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STATE-OF-THE-ART CLINICAL ARTICLE
New Uses for New and Old Quinolones and the Challenge of Resistance
David C. Hooper
More than a decade ago ciprofloxacin, the first quinolone
with broad indications, was released for clinical use in the
United States. The release of ofloxacin, which also had broad
applications, followed not long thereafter. Since that time there
has been extensive use of these 2 agents and more limited use
of other quinolones, such as norfloxacin, enoxacin, and lomefloxacin, which were limited to treatment of infections of the
genitourinary tract. Applications of these quinolones largely
employed their potent activities against gram-negative bacteria
[1, 2].
This article focuses on information developed in the past 4
years on the 4 most recently released quinolones—levofloxacin,
sparfloxacin, grepafloxacin, and trovafloxacin [3–8]—and their
spectrum of activity, pharmacokinetics, tolerability, and clinical
applications. It also focuses on new applications of the older
quinolones. Issues of quinolone resistance related to expanding
uses of quinolones will also be discussed.
Spectrum of Activity
The newer fluoroquinolones have retained much of the activity of ciprofloxacin and ofloxacin against enteric gramnegative bacteria, but none is more potent than ciprofloxacin
against these pathogens or against Pseudomonas aeruginosa.
Levofloxacin is the active stereoisomer of the racemic mixture
of the 2 stereoisomers that make up ofloxacin and thus is generally 2-fold more potent than ofloxacin [3]. Trovafloxacin [9]
and, to a lesser extent, levofloxacin generally have gram-negative coverage similar to that of ciprofloxacin, but both may
be less active against some strains of P. aeruginosa.
There may also be gaps in trovafloxacin’s coverage of some
strains of Providencia species, Proteus species, and Serratia marcescens. There are also gaps in the gram-negative coverage of
sparfloxacin and grepafloxacin. Sparfloxacin [10, 11] has only
limited potency against P. aeruginosa, S. marcescens, Citrobacter freundii, and Proteus vulgaris; and grepafloxacin [12] lacks
Received 20 August 1999; revised 28 September 1999; electronically published 1 February 2000.
Reprints or correspondence: Dr. David C. Hooper, Division of Infectious
Diseases, Massachusetts General Hospital, 55 Fruit Street, Boston, MA
02114-2696 ([email protected]).
Clinical Infectious Diseases 2000; 30:243–54
q 2000 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2000/3002-0001$03.00
From the Division of Infectious Diseases, Massachusetts General
Hospital, Harvard Medical School, Boston, Massachusetts
sufficient activity against P. aeruginosa, S. marcescens, Providencia stuartii, and Acinetobacter baumanii among gram-negative bacteria.
Like ciprofloxacin and ofloxacin, the newer agents have excellent potency against genital pathogens, including Neisseria
gonorrhoeae, Chlamydia trachomatis, and Mycoplasma hominis.
Their clinical efficacy in the treatment of genital chlamydial
infections may differ, however, as discussed below.
Against respiratory pathogens, all of the newer quinolones,
such as ciprofloxacin and ofloxacin, are highly potent against
Haemophilus influenzae and Moraxella catarrhalis. However,
these agents exhibit greater potency than ciprofloxacin and ofloxacin against Streptococcus pneumoniae, with MIC90 values
of 1–2 mg/mL for levofloxacin [13], 0.25–0.5 mg/mL for sparfloxacin [14] and grepafloxacin [15], and 0.12–0.25 mg/mL for
trovafloxacin [16]. For this reason, all have been developed for
treatment of respiratory tract infections, as discussed below.
Other respiratory pathogens, such as Legionella pneumophila,
Mycoplasma pneumoniae, and Chlamydia pneumoniae, are also
highly susceptible to all 4 newer quinolones.
Although the newer quinolones all have greater potency than
ciprofloxacin against gram-positive cocci in addition to S. pneumoniae, they will have a more limited role in treatment of staphylococcal and enterococcal infections because of marginal potency or acquired resistance. Among staphylococci, most
methicillin-susceptible strains of Staphylococcus aureus are susceptible to levofloxacin (MIC90, 0.5–1 mg/mL) [17], sparfloxacin
(MIC90, 0.06–0.125 mg/mL) [18], grepafloxacin (MIC90, 0.12 mg/
mL) [12], and trovafloxacin (MIC90, 0.03–0.125 mg/mL) [19]. In
contrast, many methicillin-resistant strains of S. aureus have
acquired high-level resistance to ciprofloxacin that causes substantial cross-resistance to all of the newer agents.
These same patterns of differing quinolone susceptibility
have been seen with methicillin-susceptible and -resistant strains
of coagulase-negative staphylococci. Activity against enterococci is marginal, with MIC90 values of 3.1 mg/mL for levofloxacin [20], 1–2 mg/mL for sparfloxacin [21], 2 to 14 mg/mL
for grepafloxacin [12], and 1–32 mg/mL for trovafloxacin [9, 19].
Against vancomycin-resistant enterococci (which in the United
States are often Enterococcus faecium), MICs often are at the
high end of these ranges.
Against Mycobacterium tuberculosis, levofloxacin appears to
have good activity (MIC, 0.5–0.75 mg/mL) [22], as does sparfloxacin (MIC90, 0.5 mg/mL) [23]. Information is not available
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Hooper
on grepafloxacin, and trovafloxacin has poor activity (MIC90,
32 mg/mL) [9].
Only trovafloxacin (of all available quinolones) has sufficient
activity against anaerobic bacteria for clinical applicability [24].
Most species of anaerobic bacteria tested have been inhibited
by <1 mg/mL, including Bacteroides fragilis, against which trovafloxacin was 32- to 64-fold more active than ciprofloxacin.
Some strains of Bacteroides thetaiotaomicron had somewhat
higher MICs of 2 mg/mL.
Pharmacokinetics
The 4 newest fluoroquinolones vary in their pharmacokinetics (table 1). Levofloxacin and trovafloxacin both have oral
and iv formulations that allow direct estimates of oral bioavailability, with values 195% for levofloxacin [25] and 88% for
trovafloxacin [26]. Maximum concentrations of drug in serum
(Cmax) are highest for levofloxacin (5.7–6.4 mg/mL) and lowest
for sparfloxacin (1.1 mg/mL) with usual dosing [27]. All of the
newer quinolones have longer half-lives of elimination than the
earlier agents and are given as single daily doses, with sparfloxacin having the longest half-life (20 h) [27] and levofloxacin
the shortest (6–8 h) [25].
