Comparative Efficacy of Once Daily, 5-Day Short-Course Therapy With Clarithromycin Extended-Release Versus Twice Daily, 7-Day Therapy With Clarithromycin Immediate-Release in Acute Bacterial Exacerbation of Chronic Bronchitis*

Key words: Acute bacterial exacerbation * Chronic bronchitis * Clarithromycin * Extended-release

ABSTRACT

Objective: The objective of this study was to compare the efficacy, tolerability, and safety of two clarithromycin regimens, extended-release (ER) 1000mg once daily for 5 days and immediate- release (IR) 500 mg twice daily for 7 days, in the treatment of acute bacterial exacerbation of chronic bronchitis (ABECB).

Patients and methods: This was a double-blind, randomized, parallel-group, multicenter study of ambulatory patients at least 40 years old with a presumptive diagnosis of ABECB, purulent sputum, and documented evidence of chronic obstructive pulmonary disease (COPD), including forced expiratory volume in one second (FEV^sub 1^) < 70% of predicted value. Clinical cure, bacteriological cure, and target pathogen eradication rates were determined at a test-of- cure visit (study days 14-40). Safety was assessed based on the incidence of study drug-related adverse events.

Results: A total of 485 patients were randomized (240 to ER and 245 to IR). Clinical cure rates were similar for evaluable patients treated with ER (84%, 157/187) and those treated with IR (84%, 172/ 204) (95% CI-7.9,7.2). The bacteriological cure rates were 87% (82/ 94) and 89% (91/102), and the overall target pathogen eradication rates were 88% (107/122) and 89% (117/131) for the respective treatment groups. The incidence of adverse events was 13% (31/240) in the ER group and 18% (45/245) in the IR group. The rate of gastrointestinal adverse events was lower with ER (8%, 19/240) compared to IR (11%, 26/245). Clarithromycin ER-treated patients reported statistically significantly fewer adverse events due to abnormal taste than did Clarithromycin IR-treated patients (3% and 8%, respectively, p = 0.012).

Conclusion: Both once-daily, 5-day, short-course therapy with Clarithromycin ER and 7-day, twice-daily therapy with Clarithromycin IR were effective in resolving clinical signs/ symptoms of ABECB and eradicating the causative pathogens, with no statistically significant difference in clinical cure rate between the treatment groups. Clarithromycin ER was better tolerated, causing fewer gastrointestinal adverse events and statistically significantly fewer reports of abnormal taste as compared with Clarithromycin IR.

Introduction

According to data from the National Heart, Blood, and Lung Institute (NHLBI), there were an estimated 9 million adults in the US in 2002 with chronic bronchitis’. Individuals with chronic bronchitis may experience recurrent acute episodes of worsening symptoms – characterized by increased dyspnea, sputum volume, and/ or purulence2. The etiology of these acute exacerbations of chronic bronchitis is multifactorial, with bacterial infection implicated in approximately half of confirmed cases3. The most common pathogens isolated from sputa of chronic bronchitis patients during an acute exacerbation include Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Haemophilus parainfluenzae, and Staphylococcus aureus3. As chronic bronchitis progresses, the acute exacerbations may become frequent and severe, leading to increased morbidity and mortality and a diminished quality of life4,5.

Meta-analyses and recent reviews support the use of antimicrobial therapy for acute bacterial exacerbations of chronic bronchitis (ABECB), agreeing that patients with severe exacerbations will benefit more than those who are less ill2,6-8. In a placebo- controlled trial, treatment of ABECB with broad-spectrum antimicrobial therapy resulted in better clinical outcomes and fewer therapeutic failures2.

The ideal duration of antimicrobial treatment for ABECB remains unclear. Traditionally a 10- to 14-day treatment course has been recommended’1, although 7- to 10-day regimens are frequently utilized” ‘”. More recently, evaluations of 5-day regimens have been conducted with broad spectrum agents, including macrolides, fluoroquinolones, and cephalosporins”~23. Results from these studies show comparable efficacy to longer regimens and suggest the potential to decrease the development of resistance, increase patient adherence, decrease the risk of adverse events, and decrease costs11,4″26.

