Infect Dis Clin N Am 18 (2004) 691716

The newer uoroquinolones

Judith A. ODonnell, MDa,*,
Steven P. Gelone, PharmDb
a

Division of Infectious Diseases, Drexel University, College of Medicine,

Medical College of PA Hospital, 3300 Henry Avenue, Philadelphia, PA 19129, USA
b
Department of Pharmacy Practice, Temple University School of Pharmacy, Room 526A,
3307 North Broad Street, Philadelphia, PA 19140, USA

The era of quinolone antibiotics began with the serendipitous discovery

of the prototype quinolone antibiotic, nalidixic acid, during the synthesis of
the antimalarial agent chloroquine in the early 1960s [1]. Although nalidixic
acid was never widely used in the treatment of systemic infections [2],
it provided the chemical foundation on which more than 10,000 analogues
have been identied.
Over the last decade, the uoroquinolones (FQs) have become a dominant
class of antimicrobial agents. No other class of antimicrobial agents has
grown so rapidly or been developed with such interest by pharmaceutical
research companies. Moxioxacin (MOX) and gatioxacin (GAT), both
8-methoxy-uoroquinolones, are the most recently approved agents in
this growing class. Gemioxacin (GEM), newly approved, and garenoxacin,
a desuoroquinolone, are on the horizon.
This article provides an overview of the newer FQ, in particular focusing
on the clinical trials published to date for these compounds. A more
thorough review of the entire class including mechanisms of action and
emerging resistance, spectrum of activity, and pharmacology has been presented by the authors elsewhere [3].

Mechanisms of action
The primary targets of the FQs are the bacterial topoisomerases [4].
Bacterial topoisomerases are a class of enzymes essential in maintaining the
cellular DNA molecule in a physicochemically stable and biologically active

* Corresponding author.
E-mail address: jao25@drexel.edu (J.A. ODonnell).
0891-5520/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.idc.2004.04.011

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state. There are four bacterial topoisomerases, classied as either Type I or

Type II enzymes. Type I topoisomerases are active during the replication
process of single-strand DNA, whereas Type II topoisomerases are responsible for that of double-strand DNA [5,6]. The quinolone antibiotics
are strong inhibitors of the Type II enzymes including DNA gyrase
(topoisomerase II) and topoisomerase IV. Type I enzymes are not sensitive
to the inhibitory activity of quinolones [7]. Topoisomerases are critical
components in bacterial DNA replication, and safe decatenation of the
subsequent daughter chromosome. Specically, DNA gyrase introduces
negative supercoils and eliminates the positive supercoils that occur ahead
of the DNA replication fork during DNA replication [8]. Without such
enzymatic activity, DNA replication is never successful. The role of
topoisomerase IV is to separate the daughter DNA once replication is
completed [6]. Any interruption in one or more of the steps of the
bacterial DNA replication process results in rapid bacterial cell death.
Available experimental data strongly suggest that quinolones bind to the
topoisomerase-DNA complex, but not to either the enzyme or DNA alone,
and form a ternary complex that leads to eventual cell death [9].
Although the bacterial DNA gyrase has long been considered the
principal target of the quinolone antibiotics, more recent data have
elucidated topoisomerase IV as another important target of FGs. In general,
among gram-negative bacteria, DNA gyrase is the primary target of the
FQs, and topoisomerase IV is the secondary or complementary target [9
11]. The reverse is true for gram-positive microorganisms [1217].
Structure activity relationships
There are several aspects of the quinolone structure that directly impact
on antibacterial activity [4,1821]. Fig. 1 depicts the chemical structure
activity relationships of the quinolone antibiotics with regard to the
antimicrobial activity and adverse eects. GEM is a uoronaphthyridone
derivative similar to trovaoxacin. Importantly, it lacks a diuorophenyl
side chain that is found on both trovaoxacin and temaoxacin, which has
been proposed to be related to unpredictable organ toxicity. GAT and
MOX are classied as 8-methoxy uoroquinolones. The presence of
a methoxy group at position 8 increases their anity for DNA gyrase and
topoisomerase IV, resulting in increased activity against Streptococcus
pneumoniae [22]. The 8-methoxy group also confers a structural advantage
that decreases the likelihood of emergence of resistance [12]. Garenoxacin is
a desuoroquinolone, which means that it lacks a uorine atom at position
6. The presence of any halogen atom (but a uorine atom in particular) at
position 6 had previously been thought to be necessary for potent
antimicrobial activity [19,20]. Despite its unique structural dierence among
the FQs, garenoxacin works by the same mechanism as uorinated
quinolones and has excellent in vitro and in vivo activity.

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693

Fig. 1. Quinolone antibacterial structure-activity relationships. (From Domagala JM.

Structure-activity and structure-side eect relationships for the quinolone antibacterials.
J Antimicrob Chemother 1994;33:685806; with permission.)

Mechanisms of bacterial resistance

The selective pressure associated with widespread use of FQs has led
to the emergence of quinolone-resistant bacteria [23,24]. Microorganisms
become resistant to FQs through two mechanisms: chromosomal mutations
or alterations in their ability to permeate the bacterial cell wall. Single or
multiple mutations in the genes encoding the bacterial DNA gyrase (gyrA or
gyrB) or topoisomerase IV (parC and parE) are the specic sites of mutation
[2529].
Importantly, FQ resistance arises in a stepwise manner. This concept,
along with the dual targets of FQ (DNA gyrase and topoisomerase IV), has
important implications. First, when the selection steps are small enough,
bacterial populations readily become resistant [30]. Thus it is not desirable
to have a FQ compound that loses its potency with bacteria that exhibit
single-step mutations. Second, recognizing this fact and the stepwise manner
in which resistance occurs, and the dual targets of the FQs, it is most
desirable to have a FQ compound that would maintain activity against
single-step mutants, and instead require the wild-type bacterial strains to
acquire two target site genetic mutations for expression of FQ resistance. In
other words, FQ compounds with equal activity against DNA gyrase and
topoisomerase IV would require concomitant mutations in the bacteria at
both sites. Double mutants occur rarely, and these compounds may restrict
the selection of resistance.

