CLINICAL THERAPEUTICS® / VOL. 26, NO.

2, 2004

Efficacy and Tolerability of Moxifloxacin in the Treatment

of Acute Bacterial Sinusitis Caused by Penicillin-Resistant
Streptococcus pneumoniae: A Pooled Analysis

Peter Johnson, MD,1 Cheryl Cihon, PhD,2 Janet Herrington, MS,2

and Shurjeel Choudhri, MD2
1Winchester Ear, Nose and Throat Center, Winchester, Virginia, and 2Bayer Pharmaceuticals Corporation, West Haven,
Connecticut

ABSTRACT

Background: Penicillin-resistant Streptococcus pneumoniae (PRSP) has become a relatively common pathogen
in upper and lower respiratory tract infections, including acute bacterial sinusitis (ABS).
Objective: The goal of this analysis was to assess the efficacy and tolerability of moxifloxacin in the treatment
of ABS caused by penicillin-sensitive S pneumoniae (PSSP) and PRSP.
Methods: Two prospective, multicenter, open-label, noncomparative US trials of moxifloxacin were included
in this pooled analysis. All patients received oral moxifloxacin 400 mg once daily for 7 to 10 days. Minimum
inhibitory concentrations (MICs) of moxifloxacin and penicillin were determined using the E-test and standard
broth-microdilution methods. The primary end point was clinical success at the test-of-cure visit (21–37 days
after completion of therapy) in patients with a positive pretherapy sinus culture. Data are presented for patients
with ABS caused by both PSSP and PRSP.
Results: Of 806 patients enrolled in the 2 studies, 146 had microbiologically confirmed bacterial infection.
Sixty-nine patients had ABS caused by S pneumoniae, including 15 confirmed cases of PRSP infection. The major-
ity of the 69 clinically evaluable patients were white (n = 63) and female (n = 46), and the mean age of this pop-
ulation was 43 years. Investigators categorized the episode of ABS as severe in 26 (37.7%) of clinically evaluable
patients and of moderate severity in the remainder (62.3% [43]); however, most patients (78.3% [54/69]) report-
ed ≥1 severe symptom. The episode of ABS was classified as severe in 8 (53.3%) of the 15 patients with PRSP
infection. Clinical and bacteriologic success at the test-of-cure visit was achieved in 93.3% (14/15) of patients
with PRSP infection, compared with 88.4% (61/69) of all patients infected with S pneumoniae regardless of peni-
cillin susceptibility. Moxifloxacin MICs against the 15 PRSP strains ranged from 0.06 to 0.25 µg/mL. Data from
805 patients were available for tolerability analysis. The most commonly occurring adverse events were nausea,
headache, and diarrhea. Generally, adverse events were mild to moderate. None of the 6 serious adverse events
reported were considered related to moxifloxacin therapy.
Conclusion: In this small cohort of patients, moxifloxacin provided clinical and bacteriologic cures in the
majority of patients with ABS caused by PRSP, including those with severe sinusitis. (Clin Ther. 2004;26:
224–231) Copyright © 2004 Excerpta Medica, Inc.
Key words: acute bacterial sinusitis, moxifloxacin, penicillin-resistant Streptococcus pneumoniae.

Accepted for publication December 11, 2003.

Printed in the USA. Reproduction in whole or part is not permitted.