Although levofloxacin has only a slightly longer half-life than
ofloxacin, it is given at a somewhat higher dose (with a 2-fold
greater potency) once rather than twice a day. This dosage is
based on pharmacodynamic modeling of quinolones that indicates concentration-dependent bacterial killing and postantibiotic effects [28], similar to what is seen for aminoglycosides. The half-lives of sparfloxacin [27], grepafloxacin [29], and
trovafloxacin [26, 30] all support once-daily dosing, and for
sparfloxacin an initial, higher loading dose of 400 mg is recommended to reduce the time to attainment of steady-state
concentrations in serum.
Routes of elimination differ among the newest quinolones.
Levofloxacin, like ofloxacin, is largely excreted by renal routes,
which include both glomerular filtration and tubular secretion.
Nonrenal routes of elimination predominate for sparfloxacin,
Table 1.
CID 2000;30 (February)
grepafloxacin, and trovafloxacin. For sparfloxacin, hepatic glucuronidation appears to be the main route of elimination, with
glucuronide conjugates found in serum, urine, and bile [31].
Grepafloxacin is excreted largely in the feces by biliary excretion
or transintestinal elimination, with only limited (!10%) formation of metabolites (glucuronide and sulfate conjugates and
a metabolite with an oxidized piperazinyl ring) [29]. Trovafloxacin is eliminated primarily by biliary excretion, with additional hepatic metabolism by glucuronidation, N-acetylation,
and N-sulfoconjugation, but minimal oxidative metabolism by
hepatic cytochrome P450 enzymes [32].
Dosage adjustments in cases of renal and hepatic failure differ (table 2). No adjustments of dosages of grepafloxacin and
trovafloxacin are necessary when renal failure occurs [33]. The
doses of levofloxacin and sparfloxacin should be reduced for
patients with creatinine clearances !50 mL/min [3, 34]. With
use of sparfloxacin, the glucuronide conjugate accumulates in
patients with renal failure. In patients with hepatic failure (without renal dysfunction), no adjustments in dosing of levofloxacin
and sparfloxacin are generally necessary.
With use of grepafloxacin there are 36% and 48% increases
in serum concentrations in patients with mild and moderate
impairment in liver function, respectively, and the manufacturer
recommends that the drug not be given to any patient with
hepatic failure [35]. For trovafloxacin, the manufacturer recommends that dosing be reduced in the presence of mild to
moderate hepatic dysfunction. In light of the hepatotoxic potential of trovafloxacin (see below), however, administration of
trovafloxacin to such patients should probably be avoided
Interactions with Other Drugs
All of the newest quinolones, like the earlier members of the
class, form complexes with multivalent cations that impair their
oral absorption. Therefore, antacids, sucralfate, and other multivalent cation–containing preparations should not be given
concurrently with any quinolone; instead, dosing should be
staggered by at least 2 h. H2-receptor antagonists do not affect
Pharmacokinetic properties of quinolones.
Renal clearance
Drug
Ciprofloxacin
Ofloxacin
Levofloxacin
Sparfloxacin
Grepafloxacin
Trovafloxacin
c
Alatrofloxacin
a
b
c
Dose (mg)
500
400
400
400
500
500
200
600
200
300
po
iv
po
iv
po
iv
po
po
po
iv
Peak serum
concentration (mg/mL)
Dosing
interval (h)
Half-life
in serum (h)
mL/min
% of total
clearance
2.2
4.3
4
7.2
5.7
6.4
b
1.1
2.3
3.1
4.3
12
a
8–12
12
12
24
24
24
24
24
24
3.3
360
50
5
200
70
6–8
120
65
20
15
10–12
25
13
10
5–10
8
400 mg IV q8h appears equivalent to 750 mg po q12h.
At steady-state after 400-mg loading dose, followed by 200 mg q24h.
An L-alanyl-L-alanyl ester of trovafloxacin that is rapidly converted to trovafloxacin in serum.
CID 2000;30 (February)
Table 2.
Quinolones: New Uses and Challenge of Resistance
245
Dosage adjustments of quinolones for patients with renal or hepatic dysfunction.
Patients with renal failure
Quinolone
Ciprofloxacin
Creatinine clearance
for change (mL/min)
!30
!5
Ofloxacin
!30–50
!5
Levofloxacin
20–50
!10–20
Sparfloxacin
Grepafloxacin
Trovafloxacin
!50
No change
No change
Patients with hepatic failure
Dose
Interval (h)
13
13
13
1/23
a
1/23
a
1/23
b
13
18
24
24
24
24
48
48
Degree of impairment
for change
Dose
Interval (h)
1/3–1/23
24
No change
No change
No change
No change
Contraindicated
c
Mild to moderate
NOTE. No additional adjustments needed for peritoneal dialysis or hemodialysis, which remove only small amounts
of fluoroquinolones.
a
250 mg, after 500-mg loading dose.
b
200 mg, after 400-mg loading dose.
c
Avoid because of risks of hepatotoxicity.
absorption. Cisapride increases the rate of absorption of sparfloxacin but does not affect its overall bioavailability [36]. Omeprazole reduces the bioavailability of oral trovafloxacin slightly
(18%) but is not known to affect the bioavailability of other
quinolones [37]. Intravenous morphine also reduces the oral
absorption of trovafloxacin by 30%–45%, presumably by reducing splanchnic blood flow [38].
Of the 4 newest quinolones, only grepafloxacin has a clinically important interaction with theophylline, reducing its elimination and resulting in increases of 28% (400-mg dose) to 82%
(600-mg dose) in the Cmax in serum [39].
Adverse Effects
The side-effect profiles of quinolones have been recently reviewed [40]. In most cases, the adverse-effect profiles of different
quinolones have not been compared directly in the same patient
population. Gastrointestinal adverse effects such as nausea,
vomiting, diarrhea, and abdominal pain generally are the most
common category of adverse effects of quinolones, with rates
in the range of 1%–4% of patients overall. An exception is
grepafloxacin, which was associated with rates of nausea of
10%–22%, significantly higher than rates associated with ciprofloxacin [41]. Gastrointestinal symptoms were more frequent
with the 600-mg dose than with the 400-mg dose. Taste perversion (described as a bitter taste in the mouth) was also reported by 13%–27% of patients receiving grepafloxacin [6].
