352

REVIEW ARTICLES

Fluoroquinolone Toxicity Profiles: A Review Focusing on Newer Agents

Benjamin A. Lipsky and Catherine A. Baker From the Veterans Affairs Puget Sound Health Care System and
University of Washington School of Medicine, Seattle, Washington; and
Providence St. Vincent Medical Center, Portland, Oregon

For 2 decades fluoroquinolones have been found to be generally well-tolerated and safe. Adverse
events may be inherent to the class or influenced by structural modifications. The commonest adverse
events are gastrointestinal tract (GI) and central nervous system (CNS) reactions; nephrotoxicity
and tendinitis are infrequent, but agents differ greatly in phototoxic potential. Fluoroquinolones are

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safe in elderly, human immunodeficiency virus – infected, and neutropenic patients, but because of
possible effects on articular cartilage, they are not currently recommended for children or pregnant
women. Four new agents have recently been licensed. Levofloxacin causes few GI or CNS adverse
events and is minimally phototoxic. Sparfloxacin infrequently causes GI or CNS effects but is
associated with relatively high rates of phototoxicity and prolongation of the electrocardiographic
QTc interval (Q-T interval, corrected for heart rate). Grepafloxacin causes relatively high rates of
GI effects, taste perversion, and QTc interval prolongation, but it is minimally phototoxic. Tro-
vafloxacin is associated with a moderate rate of GI effects and a relatively high incidence of dizziness
but has low phototoxic potential.

Since their introduction in the 1960s with nalidixic acid,
quinolone antimicrobial agents have undergone extensive syn-
thetic and clinical development, resulting in improved antimi-
crobial activity, pharmacokinetic features, and toxicity profiles
[1, 2]. Nalidixic acid had limited use and frequently caused
adverse events [3]. The pyridopyrimidine and cinnoline deriva-
tives introduced in the 1970s demonstrated broader antimicro-
bial spectra and better pharmacokinetic profiles. The most im-
portant breakthrough, however, was development of the
fluoroquinolones (FQs) in the 1980s, with broad antibacterial
spectra, excellent pharmacological properties, and a low inci-
dence of serious adverse events [2 – 4]. While the pharmacoki-
netics and efficacy of these agents have improved, a major
ongoing aim has been to further reduce adverse events [4].
This paper will review the safety profile of FQ agents, assess
differences among class members, and address the safety of
these agents in special populations. We will focus on the newest
Received 2 April 1998; revised 4 September 1998.
Financial support: Ortho-McNeil Pharmaceutical (manufacturer of ofloxacin
and levofloxacin) provided support for this project, including financial support
for secretarial assistance, assistance in producing the figures, and helping obtain
permission for reproduced figures. Dr. Lipsky has also been a member of the
Speakers Bureau for Ortho-McNeil and a member of the Speakers Bureau
and consultant for Rhône-Poulenc Rorer (makers of sparfloxacin), and he has
participated in multicenter trials of ofloxacin, levofloxacin, sparfloxacin, and
trovafloxacin.
Reprints or correspondence: Dr. Benjamin A. Lipsky, VA Puget Sound HCS;
GIMC/Antibiotic Research (111 M), 1660 South Columbian Way, Seattle,
Washington 98108-1532.
Clinical Infectious Diseases 1999;28:352–64
q 1999 by the Infectious Diseases Society of America. All rights reserved.
1058–4838/99/2802–0034$03.00
FQs approved in the past 2 years by the U.S. Food and Drug
Administration (FDA): levofloxacin, sparfloxacin, grepafloxa-
cin, and trovafloxacin.
General Overview of Toxicity of FQ Antimicrobials
With the exception of temafloxacin [5 – 7], FQs have proven
to be a well-tolerated class of drugs [8, 9], especially when
compared with other commonly prescribed antimicrobials [2,
10]. A review of safety results from 28 prospective, random-
ized, double-blind, placebo- or active-controlled clinical trials
revealed that in 22, FQ agents were not significantly different
from nonquinolone comparator agents or placebo in terms of
the proportion of patients experiencing adverse events, and in
5 studies FQ agents were significantly superior to comparator
agents [11].
Adverse events caused by various FQs are generally compa-
rable, although for individual agents the incidence and type
may differ [1, 12]. Reported rates of adverse events depend on
definitions used and how information was obtained. Prospective
comparative trials give the most reliable (and usually highest)
rates. Table 1 summarizes the most frequently reported adverse
events associated with FQ agents; the CNS and gastrointestinal
(GI) tract are most commonly involved [1]. Toxic effects ob-
served only in animal models or not shown to be clinically
relevant include chondrotoxicity, reproductive and develop-
mental toxicity, genotoxicity, and carcinogenicity [2, 4, 8, 11].
Structure – Side Effect Relationships
Structure – side effect relationships help explain some indi-
vidual differences in adverse effects among FQs (see figure 1)

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CID 1999;28 (February) Fluoroquinolone Toxicity Profiles 353

Table 1. Most frequently reported adverse events associated with
fluoroquinolone (FQ) antibacterials.
Type of
adverse event Specific adverse events
Gastrointestinal Nausea, vomiting, abdominal pain, diarrhea, anorexia
CNS Headache, dizziness, sleep disorder(s), mood
changes, confusion, delirium, psychosis, tremor,
seizure
Hepatic Transient rise in level of liver function enzymes,
cholestatic jaundice, hepatitis, hepatic failure
Renal Azotemia, crystalluria, hematuria, interstitial
nephritis, nephropathy, renal failure
Dermatologic Rash, pruritus, photosensitivity, hemorrhagic bullae,
tions, including infections of the upper and lower respiratory
tract, skin and skin structure, and upper and lower urinary tract
[15].
During phase II and III clinical trials, the safety and tolerabil-
ity of levofloxacin among 5,388 patients were assessed. In
dosage regimens ranging from 250 mg once daily for 7 – 10
days to 500 mg once daily for 14 days, the drug was generally
well-tolerated and safe [16 – 25], with fewer GI, CNS, and der-
matologic adverse events occurring than with use of ofloxacin
[15, 26]. North American clinical trials of levofloxacin found an
overall incidence of possible or probable drug-related adverse
events of 2.0% – 9.9% [16 – 25], with nausea (1% – 3%) and
diarrhea (1% – 2%) the most common. Drug-related adverse

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leg pigmentation, urticaria
Musculoskeletal Arthropathy, tendinitis, tendon rupture
Cardiovascular Hypotension, tachycardia, QTc interval prolongation
Other Drug fever, chills, serum sickness – like reaction,
anaphylactoid reaction, anaphylaxis, angioedema,
bronchospasm, vasculitis
NOTE. Occurrence and incidence of adverse events vary among the FQ
agents. QTc interval Å Q-T interval, corrected for heart rate.
events for comparators in nine trials ranged from 2.7% (for
ciprofloxacin) to 21.2% (for amoxicillin/clavulanate) [16, 17 –
19, 21 – 25]. The reported incidence of phototoxicity for lev-
ofloxacin was 1/3,460 (0.03%), vs. 9/2,449 (0.36%) for compa-
rator drugs. There were no clinically significant changes in
laboratory test values, including liver and renal function, blood
glucose, and hematologic parameters, in patients treated with
levofloxacin.