224 Copyright © 2004 Excerpta Medica, Inc.


INTRODUCTION
Acute bacterial sinusitis (ABS) can be a complication
of viral upper respiratory tract infection. ABS devel-
ops in ~0.5% to 2% of US adults—or up to 20 mil-
lion persons—with the common cold.1 Streptococcus
pneumoniae is one of the most common pathogens
cultured from patients with ABS.2 Specifically, in the
1999–2000 Respiratory Surveillance Program,3
S pneumoniae was 1 of 4 key pathogens isolated from
nasal swabs from patients with an episode of ABS.
Although many episodes of ABS do not require
antimicrobial therapy, potent activity against the
pneumococcus must be considered when selecting
empiric therapy for suspected bacterial episodes.2
In recent years, empiric treatment of ABS (as well
as of other respiratory tract infections) has become
challenging owing to a marked rise in the incidence
of infections caused by penicillin-resistant S pneumo-
niae (PRSP; penicillin minimum inhibitory concen-
tration [MIC], ≥2 µg/mL).4–8 Before 1987, <1% of
S pneumoniae isolates exhibited penicillin resistance;
however, the late 1990s saw a 30% to 60% rate of
penicillin resistance, with some variation by geo-
graphic region.9 A subsequent surveillance study in
patients with ABS found that 16% of S pneumoniae
isolates were fully resistant to penicillin, with an
additional 20% having intermediate-level resistance
(total penicillin resistance, 36%).3 A secondary con-
cern is that the development of resistance to peni-
cillin in S pneumoniae often parallels its development
of resistance to other antimicrobial agents, such as the
cephalosporins, the macrolides, and trimethoprim/
sulfamethoxazole.7,10–12
Although amoxicillin, first-generation cephalospo-
rins, and macrolide antimicrobials continue to be the
most commonly recommended empiric therapies for
ABS,13 selection of effective agents for this condition
must consider the increasing possibility of infection
with multidrug-resistant S pneumoniae.14 The deci-
sion to use a potent broad-spectrum antimicrobial is
often ill advised, primarily because of the risks of
overtreating nonbacterial causes or highly suscepti-
ble strains and of selecting for resistant mutants.13
However, a delay in appropriate treatment may cause
unnecessary morbidity and increase the rate of com-
plications.1 Use of empiric therapy to which the
infecting bacteria are resistant can lead to adverse
medical outcomes.15 Furthermore, significantly
P. Johnson et al.
higher medical costs have been documented in
patients with respiratory tract infections caused by
PRSP. Specifically, patients infected with PRSP had a
significantly longer median hospital stay compared
with those infected with penicillin-sensitive S pneu-
moniae (PSSP; 14 vs 10 days, respectively; P < 0.05)
and significantly higher median total costs ($1600;
95% CI, 257 to 2943).16 In the case of PRSP infec-
tion, there is less likelihood of adverse medical out-
comes attributable to drug resistance if patients
receive empiric therapy with an agent that has
shown activity against S pneumoniae (eg, a quin-
olone).15 If a potent broad-spectrum antimicrobial
agent is considered necessary, use of a targeted
approach to therapy (ie, one that emphasizes the
correct spectrum of activity plus the best pharma-
codynamic profile) may curtail development of anti-
microbial resistance.17,18
Moxifloxacin is a newer-generation fluoro-
quinolone with in vitro activity against PSSP and
PRSP (MIC, 0.25 µg/mL), as well as against other
common respiratory tract pathogens.19 Among the
available oral fluoroquinolones, moxifloxacin is con-
sidered to have relatively low potential for inducing
resistance in S pneumoniae.20 Furthermore, sinus
mucosal levels of moxifloxacin have been shown to
greatly exceed (ie, 5–30 times) the MIC at which 90%
of S pneumoniae isolates are inhibited (MIC90), sug-
gesting that this quinolone may provide bactericidal
activity at the site of infection.21 Based on a review of
comparative studies in the English-language litera-
ture, moxifloxacin has been reported to be efficacious
in proven episodes of ABS and has been associated
with more rapid symptom relief compared with
amoxicillin/clavulanate22 and excellent clinical out-
comes compared with cefuroxime axetil23,24 and tro-
vafloxacin.25 Rakkar et al22 found that by day 3 of a
10-day course of therapy, 24.0% (47/196) of moxi-
floxacin patients and 14.0% (28/200) of amoxicillin/
clavulanate patients reported symptom relief (P <
0.02). In addition, 90.1% (201/223) of moxifloxacin
patients and 88.9% (208/234) of cefuroxime axetil
patients showed a clinical response at the end-of-
therapy visit in one study (95% CI, –5.1 to 6.2),24
whereas in another, clinical success was statistically
greater in the moxifloxacin group compared with the