The next most common category of adverse effects has been
related to the CNS, with insomnia, dizziness, and headache
reported most often. Rates have been low for levofloxacin
(1%–2%) and sparfloxacin (2%) and similar for grepafloxacin
and ciprofloxacin (6%–9%). Dizziness was reported more frequently with use of trovafloxacin (2%–11%) than with comparison agents (3%) [8]. This symptom was generally mild,
tended to decrease with continued dosing, and led to discontinuation of the dosing for only 2% of patients. The manufac-
turer notes that dizziness is reduced if the single daily dose is
given at bedtime.
Photosensitivity reactions are rare with levofloxacin, grepafloxacin, and trovafloxacin. In contrast, sparfloxacin, which
contains a halide substituent at position 8 that is known to be
associated with phototoxicity, was associated with significantly
higher rates of photosensitivity reactions (7.9%) than were comparison agents in North American trials [40]. Reactions were
generally mild and resolved over a mean of 6 days [42]. No
case occurred 13 days after completion of therapy. Light in the
ultraviolet A range (320–420 nm), which is associated with these
reactions, is not blocked by many sunscreens, which often contain only ultraviolet B blockers. Products containing ultraviolet
A blockers such as octocrylene or Parsol 1789 (Person and
Covey; Glendale, CA) may afford some protection [40].
Prolongation of the QTc (the interval [corrected for heart
rate] between the beginning of the QRS complex to the end of
the T wave) on the electrocardiogram has been associated with
sparfloxacin and, to a lesser extent, grepafloxacin, but not with
levofloxacin and trovafloxacin. With sparfloxacin, this effect is
dose-related (2% at 100 mg q.d. and 8% at 400 mg q.d.) and
similar in magnitude to that occurring with erythromycin
(3.7%) [43]. Potentially clinically important prolongation of the
QTc of >500 msec in 1.2%–3% of patients in clinical trials was
reported, but arrhythmias have been rare with serious cardiovascular events, including some with ventricular tachycardia,
occurring in ∼1 in 100,000 courses of treatment in postmarketing surveillance. Grepafloxacin was recently withdrawn by
the manufacturer because several patients receiving the drug
have experienced cardiovascular events. Use of sparfloxacin
and grepafloxacin is contraindicated for patients with known
prolongation of the QTc or torsades de pointe and for those
patients taking other drugs known to prolong the QTc.
Laboratory abnormalities have been uncommonly reported
for patients taking quinolones. This paucity of abnormalities
was also noted overall in clinical trials of trovafloxacin. In
contrast, in 1 unpublished study of patients with chronic pros-
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tatitis, trovafloxacin given for 28 days was associated in 9% of
patients with asymptomatic increases in hepatic transaminase
levels (to >3 times the upper limit of normal), which resolved
within 2 months after discontinuation of therapy.
Subsequently, in postmarketing surveillance, there have been
reports to the US Food and Drug Administration (FDA) of
140 symptomatic hepatic reactions in patients receiving trovafloxacin, among 2.5 million prescription recipients, for a reporting incidence of 1 : 18,000. Among these were 14 cases of
acute liver failure resulting in 6 deaths, 5 of which were due to
liver failure. One additional death occurred among the 4 patients who received liver transplants.
Because of these reports, the FDA on 9 June 1999 issued a
Public Health Advisory with interim recommendations that trovafloxacin be used only for patients with life- or limb-threatening infections (nosocomial pneumonia, community-acquired
pneumonia, complicated intra-abdominal infections, gynecologic and pelvic infections, and complicated skin and skin structure infections [including diabetic foot infections]), whose physicians believe that the benefits of trovafloxacin therapy
outweigh the risks. Although the risk of hepatotoxicity appeared to be higher with courses of therapy exceeding 2 weeks,
liver failure was reported to occur in 1 patient receiving treatment for only 2 days, making uncertain the value of monitoring
serum transaminase levels to reduce the risks. The mechanism
of this rare but severe toxicity have not yet been determined.
Clinical Applications
Urinary tract infections (UTIs). Concentrations of ciprofloxacin and ofloxacin in urine are high, as are those of levofloxacin, reflecting their dominant renal routes of elimination
(renal clearance, 50%–70% of total clearance). Concentrations
of sparfloxacin, grepafloxacin, and trovafloxacin in urine are
lower than those of other fluoroquinolones, because their elimination is largely by nonrenal routes (renal clearance, 5%–13%
of total clearance). For uncomplicated cystitis in young women,
published data are available only for sparfloxacin, which when
used at full doses (a 400-mg initial dose and then 200 mg q.d.)
for a total of 3 days was comparable with ofloxacin (200 mg
b.i.d.) given for 3 days, yielding similar clinical and microbiological cure rates [44].
These results probably reflect the high level of susceptibility
of the Escherichia coli pathogens that predominated (86%) in
this study. Sparfloxacin given in a lower dose (a 200-mg initial
dose and then 100 mg q.d.), however, was less effective than
was ciprofloxacin (500 mg b.i.d.) for treatment of patients with
complicated UTIs [45]. No differences in the rates of eradication
of E. coli were seen, but sparfloxacin was inferior in eliminating
other members of the Enterobacteriaceae, Pseudomonas aeruginosa, and enterococci that are more commonly pathogens in
patients with complicated infections.
Levofloxacin has been studied for the treatment of patients
CID 2000;30 (February)
with acute uncomplicated pyelonephritis, mainly young women
with E. coli infections [46]. Levofloxacin (250 mg q.d. for 7–10
days) was similar in clinical efficacy (92% vs. 88%) and microbiological eradication (94%) to ciprofloxacin (500 mg b.i.d. for
10 days) at the completion of therapy, but relapses were somewhat higher with levofloxacin (9 of 71 [13%] vs. 5 of 77 [6.5%];
P = .31] during follow-up, suggesting the possibility that higher
doses or longer courses of therapy should be considered for
patients with acute pyelonephritis.
No published data are available on the use of grepafloxacin
and trovafloxacin for treatment of UTIs. Their low concentrations in urine and those of sparfloxacin would suggest, however,
that sparfloxacin, grepafloxacin, and trovafloxacin offer no advantage over ciprofloxacin or levofloxacin for UTIs caused by
gram-negative bacteria.