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To this end, agents with an 8-methoxy group show increased bactericidal

activity against single-step mutants [31]. This activity seems to have widespread eects on a variety of organisms. In addition, 8-methoxy FQs seem to
select resistant mutants at a lower rate than FQs with hydrogen at position 8.
Although the 8-methoxy substituent does improve activity against single-step
mutants, it does not make the mutants as susceptible as wild-type cells [30].
The other important mechanism of quinolone resistance is an active eux
pump that limits intracellular accumulation of antimicrobials and may lead
to clinically signicant quinolone resistance warranting a change in therapy
[3234]. This is independent of the quinolone resistance caused by structural
changes in DNA gyrase or topoisomerase IV, and is an energy-dependent
process that can be eectively inhibited by reserpine, a known eux pump
inhibitor. Although it is not known how widely this mechanism is distributed
in the microbial world, its presence has been demonstrated in a number of
bacteria including Escherichia coli, Klebsiella pneumoniae, Staphylococcus
aureus, S pneumoniae, and Bacteroides fragilis [10,11,14,17,29,32,33,3538].

Clinical pharmacology
The newer FQs exhibit improved pharmacokinetic properties as compared with the older compounds [39]. First, their serum half-lives are
generally longer. This allows for most to be dosed once daily. Second, oncedaily dosing allows for higher peak levels to be achieved resulting in
maximal bacterial killing. Third, their large volume of distribution results in
extensive tissue penetration [8,39,40]. A summary of the pharmacokinetic
properties, including major route of elimination, is included in Table 1.
Although these generalizations are true, it is important to recognize that
clinically signicant dierences exist among the newer agents, and that these
agents cannot be considered clinically interchangeable based on pharmacokinetic data. For example, garenoxacin and GEM exhibit lower serum
concentrations with or without higher protein binding, both of which may
then oset the lower minimal inhibitory concentration (MICs) achieved.
Table 1
Pharmacokinetic properties of the newer uoroquinolones

Drug

Dose
(mg)

Bioavailability
(%)

Cmax
(mg/L)

AUC
(mg/h/L)

Protein
Binding
(%)

t1/2 (h)

Elimination

Garenoxacin
Gatioxacin
Gemioxacin
Levooxacin
Moxioxacin

400
400
320
500
400

98
71
99
90

5.8
3.4
1
5.2
3.1

59
32.4
9
47.7
30.8

87
20
60
40
50

15
9
7
7
13

Renal/other
Renal
Renal/other
Renal
Hepatic

Abbreviations: AUC, area under the concentration time curve; Cmax, maximal concentration; t1/2, half-life.

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The FQs are bactericidal antibiotics and display a concentration-dependent killing eect [41,42]. Achieving a higher peak serum concentration
results in more rapid and complete killing of susceptible organisms.
Schentag et al [40,43,44] have described a relationship between the ratio
of the area under the curve and the MIC called the area under the
inhibitory curve. These authors have proposed that the maximal therapeutic benet of the FQs occurs when the peak to MIC ratio is maintained
at greater than 8 to 10, and that the area under the inhibitory curve should
be greater than or equal to 125 for gram-negative organisms, and greater
than or equal to 30 for gram-positive organisms. In addition, to prevent the
development of resistance, maintenance of the peak to MIC ratio at greater
than or equal to 10 or area under the inhibitory curve greater than or equal
to 125 for gram-negative bacilli and greater than or equal to 50 for grampositive cocci is necessary [40,43,44]. A summary of the pharmacodynamic
data for newer FQs is presented in Tables 2 and 3 [45].
All FQs also exhibit a postantibiotic eect [31,40,45]. The postantibiotic
eect for the FQs seems also to be a concentration-dependent parameter.
The newer compounds have been reported to have postantibiotic eect of
1 to 6 hours, depending on the pathogen and drug studied. This characteristic
has also allowed for many of the newer FQs to be dosed once daily.
In vitro activity
As a class, the FQs have a broad range of excellent in vitro activity
[45,46]. Some generalizations can be made, and may be helpful when
considering these drugs for use in clinical practice. The newer FQs have been
designed to build on the older FQs range of gram-negative bacillary
spectrum [47]. As such, many of the newer FQs have improved activity
against staphylococci and streptococci. Clinically relevant activity against
anaerobes is only present in the newer FQs MOX and garenoxacin [48]. As
a class, the FQs do not have any antibacterial activity against Nocardia spp
or treponemes [46]. They also have moderate activity against mycobacteria,
with the best activity seen in levooxacin (LVX) and MOX against
Table 2
Comparative pharmacodynamic data against S pneumoniae (AUC/MIC)
Wild type
Agent

Dose
(mg daily)

Total

Levooxacin
Gatioxacin
Moxioxacin
Gemioxacin
Garenoxacin

500
400
400
320
400

47.6
64.8
140
163.3
1000

GyrA mutant

ParC mutant

Unbound

Total

Unbound

Total

Unbound

35.2
51.8
88.2
65.4
130

11.9
32.4
70
81.7
240

8.8
25.9
44.1
32.7
31.1

23.8
16.2
140
81.7
500

17.6
12.9
88.2
32.7
65

Abbreviations: AUC, area under the concentration time curve; MIC, minimal inhibitory
concentration.

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Table 3
Comparative pharmacodynamic data against S pneumoniae (Cmax/MIC)
Wild type

GyrA mutant

ParC mutant

Agent

Dose
(mg daily)

Total

Unbound

Total

Unbound

Total

Unbound

Levooxacin
Gatioxacin
Moxioxacin
Gemioxacin
Garenoxacin

500
400
400
320
400

5.2
6.8
14
25
83.4

3.8
5.5
8.8
10
10.8

1.3
1.7
7
12.5
41.7

0.9
1.4
4.4
5
5.4

2.6
3.4
14
12.5
20.8

1.9
2.7
8.8
5
2.7

Abbreviations: Cmax, maximal concentration; MIC, minimal inhibitory concentration.