Clarithromycin is a broad-spectrum macrolide antibiotic with activity against the pathogens most frequently implicated as the cause of ABECB27. Twice daily clarithromycin, in its immediate- release (IR) formulation, is a well-established therapy for the infection. A newer, once-daily, extended-release (ER) formulation of clarithromycin has similar pharmacokinetics to clarithromycin IR and is bioequivalent to the IR formulation with respect to 24-h area under the concentration curve (AUC) for clarithromycin and its active 14-hydroxy metabolite, but with lower peak serum concentrations28. The two formulations have been compared for the treatment of ABECB, with comparable clinical and bacteriologie efficacy rates demonstrated with a 7-day regimen2629 and with a 5- day regimen23,30.

The objective of this study was to compare the efficacy, safety, and tolerability of clarithromycin ER given once daily for 5 days to that of clarithromycin IR given twice daily for 7 days in the treatment of ambulatory patients with ABECB.

Patients and methods

Study design

The study was a double-blind, randomized, parallel-group, multicenter, comparative trial, which was conducted between December 2002 and April 2004. An Investigational Review Board for each study site approved the study protocol, and patients provided written, informed consent before enrollment into the study.

Patient selection

Ambulatory male and female patients > 40 years of age with a medical history of chronic bronchitis and airway obstruction (forced expiratory volume in one second [FEV^sub 1^] < 70% of predicted value) were eligible for study entry. The diagnosis of chronic bronchitis was made based on the following criteria: cough and sputum production for more than 2 consecutive years on most days in a consecutive 3-month period and either radiographie findings consistent with chronic obstructive pulmonary disease (COPD) or documented, consistent (> 3 consecutive months), recent (past 2 years) use of medications for pulmonary disease. A presumptive clinical diagnosis of the current ABECB must have been made within 14 days prior to enrollment based on the presence of at least two of the following signs and symptoms: increased dyspnea, increased sputum volume, or increased sputum purulence (Anthonisen Type I or II criteria2). A pretreatment, qualified purulent sputum (defined in Microbiological Assessments section below) obtained within 48 h before therapy initiation was also needed to diagnose ABECB.

Excluded from the study were patients with a severe or complicated lower respiratory tract infection, including pneumonia, or any lower respiratory tract condition that would confound the assessment of the signs and symptoms of ABECB (e.g., pulmonary tumor, bronchiectasis diagnosed by computed tomography [CT], atelectasis); patients with clinically significant renal or hepatic disease; immunocompromized or oxygendependent patients; residents of a chronic care facility; and pregnant or lactating females.

Antimicrobial therapy

At each study site, patients were randomized in a 1:1 ratio to receive a 5-day regimen of clarithromycin ER lOOOmg once daily or a 7-day regimen of clarithromycin IR 500 mg twice daily. Both clarithromycin ER and clarithromycin IR tablets and corresponding placebo were packaged in a double-blind, blister-card format, with a sufficient supply for a 7-day course of therapy. All parties involved with the study, including the investigators, remained blinded to the patient’s treatment assignment throughout the course of the study.

Concomitant medication usage

The use of systemic antibiotics for another infection was not allowed within 1 week prior to enrollment (2 weeks for azithromycin and 4 weeks for a long-acting injectable antibiotic) or concomitantly during the study. Also prohibited was concomitant use of astemizole, cisapride, pimozide, terfenadine, and immunosuppressants. The previous use of selected medications (e.g., theophylline, wafarin, digoxin, phenytoin, valproate, and CYP3Ametabolized drugs [HMG-CoA reductase inhibitors, sildenafil, carbamazepine]) could be continued during a patient’s participation in the study if patients were adequately monitored.

Clinical and safety assessments

The clinical status of patients was assessed at baseline (Visit 1), study days 3-4 (Visit 2), between study days 8 and 10 (Visit 3, End of Therapy), study days 17 and 21 (Visit 4, Test-of-Cure), and study days 37 and 40 (Visit 5). Visit 2 and Visit 5 were telephone interviews conducted to assess safety. Drug safety was monitored across study visits through periodic laboratory tests (hematology and serum chemistry), medical history, physical examination, vital signs, occurrence of adverse events, and use of concomitant medication. The investigators classified the severity of clinical adverse events as mild, moderate, or severe, and the relationship of adverse events to study drug as either probably, possibly, probably no\t, or not drug related. Patients were instructed to return the blister-cards of medication at Visit 3, and compliance was determined by a tablet count of the returned study drug.