[4]. Adverse effects such as GI symptoms and arthropathy do

not appear to be affected by structural modification. Crystallu-
ria, CNS symptoms, and phototoxicity are highly related to
chemical changes [4, 13]. Chemical structures of various FQs
are shown in figure 2.
Overview of Safety with the Newest FQs
Levofloxacin
Levofloxacin (Levaquin; Ortho-McNeil Pharmaceutical,
Raritan, NJ), the active 1-isomer of racemate ofloxacin, is ap-
proximately twice as potent as ofloxacin against many suscepti-
ble pathogens [14]. It is available in both oral and parenteral
formulations and has been approved for a broad range of indica-
Sparfloxacin
Sparfloxacin (Zagam; Rhône-Poulenc Rorer Pharmaceuti-
cals, Collegeville, PA) is a difluorinated oral quinolone that
differs from other agents by having an amino group at the C-5
position of the quinolone ring. It has increased potency against
aerobic gram-positive cocci, particularly Streptococcus pneu-
moniae, and has recently been approved for treatment of com-
munity-acquired pneumonia (CAP) and acute bacterial exacer-
bations of chronic bronchitis (ABECB) [27].
In a series of 1,040 patients treated for lower respiratory
tract infections in European trials [28], sparfloxacin was at
least as well tolerated as comparator antibacterials (amoxicillin,
amoxicillin/clavulanate, ofloxacin with amoxicillin, and eryth-

Figure 1. Summary of quino-

lone structure – side effect relation-
ships. Comparisons are from high
to low (diFPh Å difluorophenyl;
GABA Å gamma-aminobutyric
acid; NSAID Å nonsteroidal anti-
inflammatory drug; pip Å piperazi-
nyl; pyrr Å pyrrolidinyl; subst Å
substituents [see {4}]). Reprinted
from The Journal of Antimicrobial
Therapy with permission from Ox-
ford University Press.