Mycobacterium tuberculosis [13,49,50]. A summary of the newer FQs MICs

against a variety of clinically important organisms is provided in Table 4.
Gram-negative bacillary activity
The newer FQs all have excellent activity against the aerobic gram-negative
bacilli. In the process of developing a FQ with enhanced gram-positive
activity, however, the newer FQs have all lost some activity against
Pseudomonas aeruginosa as compared with ciprooxacin. LVX has an
MIC50MIC90 range of 2 to 8 lg/mL against P aeruginosa, but in every other
respect has a gram-negative activity prole similar to ciprooxacin [45,46,51].
MOX has activity against P aeruginosa with MIC50-MIC90 ranging between 1
and 4 lg/mL, and is the most active of the newer FQs against P aeruginosa.
MOX has an otherwise similar spectrum of gram-negative activity as compared with LVX and ciprooxacin. GAT, GEM, and garenoxacin possess
marginal activity against P aeruginosa and should not be used to treat
infections caused by this organism. All of the FQs have variable and marginal
activity against other Pseudomonas spp, Acinetobacter calcoaceticus, and
Stenotrophomonas maltophilia [45,46] and are not likely to be useful in the
treatment of infections caused by these common nosocomial pathogens.
Gram-positive coccal activity
The newer FQs all have enhanced activity against methicillin-susceptible S
aureus. LVX is the least active with an MIC50-MIC90 range of 0.25 to 0.5 g/
mL. GAT, MOX, GEM and garenoxacin are all active with MIC50s ranging
from the lower limit of 0.1-0.125 lg/mL to MIC90s of 0.25-0.5 lg/mL [45,46].
At the present time the newer agents spectrum of activity also includes some
methicillin-resistant S aureus, and coagulase-negative staphylococci, such as
Staphylococcus epidermidis, Staphylococcus saprophyticus, and Staphylococcus haemolyticus [45,46]. Although the newer FQs possess some in vitro
activity against these microbes, their eectiveness in the clinical setting has
not been evaluated, and as such the newer FQs should not be considered rstline treatment for infections caused by the coagulase negative staphylococci.

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697

Table 4
Comparative in vitro minimum inhibitory concentrationsa
Organism

Gatioxacin Levooxacin Moxioxacin Gemioxacin Garenoxacin

S aureus
0.100.13
MRSA
0.2016
CRSA
6.25
E faecalis
0.782
E faecium
1.564
S pneumoniae
0.5
S pyogenes
0.390.5
E cloacae
0.060.20
E coli
0.0160.1
H inuenzae
0.0130.016
K pneumoniae
0.100.39
N gonorrhoeae
0.0060.025
P aeruginosa
3.1332
Salmonella spp
0.060.25
S marcescens
1.5612.5
B fragilis
0.251
C dicile
12
Peptostreptococcus spp 1
M pneumoniae
0.05
L pneumophila
0.016
C trachomatis
0.0630.125
C pneumoniae
0.0630.125
U urealyticum
0.78

0.25
16
8
13.13
3.138
13.13
1
0.06
0.03
0.06
0.13
0.016
32
0.03
8
2
8
3.13>4

0.032
0.250.5
0.250.5

0.06
4
2
1
14
0.120.25
0.25
0.06
0.008
0.06
0.13
0.016
32
0.13
8
0.12

2
0.060.12
0.015
0.030.125
0.031

0.03
4
8
4b
16
0.06
0.06
0.5
0.03
0.015
0.25
0.12
4

2
0.52

0.064
0.25
0.06

0.008
0.25

0.03

0.5a

0.12
0.25
1
0.06
0.03
0.5

16

2
1
64
0.25
0.06
0.016
0.016
0.25
0.25

Abbreviations: CRSA, ciprooxacin-resistant S aureus; MRSA, methicillin-resistant S aureus.

MIC90, micrograms per milliliter.
b
Enterococcus species.
a

Enhanced and clinically reliable streptococcal activity has made the

newer FQs popular in the treatment of community-acquired lower respiratory tract infections, and skin and skin structure infections. Activity
against S pneumoniae is present in all newer FQs, with the lowest MICs and
greatest activity found in GEM and garenoxacin. MOX and GAT are
also highly active against S pneumoniae, but less so than GEM and
garenoxacin in in vitro studies. The LVX MIC50-MIC90 for pneumococcus
is the highest among the newer FQs with a range of 1 to 3.13 lg/mL [45,46].
This does not preclude its use in the treatment of pneumococcal infections;
however, there have been treatment failures reported in the literature
[36,52]. It should be noted that in a study tracking pneumococcal resistance
patterns in Canada from 1988 to 1998, a decreased susceptibility to FQs
among pneumococci was associated with increasing numbers of FQ
prescriptions [53].
The newer FQs have activity against group A and group B b-hemolytic
streptococci, making them a potential therapeutic option for treatment of
skin and soft tissue infections in contrast to the earlier FQs that did not
possess such activity (see Table 4). Enterococcal activity remains variable
among the newer FQs, with GAT seeming most active. Additionally, the

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newer FQs exhibit activity against Listeria monocytogenes; however, the

clinical relevance of this is yet unknown [45,46].
Activity against anaerobes and atypical bacteria
Trovaoxacin is the only FQ ever specically approved for use in the
treatment of anaerobic infections, and although it remains available for use in
the United States, it is rarely prescribed because of its liver toxicity
complications. GAT has modest anaerobic activity that is probably not
relevant in clinical settings [54]. MOX, GEM, and garenoxacin all possess in
vitro activity against many clinically important anaerobic organisms with an
MIC90 for most species less than or equal to 2 lg/mL. The clinical application
of the documented in vitro anaerobic activity of these agents requires further
study. One noteworthy exception for garenoxacin is Clostridium dicile
activity, for which it possesses an MIC90 of greater than 64 lg/mL [48].
All of the newer FQs have improved or equivalent activity, as compared
with such agents as ciprooxacin or ooxacin, against Mycoplasma
pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila [55].
Safety and toxicity
The understanding of FQ structure-relationship activity has signicantly
improved over the last two decades, and with this knowledge has come
an elucidation of structureside eect relationships. Toxicities related to
side-chain or ring substitutions include crystalluria, phototoxicity, genetic
toxicity, and drug interaction potential [19,5661]. Fig. 2 summarizes these
ndings. Adverse eects unrelated to structure include gastrointestinal
symptoms and chondrotoxicity-arthropathy [56,59]. The most commonly
reported adverse events by body system and their manifestations are listed in
Table 5.
Phototoxicity
Reports of drug-induced photosensitivity reactions caused by nalidixic
acid began appearing in the literature soon after its release for human use
in the early 1960s [58]. Photosensitive reactions caused by the FQs are
predominantly phototoxic in nature, but typical photoallergic features have
also been demonstrated with certain quinolones, such as nalidixic acid,
enoxacin, and lomeoxacin [28]. The reported incidence of photosensitivity,
phototoxicity, or photoallergy of quinolones ranges from less than 0.05%
for ciprooxacin [58] to as high as 19% for a high-dose eroxacin regimen
[31]. The newer agents all seem to have a lower potential for phototoxicity,
on the order of that seen with ciprooxacin [56].
It is prudent to warn patients taking FQs of this potential side eect.
Patients should be counseled to avoid direct exposure to sunlight, UVA light,
and UVB light; wear protective clothing; use sun-blocking agents; and administer the FQ in the evening rather than in the morning whenever possible.