Microbiological assessments

Specimens for bacteriologie assessment came from either spontaneous or induced expectoration of purulent sputum, which was collected at baseline and, if available, at Visit 3 and Visit 4. Qualified purulent sputum specimens via Gram stain and culture that had < 10 squamous epithelial cells and > 25 white blood cells (WBC) per low-power field (10 objective) were considered acceptable for routine culture/susceptibility testing, which was conducted at a central laboratory (Covance Clinical Laboratory Services, Indianapolis, IN). Sputum specimens were plated semiquantitatively for aerobic growth, and potential pathogens isolated were tested for susceptibility to clarithromycin in accordance with established National Committee for Clinical Laboratory Standards methodologies31,32.

Outcome measures

The primary efficacy endpoint was the clinical cure rate. Secondary efficacy endpoints were patient bacteriological cure rate and pathogen eradication rate.

Clinical response was determined at Visit 4 (the test-of-cure visit) and classified as cure, failure, or indeterminate. Clinical cure was defined as resolution of dyspnea, sputum volume, and sputum purulence to pre-acute levels or resolution of at least two of these with improvement in at least half of the remaining ABECB signs or symptoms. Clinical failure was defined as continuation or worsening of ABECB signs and symptoms with further antimicrobial therapy needed. Indeterminate was used when evaluation was not possible.

Patient bacteriological cure and bacteriologie response were also determined at Visit 4. Patient bacteriological cure rate was the percentage of clinically and bacteriologically evaluable patients (defined below) who demonstrated eradication of pathogen (s). Bacteriologie response was defined as follows: eradication (the pathogen isolated from a pretreatment sputum sample was absent from a repeat sputum sample collected at Visit 4), presumed eradication (no repeat sputum culture available and patient was classified as a clinical cure), persistence (pathogen isolated from a pretreatment sputum sample was subsequently isolated from a sputum sample collected either at Visit 4 or at the time of study withdrawal), presumed persistence (no repeat sputum culture available and patient was classified as a clinical failure), superinfection (isolation of a new pathogen[s] during therapy in a symptomatic patient), indeterminate (the evaluation was not possible), new infection (isolation of a new pathogen from a culture taken post-treatment in a symptomatic patient), colonization (isolation of a new pathogen from a culture taken post-treatment in an asymptomatic patient), or recurrence (isolation of the original pathogen (s) from a culture taken after Visit 4 in a symptomatic patient).

Data analyses

Determination of sample size was based on an estimated clinical cure rate of 85% for both treatment groups. Assuming that the clarithromycin IR and ER groups would have similar clinical response rates, 400 clinically evaluable patients were needed to demonstrate non-inferiority with 80% power that the lower bound for the 95% confidence interval (CI) in the difference in rates was not less than -10%. With an 80% evaluability rate, a sample size of 500 patients (250 per treatment group) was set for accrual. All analyses were performed using SAS, version 8.2 (SAS Institute, Inc., SAS Campus Drive, Gary, NC 27513).

Intent-to-treat and per-protocol (clinically evaluable as well as clinically and bacteriologically evaluable) populations were analyzed for efficacy. The intent-to-treat population included all patients who took at least one dose of study drug and had a clinical diagnosis of ABECB confirmed by signs and symptoms and chest radiograph without evidence of pneumonia. To be considered clinically evaluable, patients were required to have completed at least 80% of their prescribed study regimen (or at least 3 days if the patient was determined to be a failure), and avoided the use of other antimicrobial therapy as previously mentioned. Patients who met the criteria for clinical evaluability and had at least one target pathogen isolated from an acceptable, pretreatment purulent sputum sample, were considered clinically and bacteriologically evaluable. Patient evaluability was assessed under blinded conditions. Patients who took at least one dose of study drug were included in the safety analyses.

The comparability of the treatment groups at baseline was evaluated with respect to baseline demographics and other characteristics (e.g., smoking status, lung function, frequency of presenting symptoms). Those variables that were quantitative (e.g., age) were analyzed by one-way analysis of variance (ANOVA). Categorical variables (e.g., race) were analyzed by Fisher’s exact test or its extension to R C tables. The treatment groups were compared for signs and symptoms using the Cochran-Mantel-Haenszel (CMH) test.

Clinical cure rate, patient bacteriological cure rate, and target pathogen eradication rate were compared between treatment groups at Visit 4 using Fisher’s exact test. Binomial 95% CIs, based on the normal distribution approximation with a continuity correction, were computed for the differences (clarithromycin ER-clarithromycin IR) between treatment groups. Treatment groups were also compared via the CMH test with stratification by a number of factors, including: gender, race, age, weight, study drug duration, compliance, tobacco use, alcohol use, steroid use, FEV^sub 1^, Anthonisen criteria, supportive radiologie criteria, supportive medication use, prior medical evaluation for the current infection, treatment for the current infection, investigator, and country. The pathogen eradication rate was not analyzed by stratification due to the limited number of isolated pathogens.