Sexually transmitted diseases. For treatment of uncomplicated gonorrhea, sparfloxacin (200 mg), grepafloxacin (400
mg), and trovafloxacin (100 mg) have all been shown to be
highly effective, when given as single doses, in eradicating N.
gonorrhoeae [47–49]. Small numbers of rectal and pharyngeal
infections were also eradicated by grepafloxacin and trovafloxacin. The efficacy of sparfloxacin was virtually identical to that
of ciprofloxacin (250 mg; 99% vs. 98%), and the efficacy of
trovafloxacin was similar to that of ofloxacin (400 mg; 99% vs.
100%). Thus it is not clear whether the newer agents offer any
advantage over the older agents for treatment of uncomplicated
gonorrhea.
Information on efficacy of the newer agents in patients infected with strains of N. gonorrhoeae with reduced susceptibility
to ciprofloxacin would be valuable. No published data are available on the use of levofloxacin for treatment of gonococcal
infections, but the high efficacy of ofloxacin [50] would suggest
that levofloxacin would also be effective.
Against C. trachomatis, single doses of sparfloxacin and grepafloxacin, like single doses of other quinolones, were poorly
effective. Cultures remained positive for C. trachomatis for 2
of 5 patients given single doses of sparfloxacin and 8 of 19
patients given single doses of grepafloxacin. More prolonged
courses of both of these agents, like a 7-day course of ofloxacin
[51], however, were effective in eradicating genital chlamydia.
For chlamydial urethritis in men, sparfloxacin (200 mg on
day 1 and then 100 mg q.d.) given for 7 days was as effective
as a 7-day course of doxycycline (97% vs. 96% eradication),
but a 3-day course of sparfloxacin was somewhat less effective
(88%) [52]. In women with uncomplicated chlamydial cervicitis,
7-day courses of grepafloxacin (400 mg q.d.) and doxycycline
also had similar efficacy (96% vs. 99%) [53], but only about
one-third of patients enrolled in the study returned for followup. Published data are lacking on use of levofloxacin and trovafloxacin for genital chlamydial infections.
Intra-abdominal infections. Comparative studies of treatment of intra-abdominal infections with quinolones have been
published only with regard to ciprofloxacin and trovafloxacin.
CID 2000;30 (February)
Quinolones: New Uses and Challenge of Resistance
Ciprofloxacin combined with metronidazole was compared
with imipenem [54], and trovafloxacin was compared with imipenem followed by amoxicillin-clavulanate [55]. Both studies
were of a double-blind design. In the ciprofloxacin/metronidazole study, there were 2 arms for this therapy, 1 in which
ciprofloxacin (400 mg b.i.d.) and metronidazole (500 mg q6h)
were given completely intravenously and 1 in which patients
could be switched from iv to oral medication (ciprofloxacin,
500 mg b.i.d.; metronidazole, 500 mg q6h). Imipenem was given
at a dosage of 500 mg iv q6h.
Outcomes were similar in all 3 groups, with cure rates of
82% for ciprofloxacin/metronidazole iv, 85% for ciprofloxacin/
metronidazole iv/po, and 78% for imipenem. Outcomes correlated with APACHE (Acute Physiology and Chronic Health
Evaluation) scores, and the mean APACHE scores were 9.2 in
the ciprofloxacin/metronidazole groups and 10.5 in the imipenem group. Outcomes did not differ between treatment groups
with different pathogens isolated, but failures were higher in
all treatment groups among patients from whom enterococci
were isolated than among those from whom enterococci were
not isolated (28% vs. 14%). It is not clear whether these differences reflect limited efficacy of these agents against enterococcal infection or whether the presence of enterococci was a
marker for patients with more severe infection.
In a similar study, trovafloxacin (initially 300 mg alatrofloxacin iv q.d. and then 200 mg trovafloxacin po q.d.) was compared with imipenem (1 g iv q8h). APACHE scores also correlated with outcomes and were somewhat lower overall than
in the ciprofloxacin study (6.4 for the trovafloxacin arm and
7.0 for the imipenem arm), possibly reflecting the dominance
of patients with appendicitis in the study population. Outcomes
were comparable, with 82% cures in both treatment groups.
Clinical success rates did not differ by pathogen isolated, and
in the subgroup of patients from whom B. fragilis was isolated,
clinical responses seemed satisfactory with use of trovafloxacin
(97% for trovafloxacin vs. 82% for imipenem).
Therefore the anaerobic activity of trovafloxacin appeared
to be adequate in this patient population. The results of this
study suggest that trovafloxacin may be used alone for mixed
aerobic and anaerobic intra-abdominal infections but leaves
uncertain its efficacy in more severely ill patients.
A similar regimen of iv followed by po trovafloxacin has also
been compared with a regimen of cefotetan followed by amoxicillin-clavulanate for treatment of women with acute gynecologic infections, which were largely puerperal endomyometritis
[56]. Clinical response rates were similar overall for the 2 regimens (96 [90%] of 107 vs. 102 [86%] of 119) and also did not
differ in the smaller subgroups of patients from whom gramnegative aerobes, gram-positive aerobes, and anaerobes were
isolated in cultures at study enrollment.
Skin and soft-tissue infections. Information is quite limited
on the use of levofloxacin and trovafloxacin for treatment of
patients with skin and soft-tissue infections. In a single pub-
247
lished study, levofloxacin (500 mg q.d.) was compared with
ciprofloxacin (500 mg po b.i.d.) for treatment of a group of
patients in whom cellulitis (44%), pyodermas (11%), and cellulitis with abscess (11%) constituted the majority of infections
[57]. The dominant pathogen was S. aureus (174 of 288 microbiologically assessable patients [60%]), and eradication rates
were significantly higher for levofloxacin (100%) than for ciprofloxacin (87%).
Rates of eradication of S. pyogenes among the small number
of patients from whom it was isolated were also high (14 of 14
treated with levofloxacin vs. 18 of 20 treated with ciprofloxacin).