J.A. ODonnell, S.P. Gelone / Infect Dis Clin N Am 18 (2004) 691716

Fig. 2. Fluoroquinolone structure-adverse eect relationship. (From Domagala JM. Structure-activity and structure-side eect relationships for the quinolone
antibacterials. J Antimicrob Chemother 1994;33:685806; with permission.)

699

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Table 5
Common adverse events associated with Fluoroquinolones
Body system

Specic adverse event

Cardiovascular

Hypotension, tachycardia, QTc interval

prolongation
Headache, dizziness, sleep disturbances, mood
change, confusion psychosis, tremor, seizures
Rash, pruitus, photosensitivity, leg pigmentation,
urticaria
Diarrhea, epigastric pain, nausea, vomiting
Transient increase in transaminases, cholestatic
jaundice, hepatitis, hepatic failure
Arthropathy, tendonitis, tendon rupture
Azotemia, crystalluria, hematuria, interstitial
nephritis, nephropathy, renal failure
Drug fever, chills, serum sicknesslike reaction,
anaphylaxis, angioedema, bronchospasm, vasculitis

Central nervous system

Dermatologic
Gastrointestinal
Hepatic
Musculoskeletal
Renal
Other

Chrondrotoxicity and uoroquinolone-induced arthropathy

Both the older and newer FQs induce changes in cartilage of weightbearing joints in all immature laboratory animals tested [32,6264]. This
eect has been limited to juvenile animals with the exception of peoxacin,
which produces characteristic lesions in both skeletally immature and
mature dogs [63]. The specic mechanism responsible for initiation of
quinolone arthropathy has not been elucidated. Recently, researchers have
implicated the chelation of magnesium by FQs in the process [65]. The
histopathologic changes thought to be pathognomonic of quinolone
arthropathy have been reproduced with selective nutritional deprivation
of magnesium in rats [62,6567].
There are no unequivocal human cases of quinolone-induced arthropathy. Joint swelling and pain concurrent with FQ therapy have been described
in case reports and in many clinical trials. Case reports of presumed
quinolone-associated eusion and arthralgia in children and adolescents
further fuel the connection between use of these agents and occurrence of
chondrotoxicity in humans [57,68]. The experience with FQs in the pediatric
patient population has been reported in more than 10,000 cases (many of
whom had underlying cystic brosis) [57,60,69,70]. In most, concurrent joint
disease has been explained by hyperimmune mechanisms, or the so-called
cystic brosis arthropathy or hypertrophic pulmonary osteoarthropathy.
The occurrence of arthralgia has not been reported to be greater than
expected as a result of the cystic brosis. None of the evaluated quinolones
had negative eects on linear growth of the children. Additionally, by the
end of 1994 there were 1795 case report forms of juveniles treated with
ciprooxacin. One and one-half percent developed arthralgias or arthritis,
but there were no unequivocal cases of quinolone arthropathy [70].

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701

Quinolones have also been reported to cause tendonitis and rupture of

the Achilles tendon, even after short-term use. More than 200 such cases
have been described in the literature [57]. Most cases of tendonitis have been
reported with peoxacin. Cases with other agents, such as ciprooxacin,
ooxacin, noroxacin, and enoxacin, have been reported. Since the anthrax
epidemic postSeptember 11th, however, several additional cases of
tendonitis were reported in patients receiving a prolonged course of
ciprooxacin for the treatment or prophylaxis of anthrax [66].
Levooxacin
Several premarketing and postmarketing trials with LVX have identied
an overall incidence of adverse reaction of 2% to 9.9% [31,56,71]. Nausea
(1%3%) and diarrhea (1%2%) were the most commonly reported
reactions. Its photosensitivity incidence is reported to be 0.03%. Crystalluria, QT interval prolongation, and abnormal liver function tests have been
reported rarely. Among the newer FQs, LVX seems to be very well-tolerated
and to have the lowest frequency of nongastrointestinal side eects.
Gatioxacin
Safety data on GAT are available from 3021 patients involved in clinical
studies [56,71]. The most commonly reported events were nausea (8%);
vaginitis (6%); diarrhea (5%); headache (4%); dizziness (3%); insomnia
(2%); and taste perversion (2%). There were no reports of crystalluria,
phototoxicity, or QTc interval prolongation. The incidence of signicantly
abnormal liver function tests was less than 1%. GAT has been reported to
cause dysglycemia in some patients. Close monitoring is warranted in
borderline or brittle diabetics.
Moxioxacin
Safety data on MOX are available from 4926 patients from clinical trials
[56,72]. The most commonly reported events included nausea (7.8%);
diarrhea (5.9%); dizziness (2.9%); headache (2%); abdominal pain (2%);
vomiting (1.7%); dyspepsia (1.4%); and taste perversion (1.1%). To date,
no cases of crystalluria or phototoxicity have been reported. A marginal
change in the QTc interval (mean increase of 4 millisecond) has been seen in
patients receiving MOX. Abnormal liver function tests have been reported
in 1.1% of patients. This degree of alteration in the QT interval and in liver
function tests is not clinically signicant and does not require special
monitoring or restriction of the drug in potentially at-risk populations.
Garenoxacin and gemioxacin
Limited published data are available on the safety prole of these two
new agents [56]. Overall in clinical trials published to date, they have been

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well tolerated. The most common side eects involve the gastrointestinal
tract and include diarrhea and nausea. GEM has been noted to cause
a maculopapular rash in approximately 5% of subjects. The rash seems to
be self-limited and most commonly occurs with extended durations of
therapy. Given the history of adverse events that have been reported with
FQ over the last decade during the postapproval period, it is important to
evaluate postmarketing safety data for these compounds.
Drug interactions
The absorption of all FQs can be altered by the co-administration of
divalent or trivalent cation-containing agents [71]. Aluminum-, magnesium-,
iron-, calcium-, and zinc-containing products most commonly result in
signicant decreases in bioavailability. Although the impact of calcium is
variable among the FQ class, co-administration with products containing
any of the previously noted cations should be staggered, administering the
FQs 2 hours before or 4 hours after the oending agent.
Several of the older FQs, including ciprooxacin, inhibit cytochrome P450 isoenzyme activity. This results in clinically signicant drug interactions
with a variety of compounds, most notably theophylline [73]. GAT, LVX,
MOX, GEM, and garenoxacin do not inhibit P-450 function and have no
impact on serum theophylline levels [71]. A summary of relevant drug
interactions is provided in Table 6.