/ 9c61$$fe14 01-20-99 07:41:30 cida UC: CID

354 Lipsky and Baker
Figure 2. A, B, and C: Chemical structures of the various quino-
lones under discussion.
romycin). During treatment for CAP, 13.7% of patients treated
with sparfloxacin and 17.7% treated with a comparator antibac-
terial experienced a drug-related adverse event. In patients
treated for acute exacerbation of chronic obstructive pulmonary
disease, 9.5% and 13.2% treated with sparfloxacin and amoxi-
cillin/clavulanate, respectively, experienced a drug-related ad-
verse event. Among all sparfloxacin-treated patients, 11.4% had
GI adverse events (with diarrhea [2.6%] the most commonly
reported), Ç2% experienced phototoxicity, and 4.2% reported
CNS effects (with insomnia [1.3%] the most frequently re-
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CID 1999;28 (February)
ported). The percentage of patients discontinuing therapy be-
cause of an adverse event was similar for patients treated with
sparfloxacin and those treated with comparator agents.
To date, few published articles describe the toxicity profile
of sparfloxacin, but data are available from abstracts and post-
marketing surveillance. Adverse events were evaluated in six
North American phase III trials of patients with respiratory or
complicated skin and skin structure infections [29]. The most
frequently reported drug-related adverse events that occurred
at statistically significant different rates for sparfloxacin vs. one
of several comparator agents (erythromycin, cefaclor, ofloxa-
cin, clarithromycin, or ciprofloxacin) were photosensitivity re-
actions (7.9% vs. 0.9%; P õ .001); diarrhea (4.6% vs. 6.7%;
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P Å .015); nausea (4.3% vs. 10.3%; P õ .001); insomnia (1.9%
vs. 5.6%; P õ .001); pruritus (1.8% vs. 0.8%; P Å .024);
abdominal pain (1.8% vs. 3.5%; P Å .004); taste perversion
(1.4% vs. 2.9%; P Å .004); prolongation of QTc interval (Q-
T interval, corrected for heart rate; 1.3% vs. 0.5%; P Å .035);
and vomiting (1.3% vs. 2.6%; P Å .019). Adverse events that
were serious or that led to discontinuation of therapy occurred
in 2.7% and 6.6% of sparfloxacin-treated patients, respectively,
and 3.5% and 8.9% of the comparators [29]. No clinically
important laboratory abnormalities were detected. These results
are similar to those previously reported from six similar Euro-
pean phase III comparative trials, except that the rate of spar-
floxacin-associated phototoxicity was higher than in the Euro-
pean studies [30].
Although sparfloxacin prolonged the QTc interval by a mean
of 10 msec, there were no associated clinically significant car-
diac arrhythmias. Because of reported incidents of torsades de
pointes detected post-marketing, sparfloxacin is contraindicated
for patients receiving other QTc interval – prolonging drugs and
should be avoided by those with a QTc interval prolonged for
any other reason.
Grepafloxacin
Grepafloxacin (Raxar; GlaxoWellcome, Research Triangle
Park, NC) is characterized by an N-1 cyclopropyl group, a C-
5 methyl group, and a C-7 piperazinyl moiety with an attached
methyl group. Grepafloxacin has enhanced activity against
gram-positive organisms, particularly S. pneumoniae, and atyp-
ical organisms. It is approved for oral treatment of mild to
moderate infections, including ABECB, CAP, uncomplicated
gonorrhea, and nongonococcal urethritis and cervicitis caused
by Chlamydia trachomatis [31].
Grepafloxacin has been used by over 20,000 patients world-
wide. In three double-blind comparative clinical trials involving
patients with respiratory tract infections, the proportion of pa-
tients reporting adverse events was similar among patients
treated with grepafloxacin (300 – 600 mg once daily for 7 –
14 days), ofloxacin, or amoxicillin. The most common events
associated with grepafloxacin included nausea (£10%), head-
ache (£3%), diarrhea (£3%), dizziness (£2%), and rash
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CID 1999;28 (February) Fluoroquinolone Toxicity Profiles
(£2%); these rates were similar to those for comparator drugs,
except that nausea was more frequent with use of grepafloxacin
than with use of amoxicillin (2%) or ofloxacin (£1%). Abnor-
mal laboratory parameters, primarily increases in hepatic en-
zyme levels, were reported for 12% – 16% of patients treated
with grepafloxacin (300 mg daily), vs. 7% – 11% receiving
ofloxacin [32]. During clinical trials, õ2% of patients receiving
400 mg of grepafloxacin daily and 5.4% of patients receiving
600 mg daily discontinued therapy because of adverse events
[33]. Photosensitivity has been reported less frequently than
with sparfloxacin. Drug-related cardiac adverse events were
reported in õ1% of grepafloxacin-treated patients, although
the average increase in QTc interval was 10 msec [33].
In a prospective randomized study of treatment with grep-
afloxacin vs. ciprofloxacin in 624 patients with ABECB [34],
the most frequently reported adverse events were nausea (15% –
22% vs. 13%), taste perversion (13% – 27% vs. 4%), headache
(8% vs. 11%), dizziness (8% – 9% vs. 6%), diarrhea (6% – 7%
vs. 7%), vomiting (2% – 9% vs. 4%), and photosensitivity
(0.5% – 3% vs. 0%). Drug-related adverse events caused dis-
continuation of therapy for 3.4% – 7.4% of patients receiving
grepafloxacin, compared with only 1.9% of those receiving
ciprofloxacin. An open-label noncomparative study of 273 pa-
tients with CAP treated with grepafloxacin (600 mg daily for
10 days) revealed abnormal liver function test values (2.2%),
abdominal pain (2.2%), nervousness (2.2%), and insomnia
(3.3%) [35]. Neither of these studies addressed the potential
for QTc interval prolongation.
Trovafloxacin
Trovafloxacin (Trovan; Pfizer, New York), with a trifluoro-
naphthyridone structure, is not strictly a quinolone but is gener-
ally classified as an FQ. Compared to older FQs, trovafloxacin
demonstrates increased activity against aerobic gram-positive
cocci, most notably S. pneumoniae, as well as anaerobic organ-
isms. Trovafloxacin, available in oral and intravenous formula-
tions, is approved for multiple indications, including CAP, nos-
ocomial pneumonia, ABECB, uncomplicated urinary tract
infections, skin and skin structure infections, bacterial prostati-
tis, and complicated intra-abdominal infections, including post-
surgical infections and gynecologic and pelvic infections [36].
Trovafloxacin is not soluble in aqueous solution; the intrave-
nous formulation is alatrofloxacin, the L-Ala-L-Ala prodrug of
trovafloxacin, which is rapidly converted to trovafloxacin in
vivo [37].
Data about adverse events associated with trovafloxacin are
limited. In multidose clinical efficacy studies of ú6,000 pa-
tients worldwide, therapy was discontinued for 5% because
of adverse events thought to be drug-related [36]. The most
frequently reported adverse events associated with trovafloxa-
cin involve the CNS and GI tract and include dizziness (3% –
11%), lightheadedness (1% – 4%), headache (1% – 5%), nausea
(4% – 8%), vomiting (1% – 3%), and diarrhea (2%). Other po-
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355
tential adverse events reported include sweating, flushing, ab-
dominal cramping, rash, and pruritus [38]. Toxicity studies
have demonstrated an increased incidence and intensity of
lightheadedness, headache, nausea, and emesis as a single oral
dose is increased from 30 to 1,000 mg and multiple oral doses
are increased from 100 to 300 mg daily [38 – 40].
Of note, trovafloxacin minimally interferes with the cyto-
chrome P450 system and does not substantially interact with
warfarin or theophylline. Coadministration with intravenous
morphine reduces the absorption of oral trovafloxacin, and
doses of these two agents should be separated accordingly [36,
41]. Available data suggest trovafloxacin’s phototoxic potential