Changes from Visit 1 to Visits 3 and 4 in each clinical sign and symptom were summarized by treatment group. Fisher’s exact test was used to compare the two treatment groups with respect to the percentage of patients who showed either resolution or improvement in signs and symptoms at Visit 3 and Visit 4.

Fisher’s exact test was also used to compare the difference between the two treatment groups in the incidence of study drug- related adverse events (i.e., those classified as probably- or possibly-related).

Results

Patient disposition

Four hundred and eighty-five patients were randomized and treated at 96 investigative sites in North America. Forty-one of these patients were excluded from the ITT analyses (Figure 1), leaving 444 patients (218 clarithromycin ER and 226 clarithromycin IR) in the ITT population. Ninety-four patients (53 clarithromycin ER and 41 clarithromycin IR) were excluded from the clinical efficacy analyses, the most common reason (n = 43) being the selection criteria were not met. Thus, of the clinically evaluable patients, there were 187 in the clarithromycin ER group and 204 in the clarithromycin IR group. The clinically and bacteriologically evaluable patient population included 94 and 102 patients in the respective treatment groups.

Baseline characteristics

No statistically significant differences were observed between the treatment groups at baseline based on gender, race, or age of treated patients (Table 1). Most patients were Caucasian (88%), and 52% of the patients were female. The mean ( SD) age of all patients was 61.9 years (11.8). The treatment groups were also comparable at baseline based on medical and social histories and clinical presentation. As expected based on the inclusion criteria for this study, all treated patients had a history of chronic bronchitis or COPD and met the Anthonesin criteria for Type 1 (76%) or Type 2 (24%) illness. Nearly all patients for whom an FEV^sub 1^ was performed (96%) had an FEV^sub 1^ of < 70% of predicted value. Eighty-nine percent of treated patients were either users (46%) or ex-users (43%) of tobacco products. Approximately three quarters (78%) regularly used pulmonary medications, and 56% had chest radiographie evidence consistent with COPD.

There were no statistically significant differences observed between treatment groups based on acute pretreatment clinical signs and symptoms in any patient population (i.e., all treated patients, intent-to-treat patients, valuable patients). Prior to the initiation of study drug, all treated subjects had a cough (68% moderate and 25% severe) and produced sputum (44% mucopurulent and 53% purulent). Other reported clinical signs and symptoms of ABECB at pretreatment, for both groups combined, included dyspnea (98%), rhonchi/whee/ing (82%), and less frequently, rales/crackling (37%).

Figure 1. Study population (N = 485) randomized to the two clarithromycin regimens: extended-release (ER) 1000mg once daily for 5 days and immediate-release (IR) 500mg twice daily for 7days, in the treatment of acute bacterial exacerbation of chronic bronchitis (ABECB)

Table 1. Demographic and clinical characteristics at baseline in all treated patients

Antimicrobial susceptibility

Less than half of the patients (44% [105/240] and 45% [111/245] of the clarithromycin ER- and clarithromycin IR-treated patients, respectively) had at least one respiratory tract pathogen isolated from their baseline sputum sample. Pretreatment target pathogens included H. influenzae (n = 88], H. parainfluenzae (n = 78), M. catarrhalis (n = 50), S. pneumoniae (n = 43), and S. aureus (n = 23). In vitro resistance rates to clarithromycin were 17% for S. aureus, 26% for H. parainfluenzae, and 28% for S. pneumoniae. No resistance to clarithromycin was observed at baseline in strains of H. influenzae or M. catarrhalis. Only one H. influenzae and two S. pneumoniae strains developed \resistance during treatment with clarithromycin.

Efficacy

Clinical cure

In the group of clinically evaluable patients, clinical cure rates at Visit 4 (test-of-cure visit) were similar for the clarithromycin ER group (84%, 157/187) and the clarithromycin IR group (84%, 172/204) (Table 2). The 95% CI for the difference between clinical cure rates (clarithromycin ER-clarithromycin IR) was [-7.9, 7.2], demonstrating that 5-day clarithromycin ER was comparable to 7-day clarithromycin IR. After adjusting for various prognostic factors (e.g. country, gender, race, age, weight, study drug duration and compliance, tobacco and alcohol usage, FEV^sub 1^, etc.), no statistically significant differences were observed between the two treatment groups. A similar proportion of patients in each treatment group used additional therapy, including sympathomimetic agents (20% of patients across treatment groups), adrenal corticosteroids (20%), and antitussive/expectorant/ mucolytic agents (7%). Similar results for clinical response rates were observed among intent-to-treat patients.