Rates of clinical cure were similar overall (151 of 182 [83%]
with levofloxacin vs. 155 of 193 [80%] with ciprofloxacin). The
role of levofloxacin in treatment of patients with skin and softtissue infections is not certain, because the available data,
though encouraging, are only limited, and levofloxacin has not
been approved by the FDA for this use. For treatment of infections in the feet of diabetic patients in which anaerobic as
well as gram-positive and gram-negative bacteria may be pathogens, an additional agent active against anaerobic bacteria,
such as metronidazole or clindamycin, would probably be
necessary.
Trovafloxacin, which is active against a broad spectrum of
pathogens, including anaerobic bacteria, was approved by the
FDA for treatment of soft-tissue infections, including those in
the feet of diabetic patients. No clinical data have been published, however, and no data are provided by the manufacturer
in the package insert. Sparfloxacin and grepafloxacin have not
been developed for treatment of skin and soft-tissue infections.
Respiratory tract infections. All 4 of the newest quinolones
were developed and approved in the United States for treatment
of patients with respiratory tract infections. In relation to pathogens involved in community-acquired infections, their potency, like that of ciprofloxacin and ofloxacin, is excellent for
pathogens such as H. influenzae and M. catarrhalis, and their
potency is also generally quite high for atypical pathogens, such
as M. pneumoniae, C. pneumoniae, and Legionella species, with
high intracellular concentrations of drug possibly augmenting
activity in vivo against these latter pathogens.
S. pneumoniae was the principal pathogen about which there
had been concerns with regard to the adequacy of the activity
of earlier quinolones. Each of the newer agents exhibits improved potency against this pathogen. Published clinical data
are now available concerning the use of levofloxacin, sparfloxacin, grepafloxacin, and trovafloxacin for treatment of several
types of community-acquired respiratory tract infection. No
data have been published on the use of any of these quinolones
for treatment of nosocomial pneumonia, and only trovafloxacin
has been approved by the FDA for this indication.
Acute bacterial exacerbations of chronic bronchitis (ABECB)
are often associated with isolation of H. influenzae or M. catarrhalis from sputum, with a lesser occurrence of S. pneumoniae and enteric or nonenteric gram-negative bacteria. For treat-
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ment of patients with ABECB, rates of clinical improvement
were similar for levofloxacin (500 mg po q.d. for 5–7 days)
compared with cefuroxime axetil (250 mg po b.i.d. for 10 days)
[58] and cefaclor (250 mg po t.i.d. for 7–10 days) [59]; for
sparfloxacin (200 or 400 mg on day 1 and then 100 or 200 mg
q.d. for 7–14 days) compared with amoxicillin-clavulanate (500
mg/250 mg t.i.d. for 7–14 days) [60] and ofloxacin (400 mg
b.i.d. for 10 days) [61]; for grepafloxacin (400 mg or 600 mg
q.d. for 7–10 days) compared with ciprofloxacin (500 mg b.i.d.
for 10 days) [41] and amoxicillin (500 mg t.i.d. for 7–10 days)
[62]; and for trovafloxacin (200 mg or 100 mg q.d. for 5 days)
compared with amoxicillin (500 mg t.i.d.) [63] and amoxicillinclavulanate (500 mg/125 mg t.i.d.) [64].
Rates of eradication of specific pathogens from sputum were
also generally similar, with the exceptions that sparfloxacin was
significantly better than amoxicillin-clavulanate [60] and trovafloxacin was significantly better than amoxicillin [63] for
eradication of H. influenzae. The extent to which resistance
contributed to the inferior responses to the b-lactam comparator regimens was not documented in either study. In addition,
in 1 study a trovafloxacin dosage of 200 mg q.d. was superior
to a dosage of 100 mg q.d. in eradicating S. pneumoniae from
sputum [63]. Resistance occurring in S. pneumoniae that persisted after quinolone therapy was not evaluated in this or other
studies of treatment of patients with ABECB. None of these
studies has evaluated the effect of treatment on the time to the
next exacerbation of bronchitis, as was done in studies in which
ciprofloxacin was shown to be superior to clarithromycin [65]
and comparable with cefuroxime axetil [66].
Community-acquired pneumonia involves an array of bacterial pathogens similar to those involved in ABECB, except
that S. pneumoniae is usually the most frequently identified
pathogen, and pathogens causing atypical pneumonia must also
be considered in some patients. The greater severity of illness
in some patients with pneumonia and in those with bacteremic
pneumonia, in particular, also provides more stringent tests of
the efficacy of quinolones than do studies of patients with
ABECB. Because of rising resistance of pneumococci to penicillin and (to varying extents) other b-lactams [67], fluoroquinolones with activity against S. pneumoniae have been recommended as a first-line option for treatment of patients with
community-acquired pneumonia [68].
Several randomized, comparative trials of treatment of such
patients with the newest quinolones have been published, some
of which have also been double-blind in design [69–73]. In each
of these trials, clinical outcomes with the quinolones were similar or superior to those with use of comparator agents, for
example, for levofloxacin (500 mg iv/po for 7–14 days) versus
ceftriaxone (1–2 g iv q.d. or b.i.d. for 7–14 days) and/or cefuroxime axetil (500 mg po b.i.d.) [74]; for sparfloxacin (400
mg on day 1 and then 200 mg q.d.) versus roxithromycin (150
mg b.i.d. for 10–14 days) [69], high-dose amoxicillin (1 g t.i.d.)
plus ofloxacin (200 mg b.i.d.) [70], and high-dose amoxicillin
CID 2000;30 (February)
alone (1 g t.i.d.) [71]; for grepafloxacin (600 mg t.i.d.) versus
amoxicillin (500 mg t.i.d.) [72]; and for trovafloxacin (200 mg
q.d.) versus high-dose amoxicillin (1 g t.i.d.) [73].
Significantly better overall clinical response rates were seen
for levofloxacin (217 of 226 [96%] vs. 207 of 230 [90%]) and
trovafloxacin (125 of 138 [91%] vs. 119 of 147 [81%]) than for
their comparators, although the comparator groups each had
limitations. In the levofloxacin study, it was not possible to
determine the relative proportions of patients in the ceftriaxone/
cefuroxime arm treated with ceftriaxone, cefuroxime, or both
sequentially. In addition, although erythromycin was allowed
in the ceftriaxone/cefuroxime arm for suspected atypical pneumonia at the discretion of the investigator and was given to
22% of patients in this treatment arm overall, it was not possible
to assess to what extent it was used among those patients found
to have atypical pathogens.