cefuroxime axetil group (96.7% [204/211] vs 90.7%
[204/225], respectively; 95% CI, 1.5 to 10.6).23
225
CLINICAL THERAPEUTICS®
Moxifloxacin was also found to be statistically superi-
or compared with trovafloxacin in the treatment of
ABS in adults (clinical efficacy 7–10 days posttherapy,
96.9% [216/223] and 92.1% [211/229], respectively;
95% CI, 0.6 to 8.9).25
Because there are few data concerning outcomes in
patients with ABS caused by PRSP infection, the pri-
mary purpose of this article was to assess the efficacy
and tolerability of moxifloxacin in this subpopulation
infected with highly resistant organisms.
PATIENTS AND METHODS
This study was a retrospective analysis of Bayer
Pharmaceuticals Corporation’s moxifloxacin clinical
trials database. The analysis used pooled data from 2
prospective, multicenter, open-label, noncomparative
US trials of moxifloxacin in the treatment of ABS.
Patients received oral moxifloxacin 400 mg once daily
for 7 days in one trial (N = 372) and for 10 days in the
other (N = 434). Approval was obtained from each
center’s institutional review board, and each patient
gave written informed consent before enrollment.
Acute Bacterial Sinusitis Population
Adults presenting with a clinical diagnosis of ABS
of <4 weeks’ duration, with microbiological confir-
mation of S pneumoniae as the causative pathogen,
were included in this pooled analysis. Each patient
presented with clinical signs and symptoms of sinusi-
tis and paranasal sinus radiographs (Water’s view)
confirming maxillary sinusitis (ie, air fluid level,
opacification, or mucosal thickening ≥6 mm).
Additionally, each patient had ≥2 of the following
findings at study entry: nasal congestion, postnasal
drainage/discharge, purulent nasal drainage, frequent
coughing/throat clearing, malar tenderness/pain, and
frontal headache. The investigator rated the current
episode of ABS as mild, moderate, or severe based on
the presenting signs and symptoms, using the criteria
of Lanza and Kennedy.26 In both trials, sinus aspirate
specimens were obtained by antral puncture.
In Vitro Microbiologic Assessments
The susceptibility of S pneumoniae to penicillin and
moxifloxacin was initially determined at each center’s
microbiology laboratory using the E-test (AB Biodisk,
Solna, Sweden) and the disk-diffusion techniques rec-
ommended by the National Committee for Clinical
226
Laboratory Standards.27 Clinical isolates were sub-
sequently sent to a central laboratory (Bayer Pharma-
ceuticals Corporation, West Haven, Connecticut) for
confirmation of their identity and for susceptibility
testing using the broth-microdilution method. Cation-
supplemented Mueller-Hinton broth containing 2.5%
lysed horse blood was used for testing S pneumoniae.
Colony counts were performed to ensure the accuracy of
the density of each inoculum. All broth-microdilution
susceptibility tests were performed using frozen
panels according to standard methods.28 The quality
control strain of S pneumoniae ATCC (American Type
Culture Collection) 49619 was included on each
day of testing; the approved quality control range
for moxifloxacin against this organism is 0.06 to
0.25 µg/mL.28 The MICs of penicillin and moxifloxa-
cin were recorded for each isolate.
Clinical and Bacteriologic Assessments
For the pooled analysis, only culture-confirmed
cases of PRSP and PSSP determined to be efficacy
valid were assessed for clinical and bacteriologic
response. For a course of therapy to be valid for effi-
cacy, the following criteria had to be satisfied: all
protocol-specified signs and symptoms must have
been present, and all other eligibility criteria for ABS
must have been met; moxifloxacin must have been
given for a minimum of 48 hours for the treatment
result to be judged a failure and for a minimum of 5
doses for the treatment result to be judged a success; a
clinical assessment must have been performed at the
test-of-cure visit, unless the patient was an early clini-
cal failure; adequate compliance must have been doc-
umented, with ≥80% of oral study medication admin-
istered; and there must have been no protocol violation
that could have influenced treatment efficacy.
Clinical and bacteriologic responses to antimicrobial
treatment were determined based on evaluation of the
signs and symptoms of ABS, radiography, and repeat
antral culture when possible. Clinical and bacteriolog-
ic responses at the test-of-cure visit were recorded for
each patient. In both studies, the test-of-cure visit took
place 21 to 37 days after the completion of treatment.
Clinical response at the test-of-cure visit was char-
acterized as resolution (disappearance of acute signs
and symptoms related to the infection or sufficient
improvement such that additional or alternative
antimicrobial therapy was not required), failure