Table 2. Response rate [95% CI] at the test-of-cure visit

Bacteriological cure

The bacteriological cure rate among clinically and bacteriologically evaluable patients at the test-of-cure visit was 87% for the clarithromycin ER group (82/94) and 89% for the clarithromycin IR group (91/102) (95% CI [-11.6, 7.6]). After adjusting for prognostic factors, no statistically significant differences were observed between the treatment groups for patient bacteriological cure rate. Results in the intent-to-treat population were similar to those in the clinically and bacteriologically evaluable patient population.

Target pathogen eradication

Overall target pathogen eradication rate at the testof-cure visit, in patients who were both clinically and bacteriologically evaluable, showed the treatment groups to be comparable: 88% (107/ 122) for the clarithromycin ER group and 89% (117/131) for the clarithromycin IR group (95% CI [-9.9, 6.7]). Eradication rates for target pathogens ranged from 79% to 92% (Table 3). Target pathogen eradication rates among the intent-to-treat patients were similar in the clarithromycin ER and clarithromycin IR groups. No superinfections or recurrences occurred in either treatment group.

Table 3. Target pathogen eradication rate [95% CI] at the test- of-cure visit in clinically and bacteriologically evaluable patients

Clinical vs. bacteriological response

Patient bacteriologic responses in the clinically and bacteriologically evaluable population were compared with clinical responses in both treatment groups at the test-of-cure visit. In general, clinical and bacteriological response results were well matched: all patients classified as a clinical cure also had eradication of their pretreatment target pathogen(s). Three clarithromycin ER-treated patients and two clarithromycin IR- treated patients were classified as clinical failures, but bacteriologic cures.

Symptom relief

By Visit 3, resolution/improvement in cough and sputum production, volume, and appearance was observed in ≥ 86% of evaluable patients in each treatment group, with no statistically significant treatment group differences. Resolution and resolution/ improvement rates were sustained at Visit 4 and, in all cases, were improved when compared to Visit 3.

Compliance and safety

Compliance with study drug was excellent. Mean ( SD) compliance rate was 96.5% ( 13.8%) and 97.2% ( 13.5%) for the clarithromycin ER and clarithromycin IR groups, respectively.

The study drugs were generally well tolerated as evidenced by a low frequency of premature discontinuations due to drug-related adverse events. Six patients (3%) in the clarithromycin ER-treated group were prematurely discontinued from treatment due to the occurrence of an adverse event (s) considered probably related to the study drug. These events included two patients with an allergic reaction and one patient each with urticaria, gastritis, nausea, and vomiting/dizziness/diarrhea. Four patients (2%) in the clarithromycin IR-treated group were prematurely discontinued from treatment due to the occurrence of a drug-related adverse event(s), including one patient each with dysphagia, allergic reaction, asthenia/abdominal pain/ nausea/vomiting, and abdominal pain/nausea/ vomiting.

The overall incidence of drug-related adverse events was 13% (31/ 240) in the clarithromycin ER group and 18% (45/245) in the clarithromycin IR group (Table 4). Drug-related gastrointestinal adverse events were reported by 8% (19/240) of patients in the clarithromycin ER group and 11 % (26/245) of patients in the clarithromycin IR group; the most common adverse events (> 2% of patients) were nausea and diarrhea with the ER formulation and diarrhea, nausea, and vomiting with the IR formulation. Clarithromycin ER patients reported statistically significantly fewer drug-related adverse events due to abnormal taste than did clarithromycin IR-treated patients (3% and 8%, respectively, p = 0.012). Most drug-related adverse events in both treatment groups were considered mild or moderate in intensity. Only one patient (clarithromycin IR group) experienced a serious, drug-related adverse event (myopathy) meeting the regulatory definition.

None of the changes from baseline in mean values for laboratory parameters, vital signs, or physical findings was considered clinically meaningful, and no obvious treatment group differences were observed.