In the trovafloxacin study, although high-dose amoxicillin is
commonly used in Europe for treatment of communityacquired pneumonia, it may be considered less than optimal
against b-lactamase–producing strains of H. influenzae. There
also remains uncertainty as to whether amoxicillin would be
an optimal b-lactam in the face of increasing resistance to penicillin among pneumococci. Somewhat higher rates of eradication of H. influenzae were seen with levofloxacin, grepafloxacin, and trovafloxacin than with their comparators. Clinical
responses in patients with S. pneumoniae infection were similar
with sparfloxacin (vs. high-dose amoxicillin) and somewhat better with levofloxacin, grepafloxacin, and trovafloxacin than
with their comparators.
In the small subgroups of patients with bacteremic pneumococcal pneumonia, whose illnesses probably are of greater
severity and for whom there is greater certainty of the microbiological diagnosis (relative to diagnoses from sputum cultures
alone), clinical responses to levofloxacin (9 of 9) and trovafloxacin (4 of 4) have been high. Among quinolones, the largest
number of patients with bacteremic pneumococcal pneumonia
have been treated with sparfloxacin, with a response rate of
82% (23 of 28) [69, 71]. In comparison, responses to high-dose
amoxicillin (14 [88%] of 16) and roxithromycin (2 of 2) were
somewhat higher, but the numbers were too small to be statistically significant.
There is considerably less information on the use of quinolones for treatment of patients with atypical pneumonia. Small
numbers of patients with legionella pneumonia appear to have
had good clinical responses to levofloxacin (5 of 5) [74], sparfloxacin (1 of 1) [70], and trovafloxacin (6 of 6) [73], providing
limited support to in vitro and animal data that have led to
recommendations concerning use of quinolones for hospitalized
patients with legionella infections [75]. Data on efficacy of quinolones for treatment of patients with atypical pneumonia
caused by M. pneumoniae and C. pneumoniae are difficult to
interpret because of the substantial response rates in the com-
CID 2000;30 (February)
Quinolones: New Uses and Challenge of Resistance
parator groups, which included agents not expected to have
any activity against these pathogens in vivo.
This difficulty is highlighted by the results of 2 published
trials. In the study of levofloxacin, rates of clinical response to
levofloxacin were high for patients infected with M. pneumoniae
(19 of 19) or C. pneumoniae (46 of 47) diagnosed by serological
criteria. However, response rates were similarly high in the ceftriaxone/cefuroxime arm (22 of 22 for M. pneumoniae infections
and 50 of 54 for C. pneumoniae infections) and did not differ
whether or not these patients also received erythromycin [74].
Similarly, the clinical response rates reported for patients receiving trovafloxacin (15 of 16 for M. pneumoniae infections
and 17 of 22 for C. pneumoniae infections) were similar to those
for patients receiving amoxicillin (12 of 14 for M. pneumoniae
infections and 24 of 26 for C. pneumoniae infections) [73].
Therefore, inaccuracies in serological diagnosis of these infections, unexpected clinical responses to b-lactams, or (most
likely) substantial rates of spontaneous abatement of signs and
symptoms could have contributed to these discrepancies. Studies designed to assess the time to resolution of symptoms may
be needed to determine whether there is any clinical benefit in
the use of quinolones for treatment of these types of atypical
pneumonia.
Acute purulent sinusitis acquired in the community is often
caused by a group of pathogens similar to those that cause
ABECB and may be seen as a complication of viral upper
respiratory infection. Anaerobic bacteria usually are present in
only a small percentage of patients and are more likely to be
noted if sinusitis is chronic or associated with dental infections.
The use of nasal decongestants to establish drainage of the
infected sinus cavity is an important adjunctive therapy, in addition to administration of antimicrobial agents. For treatment
of patients with acute purulent sinusitis, levofloxacin (500 mg
q.d.) has been compared with amoxicillin-clavulanate (500 mg/
125 mg t.i.d.) [76], and sparfloxacin (400 mg on day 1 and then
200 mg q.d.) has been compared with cefuroxime axetil (250
mg b.i.d.) [77] and clarithromycin (500 mg b.i.d.) [78].
Clinical responses to levofloxacin and cefuroxime axetil were
virtually identical when assessed 2–5 days after completion of
a 10- to 14-day course of therapy. In a second noncomparative
study that included analysis of sinus aspirates obtained by sinus
puncture or nasal endoscopy to determine bacterial pathogens,
a similar course of levofloxacin eradicated 93%–100% of pathogens, which were predominately H. influenzae (n = 36), S.
pneumoniae (n = 32), S. aureus (n = 33), and M. catarrhalis
(n = 15) [79]. Similarly, sparfloxacin yielded clinical responses
that were virtually identical to those with use of cefuroxime
axetil or clarithromycin in double-blind trials. Clinical response
rates were similar in the subgroups in which H. influenzae, S.
pneumoniae, and M. catarrhalis were isolated from drainage
specimens from the middle meatus at the time of enrollment
[77].
There are no published trials of the use of grepafloxacin or
249
trovafloxacin for treatment of patients with sinusitis. Levofloxacin and trovafloxacin received approval from the FDA for
this indication, but until the issues of its hepatotoxicity risks
are resolved, trovafloxacin should not be used for this indication. Thus levofloxacin may be an alternative to but offers no
advantage over cefuroxime for treatment of acute communityacquired sinusitis.
Empirical treatment of fever in patients with neutropenia.
Early trials demonstrated that quinolones used as prophylaxis
during periods of neutropenia were effective in preventing
gram-negative bacteremia, but that streptococcal bacteremia
occurred with increased frequency, particularly in bone marrow
transplant recipients. Initial trials of quinolones as therapy for
patients with fever and neutropenia had only limited success.
There has, however, been a recent increase in interest in defining
low-risk groups of neutropenic patients who might be safe candidates for oral antimicrobial therapy for fever, because of the
potential for increased convenience and reduced costs.
Quinolones have been components of such oral regimens
used in recent trials addressing this issue [80, 81]. Investigators
evaluated a combination of oral ciprofloxacin and amoxicillinclavulanate compared with iv ceftazidime in 1 trial [81] and
compared with iv ceftriaxone plus amikacin in the other [80];
the subjects had fever and neutropenia from cancer chemotherapy but were able to take oral medications and, in general,
were considered to be at low risk because of the absence of
other diseases, absence of documented infection, and a projected duration of neutropenia of !10 days.