is among the lowest of any FQ [40].
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Toxic Effects of FQs on Specific Body Systems
GI Tract
Adverse events involving the GI tract occur with all FQs
but are usually mild and seldom necessitate discontinuation of
therapy [2, 4]. These effects are the most frequently reported,
with estimated overall incidences ranging from 2% to 20% [1,
4, 9 – 11, 26, 27, 29, 42 – 45]. Reported symptoms include nau-
sea, anorexia, and dyspepsia; abdominal pain, vomiting, and
diarrhea are less frequent but more likely to necessitate discon-
tinuation of therapy [9, 45]. Clostridium difficile – associated
colitis is uncommon with FQs, perhaps because of their mini-
mal effect on anaerobic flora [11, 42]. Based on data reported
to manufacturers or derived from clinical trials, the estimated
rank order for agents in causing GI adverse events is as follows:
fleroxacin, grepafloxacin ú trovafloxacin ú sparfloxacin ú
pefloxacin ú ciprofloxacin, levofloxacin ú norfloxacin ú en-
oxacin ú ofloxacin [10, 11, 15, 27, 31, 36, 46, 47]. To date,
no one feature of the FQ structure has been associated with
adverse GI effects [4].
GI disorders were the most common drug-related adverse
events in clinical trials of levofloxacin (5.1%); specific com-
plaints included diarrhea (1.2%), nausea (1.2%), flatulence
(0.5%), abdominal pain (0.3%), dyspepsia (0.3%), taste perver-
sion (0.2%), and vomiting (0.2%) [15 – 25]. In clinical trials of
sparfloxacin, the most frequently reported GI adverse events
were diarrhea (4.6%), nausea (4.3%), dyspepsia (2.3%), ab-
dominal pain (1.8%), vomiting (1.3%), and flatulence (1.1%)
[27]. Comparative trials have demonstrated adverse GI event
rates for sparfloxacin that are similar to those of cefaclor [48]
and 2.5- to 5-fold lower than for erythromycin [49]. The inci-
dence of nausea with sparfloxacin (4.0% – 4.4%) was found to
be approximately one-third as high as for ofloxacin (10.2%)
or ciprofloxacin (13.1%) [50, 51].
GI adverse events are also the most frequently reported in
grepafloxacin clinical trials and include nausea (11% – 16%),
diarrhea (3.5% – 4%), abdominal pain (2%), vomiting (2% –
6%), dyspepsia (1.5% – 3%), anorexia (1% – 2%), and constipa-
tion (1% – 2%) [31]; a metallic taste was reported by 9% and
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356 Lipsky and Baker
18% of patients receiving 400 mg and 600 mg daily, respec-
tively. The manufacturer noted trends suggesting a reduced
incidence of nausea and taste perversion if the dose is adminis-
tered in the evening [33]. Trovafloxacin is associated with a
relatively low incidence of adverse GI events, with nausea
(4% – 8%), vomiting (1% – 3%), diarrhea (2%), and abdominal
pain (1%) the most frequently reported [36].
CNS
CNS disturbances are the second most commonly reported
adverse events with FQs [4, 11], with an overall incidence of
1% – 2% [10, 26, 27, 52]. Symptoms include headache, dizzi-
ness, and drowsiness, which usually occur on the first day of
therapy and resolve after discontinuation of the drug therapy
[10]. Other reported CNS effects include abnormal vision, rest-
lessness, sleep disorders, agitation, acute organic psychosis,
confusion, and delirium [4, 10, 45]. Convulsions and seizures
have occurred rarely, and usually in the setting of predisposing
factors (e.g., epilepsy, cerebral trauma, or anoxia), metabolic
imbalance, or concomitant therapy with interacting agents (e.g.,
theophylline or nonsteroidal anti-inflammatory drugs) [1, 10 –
12, 53]. Convulsions during FQ therapy usually develop 3 – 4
days after the start of treatment and resolve with its discontinua-
tion [42]; they have occurred during treatment with enoxacin,
pefloxacin, ofloxacin, ciprofloxacin, and norfloxacin [12, 45].
The reported overall trend in incidence of drug-related CNS
adverse events is as follows: fleroxacin ú trovafloxacin ú
grepafloxacin ú norfloxacin ú sparfloxacin ú ciprofloxacin
ú enoxacin ú ofloxacin ú pefloxacin ú levofloxacin [10, 11,
15, 27, 29, 31, 36, 46, 47]. Symptoms vary somewhat for
individual agents. Acute psychosis has been associated with
ofloxacin [54] and ciprofloxacin [55, 56], and two cases of
confusion and delirium have been attributed to pefloxacin [57].
Recent studies [18, 20 – 22, 24, 25] have shown a low inci-
dence (0.2% – 1.1%) of CNS adverse events associated with
levofloxacin and a slightly higher rate with sparfloxacin (1.9%
to 4.2%) [27, 29]. The North American trials showed sparflox-
acin was associated with somewhat lower rates of dizziness
and insomnia but a higher rate of headaches than were compa-
rators [29]. In direct comparisons with ofloxacin, sparfloxacin
was associated with a lower rate of headaches (4.2% vs. 2.9%)
[58] and insomnia (4.7% vs. 1.1% in one study and 14.9% vs.
1.5% in another) [50, 58]. CNS effects of grepafloxacin include
dizziness (4.3% – 5.4%), somnolence (1% – 1.5%), and ner-
vousness (0.6% – 1.7%) [31]. Trovafloxacin has a higher rate of
CNS effects, including dizziness (3% – 11%), lightheadedness
(2% – 4%), and headache (1% – 5%) [36]. These symptoms are
generally mild, last only a few hours, and may resolve with
continued dosing; the incidence may be reduced if trovafloxacin
is taken at bedtime or with food. CNS symptoms with tro-
vafloxacin have occurred more frequently in women and sub-
jects younger than age 45 years. Reports of patients over 65
/ 9c61$$fe14 01-20-99 07:41:30
CID 1999;28 (February)
years of age indicated a lower incidence of dizziness (3.1%)
and lightheadedness (0.6%).
The mechanism of quinolone-associated CNS toxicity has
not been fully elucidated but may involve gamma-aminobutyric
acid (GABA). Inhibition of binding of GABA to GABAA re-
ceptors in the CNS results in CNS stimulation [1]. This charac-
teristic, however, is not unique to the quinolones; penicillins,
cephalosporins, and carbacephems also antagonize this neuro-
transmitter, causing neurotoxic effects [52]. Experiments in
mice show binding of FQs to GABA receptors is enhanced by
4-biphenylacetic acid, an active metabolite of the nonsteroidal
anti-inflammatory drug fenbufen [59].
The primary excitatory effects of FQs in the CNS may also
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operate via N-methyl-D-aspartate and adenosine-receptor
mechanisms or by activation of excitatory amino acid receptors.
Preclinical studies in mice showed the following trend in epi-
leptogenic activity: enoxacin ú norfloxacin ú ciprofloxacin
ú ofloxacin § levofloxacin [1, 60]. Neither grepafloxacin nor
trovafloxacin or alatrofloxacin induced convulsions in mice
when administered in high doses in conjunction with fenbufen
[32, 36]. No single model for predicting epileptogenic activity
of the FQs has completely predicted clinical experience.
The relative incidence of CNS adverse events of FQs may
be related to their chemical structures. The R7 side chain sub-
stituent appears to have the greatest influence on the degree of
GABA binding inhibition (figure 1); a bulky side chain lowers
binding affinity for the GABA receptor [4]. FQs with an unsub-
stituted piperazinyl ring (e.g., ciprofloxacin, enoxacin, and nor-
floxacin) exhibit high binding affinity [13]. Lipophilicity and
ability to cross the blood-brain barrier may also play a role in
CNS effects [4].
Liver
Liver enzyme abnormalities have been noted in 2% – 3% of
patients receiving FQ therapy [11, 46]. Elevations in serum
transaminase and alkaline phosphatase levels are most common
[11, 61]; these are usually mild and reversible with discontinua-
tion of the therapy. On the basis of crude pooled estimates
of data supplied by manufacturers, elevated levels of serum
aspartate aminotransferase, alanine aminotransferase, or alka-
line phosphatase occurred in 24.9, 24.0, and 17.8 patients per
1,000 treated with ciprofloxacin, ofloxacin, and pefloxacin, re-
