Efficacy and tolerability of moxifloxacin in the treatment of acute bacterial sinusitis caused by penicillin-resistant streptococcus pneumoniae: A pooled analysis

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 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. 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]) reported ≥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 penicillin 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.

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INTRODUCTION

Acute bacterial sinusitis (ABS) can be a complication of viral upper respiratory tract infection. ABS develops in ~0.5% to 2% of US adults—or up to 20 million 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 pneumoniae (PRSP; penicillin minimum inhibitory concentration [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 geographic 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 concern is that the development of resistance to penicillin 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 cephalosporins, 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 decision to use a potent broad-spectrum antimicrobial is often ill advised, primarily because of the risks of overtreating nonbacterial causes or highly susceptible strains and of selecting for resistant mutants.13 However, a delay in appropriate treatment may cause unnecessary morbidity and increase the rate of complications.1 Use of empiric therapy to which the infecting bacteria are resistant can lead to adverse medical outcomes.15 Furthermore, significantly

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 pneumoniae (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 infection, there is less likelihood of adverse medical outcomes attributable to drug resistance if patients receive empiric therapy with an agent that has shown activity against S pneumoniae (eg, a quinolone).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 pharmacodynamic profile) may curtail development of antimicrobial resistance.17,18 Moxifloxacin is a newer-generation fluoroquinolone 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 considered 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), suggesting that this quinolone may provide bactericidal activity at the site of infection.21 Based on a review of comparative studies in the English-language literature, 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 outcomes compared with cefuroxime axetil23,24 and trovafloxacin.25 Rakkar et al22 found that by day 3 of a 10-day course of therapy, 24.0% (47/196) of moxifloxacin 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-oftherapy 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

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Moxifloxacin was also found to be statistically superior 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 primary 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 confirmation of S pneumoniae as the causative pathogen, were included in this pooled analysis. Each patient presented with clinical signs and symptoms of sinusitis 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 recommended by the National Committee for Clinical 226

Laboratory Standards.27 Clinical isolates were subsequently sent to a central laboratory (Bayer Pharmaceuticals Corporation, West Haven, Connecticut) for confirmation of their identity and for susceptibility testing using the broth-microdilution method. Cationsupplemented 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 moxifloxacin 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 efficacy, 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 clinical failure; adequate compliance must have been documented, with ≥80% of oral study medication administered; 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 bacteriologic 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 characterized 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

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(insufficient improvement in signs and symptoms of infection such that additional or alternative antimicrobial 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 original site), presumed persistence (no material was available in a patient considered a clinical failure), or indeterminate (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 pneumoniae isolates (both studies combined) using the normal 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

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 considered cures, whereas efficacy information was incomplete 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 investigator 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 consistent with ABS and had ≥2 symptoms of sinusitis (ie, nasal congestion, postnasal drainage/discharge, purulent nasal drainage, frequent cough/throat clearing,

Table I. Demographic and baseline medical characteristics of clinically evaluable patients from 2 pooled trials in acute bacterial sinusitis caused by Streptococcus 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

Total Patients Infected with S pneumoniae (n = 69)

Patients Infected with PRSP (n = 15)

46 (66.7) 23 (33.3)

12 (80.0) 3 (20.0)

63 (91.3) 6 (8.7) 43 11

14 (93.3) 1 (6.7) 42 12

0 (0) 43 (62.3) 26 (37.7)

0 (0) 7 (46.7) 8 (53.3)

PRSP = penicillin-resistant S pneumoniae.

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Table II. Baseline clinical signs and symptoms in clinically evaluable patients. Values are number (%).

Sign/Symptom

Total Patients Infected with Streptococcus pneumoniae (n = 69)

Nasal congestion Postnasal drainage/discharge Purulent nasal drainage Cough/throat clearing Malar tenderness/pain Frontal headache Other

68 63 63 62 59 58 58

(98.6) (91.3) (91.3) (89.9) (85.5) (84.1) (84.1)

Patients Infected with PRSP (n =15) 15 (100) 15 (100) 15 (100) 15 (100) 13 (86.7) 11 (73.3) 11 (73.3)

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 baseline, 54 were penicillin susceptible (range of penicillin MICs, 0.03–0.05 µg/mL) and 15 were categorized 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 moxifloxacin 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 susceptibility, 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 posttherapy culture was performed for 2 patients. Thus, the rate of clinical resolution/bacteriologic eradication 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 bacteri228

ologic successes (Table III). The pretherapy moxifloxacin 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 therapy, had improved to mild; nonetheless, the patient was considered a clinical failure. After 10 days of clarithromycin therapy, the patient was considered a clinical cure, with no signs or symptoms present. Tolerability Analysis

Data from 805 patients were available for tolerability 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 antimicrobials in the previous 4 to 6 weeks or to adults with moderate disease.29 These guidelines reflect the current worldwide epidemic of antibiotic-resistant respiratory pathogens, particularly multidrug-resistant S pneumoniae. The new guidelines seek to discourage the use of fluoroquinolones for milder disease, as this

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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 No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Penicillin MIC, µg/mL

Clinical Response

Bacteriologic Outcome

4 4 4 2 4 4 4 2 2 2 2 2 2 2 2

Cure Cure Cure Cure Cure Cure Cure Cure Cure Cure Cure Failure Cure Cure Cure

PE PE PE PE PE PE PE PE PE PE PE PP PE PE PE

Other Organisms

Streptococcus viridans

Staphylococcus aureus Haemophilus influenzae

Radiologic Findings*

Severity*

Severe Symptoms†

Posttreatment Assessment Day

AFL, MRC AFL AFL O AFL MT MT O O MT MT, O O AFL, MT MT AFL, O

Moderate Moderate Moderate Severe Moderate Severe Severe Severe Moderate Moderate Moderate Severe Severe Severe Severe

None A, B, D A, C, E, F F A, C, F B, C E, F A, B, D, E A None None A–D A, B, D–F A–C, E, F A–D

28 30 27 31 32 21 30 27 27 27 30 4 34 29 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 essential 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 noteworthy 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 fluoroquinolones are appropriate empiric therapy for infections caused by potentially drug-resistant strains of S pneumoniae in areas with a high prevalence of resistance (eg, >15%–20%). According to the new treatment guidelines, initial use of fluoroquinolone therapy 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 previous 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 example, several studies have found differences in the pharmacodynamic properties of the 3 oral respira229

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tory fluoroquinolones—moxifloxacin, gatifloxacin, and levofloxacin—against S pneumoniae.14,17,20,31 Schentag31 reported that moxifloxacin has a pharmacodynamic 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, partially attributable to its 4- to 8-fold greater in vitro activity. Applying the theory of the mutant prevention concentration (MPC)—the drug concentration necessary 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 gatifloxacin 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 mutations necessary to confer fluoroquinolone resistance32 and thus increasing the risk for development of fluoroquinoline 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 fluoroquinolones 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. REFERENCES 1. Gwaltney JM Jr. Acute community-acquired sinusitis. Clin Infect Dis. 1996;23:1209–1225. 2. Hadley JA. The microbiology and management of acute and chronic rhinosinusitis. Curr Infect Dis Rep. 2001;3:209–216. 230

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Address correspondence to: Peter Johnson, MD, Winchester Ear, Nose and Throat Center, 116 Medical Circle, Winchester, VA 22601. 231