(insufficient improvement in signs and symptoms of
infection such that additional or alternative antimi-
crobial therapy was required), or indeterminate (the
clinical response was not evaluable for any reason, for
example because the patient was lost to follow-up).
The bacteriologic response of S pneumoniae at the
test-of-cure visit was categorized as eradication
(absence of pathogen on culture of a specimen from
original site), presumed eradication (no material was
available due to clinical success), persistence (presence
of pathogen on culture of a specimen from the origi-
nal site), presumed persistence (no material was avail-
able in a patient considered a clinical failure), or inde-
terminate (the bacteriologic response to study drug
was not evaluable for any reason).
Statistical Analysis
Categorical values, including demographic and
baseline medical characteristics, were summarized
descriptively. Ninety-five percent CIs were generated
around the clinical success rates against all S pneumo-
niae isolates (both studies combined) using the nor-
mal approximation to the binomial distribution.
RESULTS
Demographic and Baseline Medical Characteristics
Of 806 patients initially enrolled in the 2 studies,
146 had a microbiologically confirmed bacterial
Table I. Demographic and baseline medical characteristics of clinically evaluable patients from 2 pooled trials in acute bac-
terial sinusitis caused by Streptococcus pneumoniae.
Total Patients Infected
with S pneumoniae
Sex, no. (%)
Female
Male
Race, no. (%)
White
Other
Mean age at enrollment, y
Mean duration of infection, d
Severity of infection, no. (%)
Mild
Moderate
Severe
PRSP = penicillin-resistant S pneumoniae.
P. Johnson et al.
infection. The 2 trials included 69 moxifloxacin
recipients who were evaluable for efficacy and had a
documented S pneumoniae infection regardless of
penicillin susceptibility. Data from an additional 11
patients with documented S pneumoniae infection
were not included in the present analysis because
they were invalid for efficacy assessment as outlined
in the protocol. Three of these patients were consid-
ered cures, whereas efficacy information was incom-
plete for 8. None of these 11 patients were infected
with PRSP.
The majority of the 69 clinically evaluable patients
were white (n = 63) and female (n = 46), and the
mean age of this population was 43 years (Table I).
Investigators rated the current episode as severe in 26
of these patients (37.7%) and of moderate severity in
the remainder (62.3% [43]); however, most patients
reported ≥1 severe symptom (78.3% [54]). Baseline
signs and symptoms are summarized in Table II.
Fifteen patients (21.7%) in this cohort (8 in one
trial, 7 in the other) had documented PRSP infection.
Eight (53.3%) were classified by the study investiga-
tor as having severe sinusitis (Table I), and 7 of these
8 patients had ≥4 severe symptoms at enrollment. All
patients with PRSP had radiologic evidence consis-
tent with ABS and had ≥2 symptoms of sinusitis (ie,
nasal congestion, postnasal drainage/discharge, puru-
lent nasal drainage, frequent cough/throat clearing,
Patients Infected
with PRSP
(n = 69) (n = 15)
46 (66.7) 12 (80.0)
23 (33.3) 3 (20.0)
63 (91.3) 14 (93.3)
6 (8.7) 1 (6.7)
43 42
11 12
0 (0) 0 (0)
43 (62.3) 7 (46.7)
26 (37.7) 8 (53.3)
227
CLINICAL THERAPEUTICS®
Table II. Baseline clinical signs and symptoms in clinically evaluable patients. Values are number (%).
Total Patients Infected with
Streptococcus pneumoniae
Sign/Symptom
Nasal congestion
Postnasal drainage/discharge
Purulent nasal drainage
Cough/throat clearing
Malar tenderness/pain
Frontal headache
Other
PRSP = penicillin-resistant S pneumoniae.
malar tenderness/pain, frontal headache). The mean
number of days of symptoms before treatment in this
subpopulation was 12 days. The demographic and
baseline medical characteristics of this cohort were
not different from those of the patients with PSSP
(data not shown).
In Vitro Microbiologic Activity
Of the 69 isolates of S pneumoniae cultured at base-
line, 54 were penicillin susceptible (range of peni-
cillin MICs, 0.03–0.05 µg/mL) and 15 were catego-
rized as PRSP (penicillin MIC, ≥2 µg/mL). The MIC90
for moxifloxacin against the 54 PSSP strains was
0.25 µg/mL (range, 0.03–4 µg/mL). MIC90s for moxi-
floxacin against the 15 PRSP strains ranged from 0.06
to 0.25 µg/mL.
Clinical and Bacteriologic Outcomes
For all patients with broth microdilution–
confirmed S pneumoniae, regardless of penicillin sus-
ceptibility, clinical and bacteriologic resolution was
reported in 88.4% (61/69) of moxifloxacin recipients
at the test-of-cure visit (95% CI, 0.82 to 0.95). Seven
of the 8 clinical/microbiologic failures occurred in
patients infected with PSSP. Among these 7 patients,
3 had no organism present on a culture performed
after the end of therapy; S pneumoniae persisted in 2
patients based on posttherapy culture; and no post-
therapy culture was performed for 2 patients. Thus,
the rate of clinical resolution/bacteriologic eradica-
tion in those with PSSP was 87.0% (47/54).
In the 15 cases of confirmed PRSP infection, 93.3%
(14) of patients were classified as clinical and bacteri-
228
Patients Infected
with PRSP
(n = 69) (n =15)
68 (98.6) 15 (100)
63 (91.3) 15 (100)
63 (91.3) 15 (100)
62 (89.9) 15 (100)
59 (85.5) 13 (86.7)
58 (84.1) 11 (73.3)
58 (84.1) 11 (73.3)
ologic successes (Table III). The pretherapy moxi-
floxacin MIC against PRSP in the 1 patient who failed
to respond to treatment was 0.25 µg/mL. In this
patient, it is of note that bacteriologic eradication was
documented by antral puncture at the end-of-therapy
visit. Four days after the end of therapy, this patient’s
symptoms, which were considered severe before ther-
apy, had improved to mild; nonetheless, the patient
was considered a clinical failure. After 10 days of cla-
rithromycin therapy, the patient was considered a
clinical cure, with no signs or symptoms present.
Tolerability Analysis
Data from 805 patients were available for tolerabil-
ity analysis. The majority (97.8%) of these patients
tolerated moxifloxacin well. Eighteen patients (2.2%)
discontinued therapy due to adverse events. The
most common adverse events were nausea (10.6%),
diarrhea (4.7%), and dizziness (3.1%). Adverse
events were generally mild to moderate in intensity.
Of the 6 serious adverse events reported, none were
considered related to moxifloxacin therapy.
DISCUSSION
Recently published guidelines for the treatment of
ABS recommend administering fluoroquinolones to
adults with mild disease who have received antimi-
crobials in the previous 4 to 6 weeks or to adults with
moderate disease.29 These guidelines reflect the cur-
rent worldwide epidemic of antibiotic-resistant respi-
ratory pathogens, particularly multidrug-resistant
S pneumoniae. The new guidelines seek to discourage
the use of fluoroquinolones for milder disease, as this
 P. Johnson et al.