spectively [46]. These liver enzyme abnormalities rarely led to
discontinuation of therapy.
The largest safety database available for any FQ is that for
ciprofloxacin, which has been administered to nearly 80,000
patients in clinical trials and, as of 1993, had been prescribed
to Ç80 million patients [8]. Spontaneous reports showed that
144 ciprofloxacin-treated patients had serious abnormalities in
liver function test values; small numbers of patients also devel-
oped hepatitis, liver necrosis, or hepatic insufficiency or failure.
Two cases of cholestatic jaundice, possibly induced by ci-
profloxacin, have been reported [62, 63], and hepatotoxicity
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CID 1999;28 (February) Fluoroquinolone Toxicity Profiles
has been observed during therapy with enoxacin [64], norflox-
acin [65], and ofloxacin [66].
Clinical trial data for levofloxacin indicate a very low fre-
quency (0.3%) of abnormal liver function test values [15],
none of which necessitated discontinuation of therapy. Elevated
transaminase levels were found in Ç2% of patients treated
with sparfloxacin in the North American trials [29]. Clinical
trial data for 2,500 patients treated with grepafloxacin demon-
strated increased levels of hepatic transaminases, gamma-gluta-
myl transpeptidase, and alkaline phosphatase in õ1% [31].
Among 140 patients treated with trovafloxacin for 28 days, 9%
had asymptomatic increases in hepatic transaminase levels to
§3 times normal, but they returned to normal within 2 months
following discontinuation of therapy [36].
Urinary Tract
Nephrotoxicity as a consequence of FQ therapy is uncom-
mon [4, 11, 12], but there have been some reports of hematuria,
interstitial nephritis, or acute renal failure [11, 61]. Nearly all
reported cases of acute renal failure have involved patients
over 50 years of age, and in most instances the patients were
ú65 years of age [45]. Renal failure may be due to a hypersen-
sitivity reaction, as reported for ciprofloxacin, or a direct toxic
effect, as reported for norfloxacin [45]. Adverse renal reactions
to ciprofloxacin are uncommon [8] but have included renal
failure (91 patients, of whom 12 required dialysis); elevated
serum creatinine and blood urea nitrogen levels (63 patients);
nephritis (23 patients, including 2 with consequent renal fail-
ure); and a renal tubular disorder (1 patient). The incidence
of an elevated serum creatinine level related to therapy with
ciprofloxacin, norfloxacin, ofloxacin, and pefloxacin ranges
from 0.2% to 1.3% [11]. The rate for ofloxacin (1.3%) was
slightly higher than for the other FQs (0.2% – 0.8%). Incidences
of azotemia with ciprofloxacin, ofloxacin, and pefloxacin
ranged from 1.8 to 13.1 per 1,000 patients treated [46].
Crystalluria has been linked to FQ solubility in urine,
which is pH-dependent. It has been observed in rats and
monkeys, under urinary pH conditions that do not usually
exist in humans [12]. In the normally acidic urine of humans,
crystalluria is rare [42] and not necessarily a cause of renal
damage [4, 11, 12, 45]. Nonetheless, patients should be well
hydrated, and alkalinity of urine should be avoided during
FQ therapy. Nearly all FQs are zwitterionic, owing to a basic
amine group in the R7 side chain, making them least soluble
at physiological pH [4].
Changes in molecular structure aimed at improving water
solubility in this pH range would minimize risk of crystalluria.
These include alkyl substitution of the R7 substituent and use
of CF, CCl, CCF3, and COMe as the X8 substituent (figure 1)
[4]. Crystalluria, interstitial nephritis, and acute renal failure
have not been causally associated with levofloxacin, sparflox-
acin, grepafloxacin, or trovafloxacin therapy.
/ 9c61$$fe14 01-20-99 07:41:30
357
Skin
Dermatologic adverse events with use of the available FQs
occur at an overall rate of Ç0.5% – 3% [42]. While a variety
of toxic effects on skin have been reported, photosensitivity
reactions of two types have received the most attention. Photo-
allergic reactions are rare, require previous exposure to the
offending agent, and are manifest only a day or more after
exposure. Phototoxic reactions, by contrast, are more common,
can occur on initial exposure in anyone given a sufficient dose
of the offending drug and a high enough ultraviolet (UV) expo-
sure, and develop within a few hours [67]. The mechanism of
phototoxicity appears to relate to photodegradability of individ-
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ual FQs and their ability to induce oxygen singlets and free
radicals [42]. These reactive species are thought to attack cellu-
lar lipid membranes, initiating the inflammatory process [68].
Persons with fair skin are more susceptible than those with
darker skin.
Photosensitivity reactions have been reported for most FQs
but differ in severity and incidence [4]. Clinical manifestations
range from mild erythema of sun-exposed areas to extensive
and severe bullous eruptions. Reactions may follow exposure
to direct or indirect sunlight (e.g., through glass or in shade),
as well as from UV (especially UVA) lamps. They generally
appear within a few days of the start of therapy but can occur
up to 3 weeks after its discontinuation, and they usually subside
within 1 month [11, 12, 42, 45]. Topical sunblockers that screen
against both UVA and UVB may afford some protection, but
covering the skin with clothing or avoiding the outdoors is
safer.
The approximate order for phototoxic potential among the
FQs is as follows: lomefloxacin, fleroxacin ú sparfloxacin ú
enoxacin ú pefloxacin ú ciprofloxacin, grepafloxacin ú nor-
floxacin, ofloxacin, levofloxacin, and trovafloxacin [4, 8, 13,
15, 27, 29, 31, 36, 69]. Marked differences in phototoxic poten-
tial are largely related to the X8 substituent (figure 1) [4]. The
highest frequency of phototoxicity occurs when this position
is substituted by a halogen, especially fluorine; fleroxacin [70],
lomefloxacin [71], and sparfloxacin [29] all have a CF group
in the X8 position [4]. In addition, FQs with a bulky side chain
or a methyl group at R5 are more likely to cause phototoxicity
than would be predicted solely by the X8 group [4].
Fleroxacin demonstrates a dose-related frequency of photo-
toxicity ranging from 0.6% at 200 – 400 mg daily to 16% with
800-mg doses [47]. Photosensitivity occurred in 2.4% of 2,869
lomefloxacin recipients and was judged to be drug-related in
1.7% of cases [72]. Pooled data for pefloxacin, which has a
CH group in the X8 position, indicate a phototoxicity frequency
of 9.3 per 1,000 patients [46].
Phototoxicity has been the most frequent and important ad-
verse event associated with sparfloxacin therapy. Studies con-
ducted in Japan, usually at dosages of 100 mg daily, revealed
phototoxicity in about 1% – 2% of subjects. European clinical
safety data [28, 30] from 1,040 patients revealed a 2.0% inci-
cida UC: CID
358 Lipsky and Baker
dence of phototoxicity with use of sparfloxacin (usually 100
or 200 mg daily), vs. a 0.2% incidence with comparators. Rates
of photosensitivity were the same for the two sparfloxacin
dosage regimens, and only one reaction was considered severe.
In the North American trials the overall rate of photosensitiv-
ity reactions to sparfloxacin was 7.9%, compared with a com-
bined rate of 0.9% for five different comparators [29]. Most
reactions were mild (4.2%) or moderate (3.4%), but a few
(0.6%) were severe. Because of the potential for phototoxic
reactions, patients must avoid exposure to direct or indirect
sunlight or artificial UV light during and for 5 days following
sparfloxacin therapy [27].
For levofloxacin, data from preclinical and phase I – II studies
indicate a minimal phototoxic potential, similar to that of
ofloxacin and ciprofloxacin [14, 73]. Only one of 3,490 subjects