Review of the clinical data for the newer uoroquinolones

Levooxacin
Levooxacin was originally approved for use at a maximum dose of 500
mg daily. This dosing regimen has been very well studied and described in an
earlier review of the FQs [3,74]. More recently, LVX has been studied for
Table 6
Important drug interactions for uoroquinolones

Antacids
Vitamins and minerals
Theophylline
NSAIDs
Warfarin
Digoxin
Milk products
Morphine
Medications that prolong
the QTc interval

Gatioxacin

Gemioxacin

Levooxacin

Moxioxacin

Yes
Yes
No
No
No
No
No
No
No

Yes
Yes
No

No
No
Yes?

No

Yes
Yes
No
Yes
No
No
No
No
No

Yes
Yes
No
No
No
No
No
No
No

Abbreviations: NSAIDs, nonsteroidal anti-inammatory drugs.

J.A. ODonnell, S.P. Gelone / Infect Dis Clin N Am 18 (2004) 691716

703

three indications using a 750-mg dose. This high-dose strategy is intended to

maximize the pharmacodynamic properties of LVX. The rst indication
studied is 5-day therapy at a 750-mg dose (versus 10-day therapy at a 500mg dose) for the treatment of community-acquired pneumonia (CAP). In
this multicenter, randomized, double-blind study, 528 patients with mild-tosevere CAP were enrolled and 437 were clinically evaluable. Clinical success
was achieved in 92.4% of those receiving 750 mg and 91.1% in the 500-mg
arm. Microbiologic eradication was achieved in 93.2% and 92.4% for the
750-mg and 500-mg arms, respectively [75].
The 750-mg total daily dose has also been evaluated in the treatment of
nosocomial pneumonia. In one trial, 438 patients were enrolled and
randomized to receive either LVX or imipenem-cilastatin, 500 to 1000 mg
every 6 to 8 hours. Adjunctive therapy was mandatory in those with
documented P aeruginosa or methicillin-resistant S aureus infections.
Clinical success was achieved in 58.1% of those receiving LVX and 60.6%
in those receiving imipenem (P = NS). Bacterial eradication was achieved in
66.7% and 60.6%, respectively [76].
Lastly, LVX at a dose of 750-mg has been evaluated in the treatment of
complicated skin and skin structure infections. In a study published by
Graham et al [77] high-dose LVX was compared with ticarcillin-clavulanate
with potential oral follow-up with amoxicillin-clavulanate. Clinical success
was 84.1% and 80.3% for LVX and the comparator, respectively. Bacterial
eradication was 83.7% and 71.4% (P = NS) [77].
High-dose LVX has been shown to be an eective treatment for CAP using
a 5-day regimen. In addition, 750-mg dosing provides an equally eective
regimen to standard therapy for nosocomial pneumonia and complicated
skin and skin structure infection. The safety prole of LVX at 750 mg is
similar to that seen with the 500-mg dosing regimen. Currently, and as a result
of these data, high-dose LVX has been approved by the Food and Drug
Administration for the treatment of nosocomial pneumonia and complicated
skin and skin structure infections.
Gatioxacin
Gatioxacin was approved for use in the treatment of a variety of
infections in 2000, including skin and skin structure infections, respiratory
tract infections, and genitourinary tract infections [78].
Treatment of upper and lower respiratory tract infections
Gatioxacin is approved for the treatment of acute bacterial sinusitis. In
a very large study that enrolled more than 11,000 adults with acute
uncomplicated rhinosinusitis and treated those with GAT, 400 mg daily
for 10 days, 91% of the 10,353 clinically evaluable patients were cured [79].
In a randomized study of patients with acute maxillary sinusitis by Sher et al
[80], a 5-day (short course) regimen of 400 mg of GAT was compared with

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a 10-day course of either 400 mg of GAT or 875 mg twice daily of

amoxicillin-clavulanate. Clinical cure rates were 74% for the 5-day regimen
and 80% for the 10-day GAT regimen, and 72% for amoxicillin-clavulanate
(P = NS). All three regimens were considered equivalent. Short-course
GAT therapy for acute bacterial sinusitis seems eective and is less costly
than extended durations [80].
Gatioxacin has also been studied and approved for the treatment of
acute exacerbations of chronic pulmonary disease (AECB). In a single
published study GAT at a 200- and 400-mg dose was compared with
amoxicillin-clavulanate and was found to be equivalent in both clinical and
microbiologic ecacy [81]. GAT has also been evaluated in the treatment of
AECB specically caused by Haemophilus inuenzae. In a study looking at
a variety of respiratory tract infections by Nicholson et al [82], a subgroup
of 166 patients with H inuenzae AECB were evaluated. One hundred and
fty-nine patients (95.8%) in this group were cured and cure was noted to be
independent of b-lactamase production or H inuenzae serotype. The 400mg GAT dose is approved for the treatment of AECB. Given its enhanced
gram-negative bacillary spectrum of activity and its coverage of drugresistant S pneumoniae, GAT should be considered in the treatment of patients with moderate to severe AECB.
Gatioxacin is an eective treatment for patients with mild-to-moderate
CAP, and has been approved for use in this setting at a dose of 400 mg daily
for 7 to 14 days. Several studies have demonstrated the ecacy of GAT in
the treatment of CAP. In one such study [83], which was a randomized,
open-label, multicenter trial, intravenous GAT was compared with intravenous ceftriaxone with or without intravenous erythromycin or clarithromycin in 170 adult patients. Oral conversion was allowed with either
GAT or clarithromycin, and patients received a total of 7 to 14 days of
therapy for either treatment arm. Among the 153 clinically evaluable
patients the cure rate was 97.4% for GAT and 90.9% for ceftriaxone
(P = NS) [83]. GAT is highly active in vitro against S pneumoniae and has
been shown to be very ecacious in the treatment of pneumococcal
pneumonia. In one study of 136 outpatients with pneumococcal pneumonia,
clinical cure was achieved in 95.3% of evaluable patients including 7
infected with penicillin-resistant S pneumoniae (MIC  2 lg/mL). All of the
isolates in this study were susceptible to GAT, and the bacteriologic
eradication rate was 94.5% [84]. Additionally, GAT has been evaluated
specically in the treatment of H inuenzae pneumonia, and was found to be
highly eective for this infectious disease. Of note, GAT has been studied
and shown to be eective in elderly patients with CAP including CAP
caused by both H inuenzae and S pneumoniae. In this particular trial, 1655
elderly patients received 400 mg of GAT for 7 to 14 days. Of the total, 1103
patients were at least 65 years, 405 were 65 to 79 years, and 147 were at least
80 years of age. Clinical response was noted in 96.2% of those 65 to 79
years, and 90.2% for those at least 80 years of age. Microbiologic response