Table III. Symptoms and responses at the test-of-cure visit (21–37 days after completion of therapy) in patients with acute
sinusitis caused by penicillin-resistant Streptococcus pneumoniae.

Patient Penicillin MIC, Clinical Bacteriologic Radiologic Severe Posttreatment

No. µg/mL Response Outcome Other Organisms Findings* Severity* Symptoms† Assessment Day

1 4 Cure PE AFL, MRC Moderate None 28

2 4 Cure PE AFL Moderate A, B, D 30
3 4 Cure PE AFL Moderate A, C, E, F 27
4 2 Cure PE O Severe F 31
5 4 Cure PE AFL Moderate A, C, F 32
6 4 Cure PE MT Severe B, C 21
7 4 Cure PE MT Severe E, F 30
8 2 Cure PE O Severe A, B, D, E 27
9 2 Cure PE O Moderate A 27
10 2 Cure PE Streptococcus viridans MT Moderate None 27
11 2 Cure PE MT, O Moderate None 30
12 2 Failure PP O Severe A–D 4
13 2 Cure PE AFL, MT Severe A, B, D–F 34
14 2 Cure PE Staphylococcus aureus MT Severe A–C, E, F 29
15 2 Cure PE Haemophilus influenzae AFL, O Severe A–D 28

MIC = minimum inhibitory concentration; PE = presumed eradication; AFL = air fluid level; MRC = mucus retention cyst; O = opacification; MT = mucosal
thickening ≥6 mm; PP = presumed persistence.
*Based on investigator’s assessment.
†Symptoms: A = nasal congestion; B = postnasal drainage/discharge; C = purulent nasal drainage; D = cough/throat clearing; E = frontal headache; F = malar

tenderness/pain.