had a potentially phototoxic reaction [73]. Studies of the rela-
tive phototoxic effect on mice of a 200-mg/kg dose of various
FQs found evidence of toxicity with use of sparfloxacin, lo-
mefloxacin, and to a lesser degree, enoxacin; ofloxacin, ci-
profloxacin, and grepafloxacin had slight or no effects [74].
Clinical trial data for grepafloxacin regimens (400 – 600 mg
daily) showed photosensitivity in õ2% of patients [31]. Cur-
rently available data suggest grepafloxacin has weak photosen-
sitizing potential, similar to that of ciprofloxacin [75]. In studies
of mice, trovafloxacin caused only mild photosensitivity reac-
tions, and preliminary evaluations in humans suggest a lower
phototoxic potential for trovafloxacin than for lomefloxacin
or even ciprofloxacin [68, 76]. Phototoxicity was observed in
õ0.03% (two) of 7,096 patients treated with trovafloxacin [36]
in clinical trials, making it among the least phototoxic FQ
agents.
Other skin reactions during FQ treatment are uncommon.
Occasionally reported reactions include rash, pruritus, urticaria,
vasculitis, edema, blue-black pigmentation of the legs, erup-
tions with hemorrhagic bullae, and Henoch-Schönlein purpura
[46, 61, 77, 78].
Immune System
Hypersensitivity reactions, often with skin manifestations,
have occurred at a frequency of 0.6% – 1.4% in FQ clinical trials
[10]. Erythema, pruritus, urticaria, and rash may be caused by
allergic reaction or a histamine-release phenomenon [79]. Fatal
hypersensitivity vasculitis has occurred during ciprofloxacin
and ofloxacin therapy [43, 80], and cutaneous erythema, itch-
ing, and a burning sensation have been reported to occur during
intravenous infusion of ciprofloxacin [81]. Serum sickness –
like illness has also been reported in association with ci-
profloxacin use [82].
Anaphylactoid and anaphylactic reactions have been ob-
served from 5 minutes to 1 hour following FQ administration,
in an estimated 0.46 to 1.2 cases per 100,000 [42, 45]. History
of hypersensitivity to one quinolone precludes or at least re-
quires extreme caution with the use of another [12, 42].
/ 9c61$$fe14 01-20-99 07:41:30
CID 1999;28 (February)
Musculoskeletal System
FQ-induced arthropathy is noted in Ç1% of patients [83,
84]. It most frequently affects weight-bearing joints in those
õ30 years of age and presents with pain, stiffness, and joint-
swelling. Onset is in the first few days of treatment, and the
arthropathy usually resolves within a few days or weeks after
discontinuation of the treatment [1, 84]. The potential for quin-
olone-induced arthropathy is a class effect, and structural modi-
fication may not reduce this risk [4]. Chondrotoxicity has been
observed in animal studies, but there is little evidence of clini-
cally important quinolone-induced arthropathy in humans [1,
4, 85].
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More recently, the possibility of tendinitis and tendon rupture
associated with FQs has been raised [85 – 90]. A survey con-
ducted in France between 1985 and July 1992 found tendon
disorders in 100 patients, including 31 with tendon rupture
[89]. As of October 1994, 25 cases of FQ-associated tendon
rupture were reported to the FDA, 22 of which had occurred
outside the United States [88]. Four cases of Achilles tendinitis
complicating FQ treatment in the Netherlands have been de-
scribed [91]. Tendon disorders have most often involved the
Achilles, with some occurring in the shoulder joint or hand
[88 – 91]. Symptoms may begin from 1 to 42 days (average,
13 days) after the start of FQ treatment and may occur after
the offending agent has been withdrawn [88 – 90].
In contrast to arthropathy, tendon disorders or rupture gener-
ally occurs in individuals ú50 years of age [84], although
reports include those from 25 to 84 years old [88, 89]. More
men than women are affected, and concomitant use of cortico-
steroids appears to increase the risk [88, 89]. In the French
series [89], the clinical course of patients with tendon disorders
was usually favorable, although symptoms persisted for ú2
months in one-third of cases. Among patients reported to the
FDA, 11 of 25 were hospitalized, had surgical repairs, or had
a prolonged period of disability [88].
Specific agents reported to cause tendon disorders include
norfloxacin, ciprofloxacin, pefloxacin, enoxacin, and sparflox-
acin [30, 90, 92]. During preclinical development studies with
levofloxacin, one case of possibly drug-related tendinitis was
reported; tendon rupture was not reported for levofloxacin in
clinical trials [16 – 25]. Postmarketing surveillance in Japan and
Europe has uncovered occasional cases of tendinitis and tendon
rupture associated with sparfloxacin. In the French sparfloxacin
pharmacovigilance data, estimated rates were 0.7 and 0.005
per 1,000 treated patients, respectively [30]. Postmarketing sur-
veillance will be necessary to assess association with grep-
afloxacin or trovafloxacin. Until additional information is avail-
able, the FDA recommends that patients discontinue FQ
therapy at the first sign of tendon pain or inflammation and
refrain from exercise until the diagnosis of tendinitis can be
confidently excluded [86 – 88]. MRI may be useful for early
detection and monitoring of tendinitis or tendon degeneration
[90].
cida UC: CID
CID 1999;28 (February) Fluoroquinolone Toxicity Profiles
Cardiovascular System
Systolic and diastolic hypotension has been noted in animals
following rapid intravenous administration of most quinolones,
probably as a result of histamine release [12]. In humans, hypo-
tension, tachycardia, syncope, and migraines have followed
oral administration of quinolones [12, 43]. Because QTc inter-
val prolongation [93] was noted during preclinical development
of sparfloxacin, careful electrocardiographic evaluation was
conducted in subsequent clinical trials. These revealed that
1.2% to 3% of sparfloxacin-treated patients experienced a po-
tentially clinically important QTc interval prolongation, to
§500 msec [29, 94, 95]. The magnitude of change appears
dose-related, with a mean prolongation of QTc interval of 2% –
8% associated with doses from 100 mg daily to 400 mg daily,
respectively. This appears less than that associated with eryth-
romycin therapy [92, 94], and QTc interval prolongation due
to sparfloxacin generally has not been associated with clinical
symptoms, cardiac arrhythmias, or other cardiovascular events.
One case of torsades de pointes leading to cardiopulmonary
resuscitation was reported as probably associated with spar-
floxacin therapy [96].
An international safety board reviewed data collected from
Ç750,000 patients treated with sparfloxacin as of May 1995
[94]. Seven serious adverse cardiovascular events were re-
ported, all in patients with an underlying cardiac condition.
The adverse cardiovascular event rate was not significantly
different between sparfloxacin-treated patients and those who
received comparator antibacterials. The international safety
board concluded that the QTc interval prolongation was not a
cause for concern, but coadministration of sparfloxacin with
medications known to increase the QTc interval or to induce
bradycardia should be avoided, and concomitant administration
of amiodarone or sotalol was contraindicated.
In preclinical and clinical studies, levofloxacin was not asso-
ciated with QTc interval prolongation. Grepafloxacin caused
QTc interval prolongation in clinical trials [31], but the magni-
tude of effect is unclear. Presently, grepafloxacin is contraindi-
cated in patients with known QTc interval prolongation or those
concomitantly treated with other medications that may increase
the QTc interval or induce torsades de pointes, unless appro-
priate cardiac monitoring is available. It is not recommended
for use in patients with ongoing proarrhythmic conditions. One