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705

rates were very high for S pneumoniae regardless of age, but there was a trend
toward a better response rate in the younger subset infected with H
inuenzae (100% versus 71.4%). The reason for this trend was not clear,
and not predicted by susceptibility [85]. Overall GAT is a safe, eective, and
valuable addition to the drug armamentarium for treatment of bacterial
sinusitis, AECB, and CAP in the adult population.
Treatment of otitis media in children
Gatioxacin has recently been evaluated in two separate trials for the
treatment of recurrent otitis media in children. These studies mark the rst
time a FQ has been specically evaluated for this common pediatric
infectious disease [86]. The rst study was an open-label, multicenter trial
of children from 6 months to 7 years of age diagnosed with recurrent otitis
media or acute otitis media treatment failure. All children were treated with
10 mg/kg of GAT daily for 10 days. Two hundred fty-four patients were
enrolled, with 52% having recurrent otitis, 17% with acute otitis media
treatment failure, and 28% having both. Posttreatment cure was achieved in
88% of 198 clinically evaluable patients. Sustained cure at 4-weeks posttreatment was achieved in 83% of children. Forty-ve children had documented S pneumoniae as the causative pathogen. Of these 83% were cured,
including 25 of 28 with penicillin-nonsusceptible strains [86].
The second trial was an open-label, noncomparative study that evaluated
168 children from 6 months to 4 years of age with recurrent or nonresponsive acute otitis media. Again, children received 10 mg/kg of GAT
daily for 10 days. One hundred twenty-eight patients completed therapy.
Clinical improvement or cure at the end of treatment was seen in 103 (90%)
of 114 clinically evaluable patients. Bacteriologic eradication was achieved
for 118 (98%) of 121 pathogens. Clinical recurrence occurred in 31 patients.
Of these 31 recurrences, 27 had a tympanocentesis performed. Sixteen had
new infection, four were culture-negative, and seven were bacteriologic
relapses [87].
The adverse events most commonly identied in both of these studies in
children were predominantly gastrointestinal in nature (nausea and diarrhea). There were no reports of arthropathy, although the follow-up
period may have been too brief to assess adequately for this potential
complication.
Although not yet approved by the Food and Drug Administration for
this indication, GAT seems to be a promising therapy for children with
acute otitis media, particularly in those with recurrent, relapsed, or
nonresponsive infection. Further long-term studies would be useful specifically to discern the potential for bone or joint toxicities.
Treatment of genitourinary tract infections
Gatioxacin has been evaluated and found to be eective in the treatment
of uncomplicated and complicated urinary tract infection and pyelonephritis.

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Specically, the treatment of uncomplicated urinary tract infection with

GAT was evaluated in a randomized, double-blind, multicenter trial
comparing a single dose of 400 mg GAT with GAT, 200 mg daily, or
ciprooxacin, 100 mg twice daily for 3 days. The bacterial eradication rates
were 90%, 95%, and 89%, whereas the clinical response was 93%, 95%, and
93% for the single-dose GAT, 3-day GAT, and 3-day ciprooxacin,
respectively [88]. GAT has been approved for treatment of uncomplicated
urinary tract infection at a 200-mg daily dose in a 3-day regimen.
A study to evaluate the clinical and bacteriologic ecacy and tolerability
of GAT in the treatment of complicated urinary tract infections and
pyelonephritis has also been conducted and published. In this double-blind,
multicenter, randomized, comparative study of GAT, 400 mg daily, versus
ciprooxacin, 500 mg twice daily for 7 to 10 days, 372 adults were
randomized to treatment arms (189 received GAT and 183 were given
ciprooxacin). Pathogen eradication in patients with complicated urinary
tract infection was achieved in 92% with GAT and 83% with ciprooxacin,
and 92% for GAT and 85% for ciprooxacin for pyelonephritis. Clinical
response rates were in excess of 90% for both agents in both diseases.
Sustained bacterial eradication rates were 76% for GAT and 66% for
ciprooxacin [89]. GAT has denitively been shown to be an appropriate
choice in the treatment of both complicated urinary tract infection and
pyelonephritis, and is approved for these infections.
Gatioxacin, like the other FQs, is highly active against Neisseria
gonorrhoeae in vitro, and has been evaluated in the treatment of uncomplicated gonorrhea. A double-blind, randomized study was conducted
to compare a single dose of 400 mg and 600 mg of GAT with ooxacin, 400
mg, in patients with uncomplicated gonorrhea [90]. Three hundred forty men
and 388 women at least 16 years of age were enrolled. Bacterial eradication
rates in men were 99%, 100%, and 100% for GAT, 400 mg, 600 mg, and
ooxacin, respectively [90]. Based on this study GAT is a very ecacious
therapeutic option for uncomplicated gonorrhea, although it has not yet
been identied in the Centers for Disease Control and Preventions STD
Treatment Guidelines as a rst-line treatment for this sexually transmitted
disease. The ecacy of GAT in complicated gonococcal infection, including
pelvic inammatory disease, has not been evaluated clinically.
Moxioxacin
Moxioxacin, like GAT, was rst approved for use in the United States
in 2001, and is indicated for the treatment of upper and lower respiratory
tract infections and skin and skin structure infections. It has been studied
extensively and used predominantly in respiratory tract disease, and some of
this experience is detailed next.
Moxioxacin has very good streptococcal activity, and reliable activity
against methicillin-susceptible S aureus, and has been studied in the