is likely to promote resistance to this class of agents.
Therefore, prudent use of fluoroquinolones is essen-
tial to maintaining class efficacy, and these agents
should not be prescribed for all patients with ABS.
The key finding of the present pooled analysis was
that moxifloxacin was efficacious in the treatment of
ABS caused by PRSP, as well as by PSSP. It is also note-
worthy that the 15 patients with PRSP had significant
disease, more than half being classified as having
severe sinusitis. The clinical and bacteriologic
response to moxifloxacin was at least as effective in
patients whose infection was caused by PRSP (93.3%)
as in those whose infection was caused by PSSP
(88.4%). The bacteriologic success rate observed in
this study (88.4% overall) is consistent with rates
obtained with moxifloxacin in other noncomparative,
open-label “tap” studies (in which a bacterial etiology
is confirmed by culture of specimens obtained by
antral puncture) in patients with ABS (data on file,
Bayer Healthcare).
Despite the effectiveness of moxifloxacin in the
treatment of ABS caused by S pneumoniae,22–25 we do
not advocate indiscriminate use of fluoroquinolones
in ABS, as such use may result in increasing resistance
to this antibiotic class. We believe that fluoro-
quinolones are appropriate empiric therapy for infec-
tions caused by potentially drug-resistant strains of
S pneumoniae in areas with a high prevalence of resis-
tance (eg, >15%–20%). According to the new treat-
ment guidelines, initial use of fluoroquinolone thera-
py is also justified in patients who have failed to
respond to recent beta-lactam or macrolide therapy,
those with ABS of moderate severity, and those who
have experienced multiple episodes of ABS in the pre-
vious year.29 The results of a recent study by Gehanno
et al30 support this recommendation, demonstrating
95.8% (207/216) bacterial eradication rates at days 3
to 4 of a 7-day course of moxifloxacin in patients with
ABS who had failed first-line therapy or were at high
risk for complications. (Such patients are more likely
to be infected with drug-resistant strains.)
Importantly, there is evidence suggesting that
the fluoroquinolones are not equivalent in their
ability to eradicate S pneumoniae.14,17,20,31 For exam-
ple, several studies have found differences in the
pharmacodynamic properties of the 3 oral respira-

229
CLINICAL THERAPEUTICS®
tory fluoroquinolones—moxifloxacin, gatifloxacin,
and levofloxacin—against S pneumoniae.14,17,20,31
Schentag31 reported that moxifloxacin has a pharma-
codynamic profile against the pneumococcus that is
more likely to lead to pneumococcal eradication than
that of levofloxacin, based on a higher 24-hour area
under the concentration-time curve/MIC index, par-
tially attributable to its 4- to 8-fold greater in vitro
activity. Applying the theory of the mutant prevention
concentration (MPC)—the drug concentration nec-
essary to prevent selection of first-step bacterial
mutants—Blondeau et al20 tested 5 fluoroquinolones
against clinical isolates of S pneumoniae and found
that moxifloxacin appeared to have the lowest risk of
inducing pneumococcal resistance, followed by gati-
floxacin and levofloxacin. These authors also claimed
that the levofloxacin concentrations achieved after a
500-mg dose were insufficient to achieve the MPC,20
permitting selection of mutants with 1 of the 2 muta-
tions necessary to confer fluoroquinolone resistance32
and thus increasing the risk for development of fluo-
roquinoline resistance.
CONCLUSIONS
This pooled analysis found that moxifloxacin was
both clinically and bacteriologically effective in the
treatment of moderate to severe episodes of ABS
caused by PRSP. Although routine first-line use of flu-
oroquinolones for ABS is not advocated, moxifloxacin
may be an appropriate option for empiric therapy
in regions where the prevalence of PRSP is high
(>15%–20%). It may also be considered for initial
therapy in patients who are at high risk for
antimicrobial-resistant S pneumoniae infection (eg,
those who have failed to respond to a recent course of
therapy with conventional antimicrobials) and those
who are unable to tolerate beta-lactam agents.
ACKNOWLEDGMENTS
The authors thank Brian G. Shearer, PhD, and Teresa
Tartaglione, PharmD, for their editorial contributions.
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