradicate skin
and mucosal colonization of methicillin- resistant strains of S. aureus with ciprofloxacin
therapy alone have also had only limited long-term success90,91 and have been
complicated by the appearance of strains of S. aureus resistant to both ciprofloxacin and
methicillin.90 In a few patients, longer-lasting eradication of the organisms was achieved
by a combination of ciprofloxacin and rifampin.91

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

sulfamethoxazole in preventing gram-positive bacteremias.3 In four trials (two with

norfloxacin3,103 and two with ofloxacin104,105), the time to first fever was longer, or
the number of patients who had no fever was greater, in the group receiving quinolone
than in the groups receiving other agents. There is as yet no consensus about whether
quinolones should be reserved as alternative therapies for patients with fever and
neutropenia or used for prophylaxis.

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.

Conclusions and Indications for Use

As clinical experience with the quinolones accumulates, our understanding of their
optimal use will evolve. There have been too few direct comparisons of the various
quinolones to provide clear choices among the derivatives, except that the use of
norfloxacin is limited to infections of the genitourinary and gastrointestinal tracts and
ofloxacin is apparently superior for the treatment of chlamydial infections. In patients
who are concurrently receiving theophylline, it may be preferable to use norfloxacin,
ofloxacin, fleroxacin, or lomefloxacin.
In general, infections with facultative and aerobic gram-negative bacilli and cocci are
those most likely to respond to quinolones, although we do not believe that they are the
definitive agents of choice for any specific infection. There are, however, six conditions
in which these agents may be given preference over other agents currently available

(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.