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707

treatment of uncomplicated skin infections. In one such study [91], oral

MOX, 400 mg daily, was compared with cephalexin, 500 mg three times
daily for 7 days, and the clinical outcome was evaluated in 351 patients.
Clinical and bacteriologic success was equivalent between MOX and
cephalexin (clinical 90% versus 91%; bacteriologic 92% versus 93%). Of
note, MOX was more eective in patients infected with Streptococcus spp
(90% versus 82%) [91]. Although MOX has been approved for treatment in
uncomplicated skin and skin structure infections, its use should be reserved
for special patient populations. Specically, given its broad spectrum of
gram-negative bacillary activity along with its anaerobic activity, MOX
should be prescribed in clinical situations where there is a high likelihood of
a polymicrobial infection, or in patients with multiple allergies that preclude
the use of the more common and less expensive rst-line antimicrobials for
uncomplicated skin infections.
Treatment of upper and lower respiratory tract infections
Moxioxacin has excellent activity against the most common pathogens
in acute bacterial sinusitis (ABS), and its in vitro activity against anaerobes
makes it an attractive therapeutic option for this infectious process. MOX
has been studied and approved for use in ABS at a dose of 400 mg daily for
10 days. This particular dosing regimen of MOX was compared in one study
with oral trovaoxacin, 200 mg daily. The clinical response rates were 96.9%
versus 92.1%, respectively, in the 452 clinically evaluable study patients. The
bacteriologic success rates were 94.1% and 90.1%, respectively [92].
In another study MOX, 400 mg for 7 days, was compared with
cefuroxime, 250 mg twice daily for 10 days, in the treatment of ABS. The
clinical success rate was signicantly better with MOX (96.7 versus 90.7%).
The bacteriologic eradication rate in this trial was also higher for MOX [93].
MOX is equivalent to trovaoxacin and superior to low-dose oral
cefuroxime in the treatment of ABS.
Moxioxacin has been well-studied in the treatment of AECB, and has
been approved for this indication at a dose of 400 mg daily for 5 days and 10
days. In particular, the 5-day, short-course regimen has been evaluated in
several studies, comparing MOX to the other antimicrobial agents commonly prescribed for AECB. In a study that compared short-course MOX,
400 mg daily for 5 days, with either the same dose of MOX for 10 days or
clarithromycin, 500 mg twice daily for 10 days, clinical resolution was 89%
for the 5-day therapy and 91% for both 10-day treatments [94]. Given these
and other data, short-course MOX seems to be an eective alternative to 10
days of therapy, is less costly, and may be associated with less antibioticassociated side eects.
In one trial [95] that evaluated two dierent short-course treatment
regimens, MOX, 400 mg daily for 5 days, was compared with a 7-day
regimen of intramuscular ceftriaxone. The clinical success rates and
bacterial eradication rates were similar in this study (statistically

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noninferior). Interestingly, however, during the 6-month follow-up period,

there was a trend toward less relapses in the MOX group (P = NS) [95].
Short-course MOX for AECB has also been compared in a multicenter,
randomized, open study with co-amoxiclav, and the two agents were found
to have equivalent cure and bacterial eradications rates [96]. In yet another
study [97], MOX was compared with azithromycin in the treatment of
AECB. Both clinical and bacteriologic success was equivalent between
MOX and azithromycin. Of note, in this particular study the authors found
that the eradication rates for H inuenzae and H parainuenzae for MOX
were signicantly better than those for azithromycin (97% and 88% versus
83% and 62%, respectively) [97]. MOX is active against the many pathogens
that contribute to AECB, has been found to be eective in the management
of AECB, can be use condently for cure with a 5-day short-course regimen,
and may be preferred over a macrolide in those known to be infected with
Haemophilus spp.
Moxioxacin has been evaluated in the treatment of CAP in many published studies, and has been approved for use in CAP at a dose of 400 mg
daily for 10 days. MOX may oer some advantage over b-lactam agents in
the management of CAP. Data from one study supporting this idea were
published by Finch et al [27]. In their trial MOX, 400 mg intravenously
daily, was compared with co-amoxiclav, 1.2 g intravenously three times
daily with or without clarithromycin, 500 mg intravenously daily, in the
treatment of CAP that required initial parenteral therapy. Oral follow-up
therapy was permitted. Duration of therapy was from 7 to 14 days. A total
of 628 patients were enrolled and randomized. A statistically signicant
clinical improvement was noted in favor of MOX (93.4% versus 85.4%,
P = .004). In addition, a signicantly better bacteriologic response was
reported in favor of MOX (93.7% versus 81.7%). Superiority was
irrespective of severity of CAP or the presence or absence of macrolide
therapy [37]. In a separate publication [98], data were pooled from two
prospective, randomized trials of hospitalized patients with CAP. Patients
received one of four regimens: (1) intravenous or oral MOX, 400 mg daily
for 7 to 14 days; (2) intravenous or oral amoxicillin-clavulanate, 1200 and
625 mg three times daily  intravenous or oral clarithromycin, 500 mg twice
a day; (3) intravenous or oral alatrooxacin-trovaoxacin, 200 mg daily; or
(4) intravenous or oral LVX, 500 mg daily. Clinical success rates were 88%
for MOX and 83% for comparator agents. MOX was more commonly
converted to oral therapy than comparator, and a trend toward a lower
mortality was noted in favor of MOX [98].
To evaluate a lower dose of MOX in the treatment of mild CAP, oral
MOX, 200 mg, was compared with oral MOX, 400 mg, or clarithromycin,
500 mg twice daily for 10 days. The clinical success rates were 93.9%,
94.4%, and 94.3% for 200- and 400-mg MOX and clarithromycin,
respectively. Bacteriologic success was documented in 72.5% for 200 mg,
78.7% for 400 mg, and 70.7% for clarithromycin [99]. Oral MOX was also

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709

evaluated in the treatment of suspected pneumococcal CAP in adults [100].