Rates of treatment success among patients given the oral and
parenteral regimens were similar in both studies, although the
oral regimen was associated with an unexpectedly higher incidence of adverse effects (16% vs. 1%), largely nausea and
vomiting, in 1 study [81]. Renal failure, reported in an earlier
trial of ciprofloxacin plus clindamycin for treatment of a similar
group of patients, was not seen in these trials [82]. Whether
oral therapy can also be safely translated into outpatient therapy for patients at rigorously defined low risk, however, remains
to be determined. Although 2 feasibility trials of ofloxacin suggest that it may be possible to manage low-risk cases safely
outside the hospital [83, 84], the power of these studies to detect
clinically important differences in preventable poor outcomes
among such outpatients has been small, as was pointed out in
a recent editorial accompanying the most recent studies [85].
Bacterial Resistance Associated with Use of Quinolones
The selection pressures of exposure to antibiotics can promote the occurrence of resistance by providing a growth advantage for bacteria that have acquired exogenous resistance
genes or for those bacteria in a population that contain spontaneous chromosomal resistance mutations. When resistance
mechanisms result largely from acquisition of resistance genes
(often on plasmids or other mobile genetic elements, e.g., ami-
250
Hooper
noglycoside resistance due to aminoglycoside-modifying enzymes) rather than by chromosomal mutation, selection pressures may have little effect until the requisite resistance genes
have been introduced into the bacterial population under selection. Once the resistance gene has entered this population,
however, there is an opportunity not only for clonal expansion
but also for additional gene transfer among strains and species
may occur.
In contrast, when resistance occurs largely by chromosomal
mutation, all sufficiently large populations of bacteria will probably contain small numbers of spontaneously resistant mutants,
which may then undergo clonal expansion under selective
pressures.
Quinolone resistance in clinical settings appears to occur
largely by chromosomal mutation [86], although the extent to
which the recently reported plasmid-mediated quinolone resistance found in several clinical isolates of Klebsiella pneumoniae
has spread is unknown [87]. Chromosomal mutations have been
of 2 general types: those that alter the subunits of the 2 quinolone target enzymes, DNA gyrase and topoisomerase IV, and
those that affect drug permeation to these cytoplasmic targets
by altering expression of porin-diffusion channels across the
gram-negative outer membrane, altering expression of endogenous efflux pumps located in the inner membrane (also linked
to proteins traversing the periplasm and outer membrane in
gram-negative bacteria), or both types of alteration.
Individual mutations of both types cause distinct increments
in resistance that may vary among different quinolones. For
example, a common mutation in the A subunit of DNA gyrase
of E. coli causes a 128-fold increase in the MIC of nalidixic
acid (the oldest quinolone) but only a 4-fold to 8-fold increase
in the MIC of ciprofloxacin and other fluoroquinolones. Similarly, a mutation that increases the expression of the NorA
efflux pump of S. aureus increases resistance to ciprofloxacin
by about 4-fold but has no effect on the activity of sparfloxacin.
For most of the newer quinolones, in general, any single mutation causes a <16-fold increase in resistance.
Thus, if the therapeutic index (the ratio of quinolone concentration at the site of infection to the MIC for the pathogen)
for a quinolone exceeds this factor, it is likely that the growth
of spontaneous single-step resistance mutants will still be inhibited rather than selected by quinolone use. Therefore, use
of low doses of quinolones or existence of pathogens at body
sites in which drug delivery is poor may promote resistance by
lowering the therapeutic index. Multiple mutations may also
potentially accumulate when there are repetitive quinolone exposures for organisms that exist in reservoirs that allow persistence of early-step mutants.
During the past decade of use of ciprofloxacin and ofloxacin,
different patterns of resistance in different pathogens have
emerged. Most striking has been the rapid emergence of a high
prevalence of quinolone resistance (190%) among methicillinresistant but not methicillin-susceptible strains of S. aureus in
CID 2000;30 (February)
many parts of the world [88, 89]. This same difference in prevalence of quinolone resistance also exists between methicillinresistant and -susceptible strains of coagulase-negative staphylococci [90].
For these organisms, several factors may have operated in
concert. The delivery of drug in low concentrations to skin,
sweat, and mucosa, the normal body-surface habitat of reservoirs of staphylococci, and a relatively low therapeutic index
for drug concentrations in serum (about 3 for ciprofloxacin)
probably contributed to ease of selection of individual resistant
strains by quinolone exposure [91]. These factors, however,
would have been expected to operate similarly for methicillinresistant and -susceptible strains. For methicillin-resistant
strains, additional factors were probably operative to amplify
the prevalence of quinolone resistance, including nosocomial
spread of resistant strains [92] and coselection by exposure to
any of several antibiotics because of the multidrug-resistance
phenotype of the methicillin-resistant strains [90].
For another pathogen with a similarly low therapeutic index,
P. aeruginosa, the evolution of resistance has been substantial
but more gradual [93]. Possibly, smaller endogenous reservoirs
of these organisms and fewer opportunities for nosocomial
spread have contributed to the more gradual increase in
resistance.
Most surprising, however, has been the emergence of resistance in pathogens that are intrinsically highly susceptible to
the modern quinolones, such that strains identified as resistant
by break-point criteria of the clinical microbiology laboratory
generally have 2 and in some cases multiple resistance mutations. These organisms include N. gonorrhoeae, E. coli, and
Campylobacter jejuni. In the case of N. gonorrhoeae, outbreaks
of resistant strains have been reported in isolated areas of the
United States, but resistance has become highly prevalent in
parts of the Far East [94].
In 1 study in the United States, resistant strains were clonal
and were less likely than susceptible strains to be detected by
gram stains of urethral exudates, possibly contributing to reduced detection and fewer treatment regimens [95]. Intercity
spread was also detected [96]. The relative extents to which
quinolone use and clonal spread of resistant strains by sexual
contacts contribute to the high prevalence of gonococcal quinolone resistance in other parts of the world is not certain.