study found no clinically significant abnormal vital signs or
electrocardiographic changes during intravenous infusion of
alatrofloxacin in doses up to an equivalent dose of 300 mg of
trovafloxacin [37]. Clinical trials data cited in trovafloxacin
product information do not include occurrences of a prolonged
QTc interval.
Special Patient Populations
Pediatric
Because FQ-treated juvenile animals develop lesions in the
articular cartilage, these agents are not recommended for chil-
/ 9c61$$fe14 01-20-99 07:41:30
359
dren and growing adolescents [1, 88, 97, 98]. The mechanism
of this chondrotoxicity is largely unknown [1, 85, 97, 99].
Despite concerns about toxicity, pediatric patients have re-
ceived FQ therapy on a compassionate basis and in clinical
trials in special situations [97, 100, 101]. In one analysis, com-
prehensive clinical, MRI, and histopathologic monitoring of 18
patients aged 6 – 24 years for up to 22 months after a 3-month
course of ciprofloxacin therapy demonstrated no evidence of
FQ-induced arthropathy [97]. Review of several published pe-
diatric clinical trials involving ú1,000 prepubertal children
revealed good to excellent efficacy, with mild and reversible
adverse events in 5% – 15% of patients [101]. Reversible ar-
thropathies were reported to occur in young patients with cystic
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fibrosis treated with ciprofloxacin (8 of 634; 1.3%) or pefloxa-
cin (9 of 63; 14%). Some patients who had joint manifestations
with pefloxacin therapy later tolerated ofloxacin without prob-
lems [85].
The 1991 worldwide ciprofloxacin compassionate-use proto-
cols involved 634 children aged 3 days to 17 years [100],
most of whom had an acute pulmonary exacerbation of cystic
fibrosis. Mean oral and intravenous daily doses of ciprofloxacin
were 25.2 mg/kg and 7.0 mg/kg, respectively. Eight children
(1.3%), all of whom had cystic fibrosis, had arthralgia that
was reversible upon discontinuation of treatment. In the 1997
cumulative data from worldwide ciprofloxacin compassionate-
use protocols involving 1,795 case reports, 26% of the patients
were 12 – 17 years of age, and 28% had cystic fibrosis. Arthral-
gia occurred in 31 (1.5%) of 2,030 treatment courses, but no
unequivocal case of ciprofloxacin-induced arthropathy was
documented [85]. In another ciprofloxacin treatment study
[102], only five of 202 children with cystic fibrosis under 18
years of age experienced arthralgia. Arthralgias have been re-
ported by cystic fibrosis patients treated with antimicrobials
other than FQs and may also be due to underlying disease
processes [100, 101].
Less information is available for other FQs. No arthropathies
were observed among 37 patients from 2 to 20 years of age
treated with ofloxacin [45]. At least one case of destructive
polyarthropathy has been reported, involving a 17-year-old
atopic boy who received pefloxacin (800 mg/d for 3 months)
[103]. A review of FQ use in more than 7,000 skeletally imma-
ture patients [85] concluded that reversible episodes of arthral-
gia do not lead to long-term sequelae when treatment with the
offending agent is discontinued. Thus, prospective studies of
selected quinolone agents for therapy in children seem justified,
and the FDA has encouraged such studies [104].
Geriatric
In the elderly, FQ bioavailability — and thus maximal serum
concentration — may be increased by diminished first-pass me-
tabolism or by concurrent medications. Furthermore, area under
the concentration vs. time curve may be increased by dimin-
ished drug clearance caused by age-related decline in renal or
cida UC: CID
360 Lipsky and Baker
hepatic function. There is relatively little published information
regarding toxicity of FQs for patients ú55 years of age, but it
is likely that they are safe. In a summary of clinical data for
oral ciprofloxacin [105], nearly one-fourth of the 1,652 patients
were ú70 years old. There was a tendency for all adverse
events to occur more frequently in elderly patients than in
younger ones, and three of four episodes of hallucinations were
reported by elderly patients. A reported case of acute delirium
associated with ciprofloxacin therapy occurred in a hospitalized
elderly patient [106].
Tendon disorders may also occur more frequently in older
patients. In the French series [89] of 100 patients with tendon
disorders or ruptures, the mean age of the affected patients was
63 years, within a range of 25 – 84 years. One American case
report described bilateral Achilles tendinitis in an 85-year-old
patient with polymyalgia rheumatica who was receiving both
steroid and enoxacin therapy [87]. Caution seems prudent in
such situations.
Results of sparfloxacin clinical trials conducted in Europe
demonstrated no difference in incidence of drug-related adverse
events or rate of treatment discontinuation among the one-third
of patients who were older than 65 years, vs. among those who
were younger [28]. A recent study investigated the effect of
age on single-dose pharmacokinetics in healthy young volun-
teers (18 – 40 years of age) as compared with elderly volunteers
(§65 years of age) [107] and found no difference in incidence
of adverse events following an oral dosing of 500 mg of lev-
ofloxacin.
No dosage adjustment is required for either grepafloxacin or
trovafloxacin for elderly patients. In healthy patients aged 64 –
81 years who received grepafloxacin (400 mg/d for 7 – 9 days),
volume of distribution and clearance were decreased, resulting
in a 48% increase in the area under the curve compared to that
for younger subjects [32]. For both agents renal excretion is
minimal, with hepatic and biliary systems predominantly in-
volved in metabolism and clearance [31, 39]. In multiple-dose
clinical trials with trovafloxacin, the overall incidence of drug-
related adverse events in the 27% of patients who were at least
65 years of age was actually less than that among younger age
groups [36].
HIV-Infected
Patients infected with HIV may experience adverse events
associated with their disease that are difficult to distinguish
from those that are drug-induced [108]. Some data suggest
the frequency of anaphylactic reactions during ciprofloxacin
therapy may be increased in HIV-infected patients [45]. In the
cases reported, the reaction usually occurred after the second
exposure to an FQ [109 – 111]. Acute renal failure in one patient
with AIDS who was treated with ciprofloxacin has been re-
ported [112].
In two studies of patients with asymptomatic HIV infection
[108, 113], subjects received single and multiple 350-mg doses
/ 9c61$$fe14 01-20-99 07:41:30
CID 1999;28 (February)
(three times daily) of levofloxacin. Among 10 HIV-infected
subjects who were not receiving concomitant zidovudine treat-
ment [108], the most commonly reported adverse events were
equally frequent in the levofloxacin and placebo groups and
involved the GI tract (9 subjects in each group), CNS (3 patients
in each group), and skin (2 levofloxacin-treated and 4 placebo-
treated subjects). Transient elevations in hepatic transaminase
levels also occurred in both groups. No subjects were with-
drawn because of adverse events. In 16 subjects whose CD4
cell counts ranged from 100/mm3 to 550/mm3 and who were
taking zidovudine concomitantly, there were no clinically sig-
nificant differences in adverse clinical or laboratory events be-
tween the levofloxacin and placebo groups, nor did any adverse
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event require discontinuation of therapy or dosage reduction
[113].
Neutropenic
Neutropenic patients may be exposed to higher doses and
more prolonged courses of antibiotic prophylaxis with FQs
than nonneutropenic patients [114]. Prolonged therapy or an
increased dosage may be associated with a higher incidence of
adverse events with quinolones. Little safety information on