Patients were randomized to receive MOX, 400 mg daily, or amoxicillin,
1000 mg three times daily. A total of 362 patients were clinically evaluable.
The cure rate in those with documented pneumococcal pneumonia was
87.8% in both groups, whereas the bacteriologic success rate was 89.7%
versus 82.4% in favor of MOX (P = NS) [100].
All of these studies provide evidence showing MOX to be a very eective
drug in the treatment of mild-to-moderate CAP, and CAP severe enough to
require hospitalization and initial parenteral therapy. Moreover, MOX has
excellent and reliable activity against the pneumococcus. MOX may be
preferred over b-lactam antibiotics in the treatment of CAP.
Gemioxacin
Gemioxacin was approved for use in the United States in 2003, and has
been best evaluated in the management of upper and lower respiratory tract
infections. Although approved at the time of publication of this article, GEM
had yet to become commercially available. GEM has the best activity against
the pneumococcus of any FQ that has come to market, and also retains a fairly
broad spectrum of activity against many gram-negative bacilli, excluding
Pseudomonas.
Treatment of upper and lower respiratory tract infections
Gemioxacin, like MOX and GAT, has a spectrum of activity that makes
it an ideal agent for treatment of ABS. Also like the other newer FQs, GEM
has been specically evaluated for its ecacy with short-course therapy. In
one study, short-course (5-day) GEM was compared with 7-day GEM in the
treatment of ABS in 421 patients. Short-course therapy was equivalent to 7
days both clinically and bacteriologically [101]. Studies comparing GEM
with other standard agents in the treatment of ABS or other FQs have yet
to be published. GEM seems to be a reasonable option, however, for the
treatment of ABS in adults.
Just like MOX and GAT, GEM has been targeted for use in the
management of AECB, and several studies have evaluated its eectiveness,
including the ecacy of short-term GEM therapy. In one such randomized,
open-label, controlled multicenter study [102], oral GEM, 320 mg daily for 5
days, was compared with intravenous ceftriaxone, 1 g daily, with or without
oral follow-up therapy with cefuroxime, 500 mg twice daily (total of 7 days
therapy), in the treatment of hospitalized patients with AECB. The clinical
response rate was 86.8% for GEM and 81.3% for cefuroxime. In the intentto-treat population GEM had a signicantly better response (82.6% versus
72.1%). The median time to discharge was also shorter in the GEM
population (9 versus 11 days, P = 0.04) [102]. In a second study, GEM (5
days) was compared with clarithromycin (7 days) in the treatment of AECB.
Seven hundred twelve patients were enrolled in the study and 438 were also

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included in a long-term follow-up analysis (6 months posttherapy). Clinical

and bacteriologic success rates were equivalent between groups. Interestingly, in the 6-month follow-up period, signicantly more patients in the
GEM group remained free of AECB recurrences (71% versus 58.5%,
P = .016) [103].
In a third study comparing GEM (5 days) with co-amoxiclav (500 mg)
three times daily for 7 days clinical response was equivalent, but a trend
toward an improved bacteriologic response in favor of GEM was seen (90%
versus 79.5%, P = NS) [104]. Finally, short-course GEM has also been
compared with a 5-day course of trovaoxacin in the treatment of AECB. In
the entire study population, clinical and bacteriologic success rates were
similar between treatments. In the intent-to-treat population, clinical response was statistically superior in the GEM-treated group [105].
Gemioxacin seems to be an excellent agent for management of AECB,
including those patients requiring hospitalization for more severe disease.
Moreover, like GAT and MOX, GEM is also ecacious when given for
a 5-day total course, which may provide potential advantages enumerated
previously.
Gemioxacin has also been studied and approved for the treatment of
CAP at a dose of 320 mg daily for 7 days. A randomized, multicenter, openlabel study was conducted to compare oral GEM with intravenous
ceftriaxone, 2 g daily, followed by oral cefuroxime, 500 mg twice daily 
macrolide therapy for 7 to 14 days in the treatment of hospitalized patients
with CAP [106]. A total of 345 patients were enrolled. Clinical response was
92.2% for GEM and 93.4% for the comparator. Bacteriologic eradication
was also equivalent. For those enrolled patients categorized in ne-risk
classes IV and V, the clinical success rate was 87% versus 83.3% [106]. A
second study randomized 571 patients to GEM or oral trovaoxacin, 200
mg for 7 to 14 days, in the treatment of CAP. Clinical success rates were
similar between both groups (95.8% versus 93.6%), but in the intent-totreat population, GEM had a slightly higher response rate [107]. GEM is
likely another appropriate drug option in the treatment of CAP.
Summary
The quinolone class of antimicrobial agents has expanded further over
the last several years, as pharmaceutical researchers have continued to
manipulate the chemical foundation of these compounds. Such research has
given rise to GAT, MOX, and GEM, and the latest compound garenoxacin,
a desuoroquinolone. When compared with the older FQs ooxacin and
ciprooxacin, these newer FQ agents and LVX all provide improved grampositive coccal activity, enabling them to be used in a wider array of
infectious diseases. In particular, the newer FQs including LVX have been
shown to be highly eective in the treatment of upper and lower respiratory
tract infections and skin and skin structure infections.

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Another novel attribute of the newer FQs is their ecacy when given for
shorter courses of therapy (5-day therapy). Short-course therapy with
a newer FQ has been shown to be as eective as longer durations of
treatment with both other FQs and other classes of antimicrobials. In some
instances short-course therapy with the newer FQs has been documented to
lead to decreased relapse rates, decreased length of hospital stay, and lower
mortality rates. The advantages of short-course therapy include lower total
cost; decreased potential for patients to discontinue drug prematurely; and
possible decreased occurrence of antibiotic-associated side eects, such as
diarrhea and vaginitis.
The challenge to all clinicians is to understand when to prescribe the
newer FQs, so that appropriate use is maximized. As a class of antimicrobials, the FQs have been overused in many settings, and this misuse has led
to the emergence of resistance to the class. To preserve the activity of these
agents and benet from their use, they must be prescribed judiciously. To
that end, one example is that although GAT and MOX are approved for use
in skin and skin structure infections, it is prudent to reserve these drugs only
for patients with multiple allergies or a high likelihood of polymicrobial or
gram-negative bacillary infection. Prescribing them for simple cellulitis
caused by streptococci or methicillin-susceptible S aureus is unnecessary and
overly broad coverage. Prudent application of these agents lengthens their
clinical use, and it is hoped delays emergence of resistance.
Although not discussed here the FQs, in particular the older FQs, remain
important drugs with distinct therapeutic advantages in the management of
gram-negative bacillary osteomyelitis, travelers diarrhea, prostatitis, complicated urinary tract infection, and certain nosocomial infections. Appropriate prescribing of all agents within the FQ class is a necessity if their
activity is to be maintained; good antibiotic stewardship is critical whenever
antimicrobials are prescribed.
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