For C. jejuni, quinolone resistance has emerged in Europe in
parallel in both human and food-animal populations and was
temporally associated with the use of quinolones in both populations [97]. Contamination of food products with resistant
campylobacters has been demonstrated [98], but the relative
extent to which administration of quinolones to humans and
animals contributed to resistance in these human populations
has been uncertain. Recently, surveillance in the United States
has identified an increase in domestically acquired cases of quinolone-resistant C. jejuni diarrhea in patients who had not previously received quinolone treatment [99]. This study also iden-
CID 2000;30 (February)
Quinolones: New Uses and Challenge of Resistance
tified substantial overlap in the resistant strain types of C. jejuni
isolated from animal sources and those isolated from humans,
linking human disease with animal sources of these pathogens.
Patients infected with resistant strains who were treated with
quinolones were further shown to have slower-resolving diarrhea than patients infected with susceptible strains. Resistance
has also been reported to have developed in a few patients
during quinolone therapy for diarrhea caused by initially susceptible isolates of C. jejuni [100]. The diarrhea resolved but
resistant organisms were shed in stool; no relapse of symptoms
occurred.
Quinolone-resistant strains of E. coli have also emerged in
Europe and have become prevalent in outpatients with UTIs,
a particularly surprising circumstance not only because of the
usually high susceptibility of the wild-type E. coli strains but
also because of the high concentrations of many quinolones in
urine, a combination of which should create exceptionally high
therapeutic indices that would be expected to discourage emergence of resistance associated with quinolone use. Risk factors
for acquisition of resistance in such patients in Spain have included use of quinolones, complicated infections, and use of
urinary catheters [101].
Clinically important resistance of E. coli has also developed
in some hematology-oncology units in Spain and Germany in
which quinolones were used as prophylaxis during periods of
neutropenia [102, 103], as well as in nonneutropenic patients
in Spain [104]. In these units, breakthrough bacteremia with
quinolone-resistant E. coli has become a problem. Such bacteremia and colonization of the fecal flora with quinoloneresistant E. coli [105] have been associated with quinolone use
as prophylaxis and were caused by distinct strains, not clonal
spread within the units. A few patients in these studies were
noted, however, to have fecal colonization with resistant E. coli
without prior quinolone exposure or hospitalization [105].
Subsequently, a more extensive study of community fecal
colonization with resistant E. coli in Spain has identified an
unexpectedly high prevalence of 24%–26% among adults as well
as children, for whom quinolones would not likely be used [106].
Also noteworthy were the findings in the earlier study of UTIs
caused by quinolone-resistant E. coli. In that study, 14% of the
isolates from control patients with UTIs due to fluoroquinolone-susceptible E. coli were resistant to pipemidic acid, an
early-generation quinolone. This resistance, like that to nalidixic acid, is a more sensitive detector of first-step resistance
mutations [101]. None of these control patients had a history
of treatment with a quinolone, suggesting acquisition rather
than selection as the source of the initial pipemidic
acid–resistant strains.
These findings, in conjunction with earlier findings of high
rates of colonization of poultry with resistant E. coli in Spain
[107], raise the possibility that contamination of the food supply
with resistant E. coli may contribute to high baseline colonization rates in human fecal reservoirs. Furthermore, analysis
251
of the resistant E. coli bloodstream isolates from patients with
cancer identified strains with high levels of resistance, probably
requiring multiple chromosomal mutations, an occurrence unlikely to have developed without several cycles of selection and
persistence in vivo. Therefore, it is possible that these problems
of resistance are the result of separate selection pressures acting
on intersecting populations of bacteria.
First early-step mutant E. coli strains may have the opportunity to colonize the intestinal tracts of persons who have
ingested contaminated food from animals that have been exposed to quinolones during production. When such persons are
subsequently exposed to quinolones for treatment of UTIs, for
prophylaxis during chemotherapy for cancer, or possibly for
other indications, these early-step mutants may become the
substrate from which selection of later, multistep highly resistant mutants becomes possible. It is noteworthy that the problems with resistant E. coli seen in Europe have not yet emerged
in the United States, which has only recently allowed more
limited use of quinolones in food-animal production.
As yet, the evidence suggesting a relationship between the
high levels of resistant E. coli in humans and food animals in
Europe is circumstantial; thus it will be important to perform
epidemiological studies similar to those performed with resistant campylobacters to provide a link between resistant animal
and human isolates, as well as further studies to provide a link
between resistant E. coli in food-animal sources and the use of
quinolones in production.
Quinolone resistance among respiratory pathogens has remained quite low, possibly because only recently has treatment
of respiratory tract infections become a focus of quinolone use
and possibly because the reservoir of some pathogens such as
S. pneumoniae is children, a group in which quinolones have
not been used routinely. Quinolone-resistant strains of S. pneumoniae, however, have been reported recently from Hong Kong
[108] and Canada [109], as has an increase in resistant isolates
from older Canadians, from !1% in 1995 to 13% in 1998. No
such increase in resistance was seen in isolates from Canadian
children, a finding suggesting a relationship between quinolone
use and the early emergence of resistance.
Particularly worrisome was the reported association of quinolone resistance with penicillin resistance in pneumococci, since
it is for infections due to penicillin-resistant strains, which are
commonly multiply resistant, that the need for alternative
agents is most compelling. As quinolones become used more
regularly for treatment of respiratory tract infections, surveillance for emerging resistance in respiratory pathogens will become increasingly important. Since still only a minority of S.
pneumoniae strains in the United States are fully resistant to
penicillin (10%–15%), it is reasonable to administer nonquinolone agents to many patients with mild disease and to reserve
the newest quinolones for those patients whose conditions do
not improve promptly with use of other agents and for patients
252
Hooper
with more severe disease, in whom any delay in initial response
would have important clinical implications.
Routine use of quinolones to the exclusion of other agents
for treatment of respiratory tract infections will probably create
substantial selection pressures. Therefore, to minimize the risks
for resistance, quinolones should be considered as 1 of several
possible choices for treatment of bacterial respiratory tract infections and, like other antibiotics, should not be used for respiratory syndromes likely to be of viral origin. Continued
avoidance of routine administration of quinolones to children
will also probably be important for avoiding particularly highrisk selection pressure in a pneumococcal reservoir population.
Further research will also be important to evaluate the impact
of the choice of quinolone as well as dose and duration on the
risk of resistance.
CID 2000;30 (February)
18.
19.
20.
21.
22.
23.
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