FQs has been derived from studies of neutropenic patients, in
whom occurrence of potential adverse events is confounded by
many factors.
A meta-analysis examined international safety data from 29
studies of neutropenic patients who received FQ therapy (16
studies) or prophylaxis (13 studies) [114]. The FQs were com-
pared with several nonquinolone antibiotics or placebo. Rash
and GI tract disorders were the most common adverse events
with FQs. The incidence of adverse events was significantly
higher (P õ .05) among neutropenic patients receiving treat-
ment with FQ monotherapy than among nonneutropenic pa-
tients (12.6% vs. 6.4%, respectively). In addition, the overall
incidence of adverse events was significantly higher (P õ .05)
when FQs were used as therapy, generally at higher doses,
than when used as prophylaxis. In all prophylaxis studies except
one, the incidence of adverse events associated with trimetho-
prim-sulfamethoxazole was higher than that with FQs. In stud-
ies evaluating monotherapy, there was no statistically signifi-
cant difference in incidence of adverse events between FQs
(12.6%) and comparator agents (10.3%).
When FQs were used in combination therapy, the incidence
of adverse events (14.9%) was not significantly different from
that associated with monotherapy (11.6%) or with comparator
agents (13.6%). Nephrotoxicity was more frequent with FQ
combination regimens than with FQ monotherapy. While the
incidence of adverse events is higher than that observed for
nonneutropenic patients, the general profile of events is similar,
and FQs appear to be at least as safe as other antibiotics.
Pregnant and Nursing Women
FQs are not recommended for pregnant or nursing women,
mainly because of the theoretical potential for causing arthropa-
cida UC: CID
CID 1999;28 (February) Fluoroquinolone Toxicity Profiles
thies in children. Additional concerns based on preclinical data
include their ability to impair bacterial DNA synthesis through
inhibition of DNA gyrase (topoisomerase II) and abortifacient
effects when administered at maternally toxic doses [8, 115].
Maternally nontoxic doses of ciprofloxacin administered to
pregnant cynomolgus monkeys caused no increase in abortions,
nor was there any effect on development of the embryo or
fetus [115]. Other animal studies, however, have demonstrated
fetal wastage and embryotoxic effects such as malformations
with large doses of ciprofloxacin, ofloxacin, norfloxacin, tro-
vafloxacin, and temafloxacin [11, 36, 61].
In a clinical study involving 38 pregnant women who re-
ceived either norfloxacin or ciprofloxacin during pregnancy,
there was no evidence of increased risk of infant malformations
or musculoskeletal problems when compared to the outcome
of a matched control group [116]. Most women in the study
were being treated for a urinary tract infection and most were
in the third trimester of pregnancy. Cesarean delivery (45%)
and fetal distress (40%) were significantly more common
among women treated with an FQ, and mean birth weight of
infants born to FQ-treated mothers was 8.5% higher than that
of infants born to mothers in the control group. There was no
evidence of infant musculoskeletal problems.
In a recent prospective study, 200 pregnant women exposed
to an FQ (mostly ciprofloxacin or norfloxacin) were matched
with 200 controls who were treated for various infections with
an antibiotic known to be nonteratogenic and nonembryotoxic
[117]. Quinolone-treated women had therapeutic abortions at
a higher rate, but rates of congenital malformations and other
measures of pregnancy outcome and infant health did not differ
for the two groups. While the authors of this large multicenter
trial concluded that use of FQs during embryogenesis appeared
safe, it seems prudent for pregnant or nursing women to avoid
these drugs unless the potential benefit clearly outweighs the
potential risk [8].
High-Risk FQs
Some FQs are notable for a relatively high level of toxicity.
In addition to temafloxacin, another agent associated with an
unexpectedly high incidence of adverse experiences is flero-
xacin, a trifluorinated compound [10, 118]. The overall inci-
dence of reported adverse events with fleroxacin was 84% in
79 subjects, with severe reactions in 48%. The incidence and
severity of adverse events were dose-related; such events oc-
curred in 69%, 85%, and 96% of patients treated with doses
of 400 mg, 600 mg, and 800 mg, respectively. The most com-
mon events were those involving the CNS and GI tract. Dose-
related phototoxicity with fleroxacin was mentioned earlier.
This unusually high frequency of adverse events may be related
to three fluorine atoms in the fleroxacin molecule [10].
Phototoxicity is a problem with sparfloxacin. The reaction is
avoidable, usually only mild to moderate, and fully reversible.
Nevertheless, the manufacturer of sparfloxacin made the admi-
/ 9c61$$fe14 01-20-99 07:41:30
361
rable decision to apply for FDA approval only for the most-
needed indication for this agent, i.e., lower respiratory tract
infections.
Summary
The important advance in antibacterial activity ushered in by
FQs has fortunately been accompanied by a generally excellent
safety record. Ongoing research in the development of new FQ
agents is aimed at further improvement in the safety profile,
while maintaining or enhancing antimicrobial efficacy. As new
agents become available, certain predictions can be made re-
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garding possible adverse events, on the basis of their molecular
structure. The four newly approved agents demonstrate the
importance of an agent’s safety profile in selecting an FQ for
therapy. All represent an advance in therapeutic efficacy over
previously available agents, but the adverse event profiles for
sparfloxacin and grepafloxacin are likely to limit their use com-
pared with use of levofloxacin and trovafloxacin.
Levofloxacin appears to be at least as safe and well toler-
ated as other agents in its class. It has demonstrated a low
incidence of GI and CNS adverse events, very little photo-
toxicity, and no cardiotoxicity. While the rates of most ad-
verse events with sparfloxacin are similar to or lower than
those with other agents, it is hampered by a relatively high
rate of phototoxicity and QTc interval prolongation. The
most frequently reported adverse events with grepafloxacin
are GI symptoms and taste perversion, particularly at high
doses. Grepafloxacin has been associated with QTc interval
prolongation, but the incidence of associated phototoxicity
appears less than that with sparfloxacin.
Trovafloxacin appears to cause an increased rate of mild
CNS effects, mainly dizziness, but it has not been reported to
prolong the QTc interval and has a low phototoxic potential.
The implications of trovafloxacin’s structure with respect to
temafloxacin-like adverse events are uncertain, but no problems
were noted in ú200,000 subjects in clinical trials. These latest
FQ additions further advance this group of relatively safe and
highly effective antimicrobials that are now widely used in
clinical practice.
Acknowledgment
The authors thank Tina Torey, of the Antibiotic Research Clinic
(Seattle), for her help in preparing the manuscript.
Addendum
After this manuscript was accepted for publication, additional
post-marketing surveillance data for trovafloxacin became avail-
able that revealed the potential for liver enzyme abnormalities
and/or symptomatic hepatitis during short- or long-term therapy
[36]. In addition, symptomatic pancreatitis was reported. It is rec-
ommended that clinicians monitor liver function tests and pancre-
cida UC: CID
362 Lipsky and Baker
atic function tests in patients who develop symptoms consistent
with hepatitis and/or pancreatitis, as clinically indicated.
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