Discussion

Bacterial infection resulting in ABECB is a common complication of chronic bronchitis, with viral infection, allergic reaction, and environmental factors like air pollution and smoking established as other causes of this disease. Most commonly observed in patients over 40 years of age with COPD, ABECB is part of the natural history of chronic, disabling respiratory disease33.

Table 4. Most commonly* reported treatment-related adverse events

Severity of disease has been shown to directly affect the value of anti-infective treatment for ABECB2,6-8, therefore, it is important to design clinical studies that evaluate antimicrobial therapy in the appropriate ABECB patient population. In this study comparing 5 days of clarithromycin ER administered once daily to 7 days of clarithromycin IR administered twice daily, strict patient entry criteria were employed to select appropriate patients with ABECB: eligible patients were to be older than 40 years of age, have an FEV^sub 1^ < 70% of predicted, and have a pretreatment qualified sputum sample. Enrollment was allowed only for patients meeting Anthonisen Type 1 or Type 2 criteria, and patients with pneumonia were excluded.

Clarithromycin is an appropriate treatment choice for ABECB based on broad-spectrum antimicrobial activity that includes the primary etiologic pathogens and a well-established clinical and bacteriologic track record. Numerous studies have documented the safety, tolerability, and efficacy of clarithromycin IR and ER, administered for 5days-14days, for treatment of ABECB13,15,21- 23,26,29,30,34-43. Across these studies, the clinical success rate in clarithromycin-treated patients ranged from 82% to 98% and was similar to that of the comparator, including fluoroquinolones (ciprofloxacin, gatifloxacin, grepafloxacin, gemifloxacin, moxifloxacin, and sparfloxacin) and β-lactam agents (ceftibuten, amoxicillin/clavulanate, and cefprozil).

Short-course therapy with clarithromycin ER is of interest because, given equivalent efficacy, fewer days of anti-infective therapy may have several potential benefits. Compliance decreases with oral antimicrobial agents used to treat respiratory tract infections after 7 days25. Fewer days of therapy exposes the patient to fewer potential adverse events11.

In this study, a short, 5-day course therapy with clarithromycin ER was comparable to clarithromycin IR administered for 7 days based on a clinical cure rate of 84% at the test-of-cure visit in ABECB patients meeting Anthonisen Type I or II criteria. Clinical signs and symptoms of ABECB resolved or improved in the majority of patients treated with both formulations, and there was consistency between clinical and bacteriologic responses. Lack of an active treatment arm administered for 10 days-14 days limits our ability to quantify the impact of short-course clarithromycin ER therapy on compliance.

Our results support those of other short-course therapy clinical trials comparing clarithromycin ER vs. IR23,30. In a recently published report by Nalepa et al., treatment with clarithromycin ER or clarithromycin IR for 5 days resulted in clinical cure rates of ≥ 97%, bacteriological cure rates of 89%, and target pathogen eradication rates of 90% in both treatment groups23. Similarly, Adam et al. documented excellent clinical (≥ 97%) and bacteriological (≥ 92%) response rates with a 5-day course of either clarithromycin ER and IR30.

While clarithromycin has been shown to be generally well tolerated in studies conducted over the last 12 years44, the ER formulation may be better tolerated than the IR formulation. The rate of gastrointestinal adverse events in the current study was 25% lower with clarithromycin ER as compared with clarithromycin IR. Additionally, the rate of adverse events due to abnormal taste was significantly lower for clarithromycin ER as compared with clarithromycin IR.

In summary, both short-course, 5-day once-daily therapy with clarithromycin ER and 7-day, twice-daily therapy with clarithromycin IR were effective in resolving clinical signs/symptoms of ABECB and eradicating the causative pathogens. Clarithromycin ER was better tolerated, causing fewer gastrointestinal adverse events and statistically significantly fewer reports of abnormal taste as compared with clarithromycin IR.

Acknowledgments

This study was supported by a grant from Abbott Laboratories, Abbott Park, IL.

We wish to acknowledge t\he investigators who enrolled patients in this study:

Thomas Adams, Murray, KY; Lance Atkinson, Springfield, MO; James Baker, Lake Oswego, OR; Robert Broker, Simpsonville, SC; Patricia Buchanan, Eugene, OR; James Capo Jr., Atlanta, GA; David Cardona, Fresno, CA; Mario Castro, St. Louis, MO; Thomas Chiambretti, Dewitt, MI; Joseph Chien, Scarborough, Ontario; David Claassen, Ozark, AL; Lisa Cohen, New Port Richey, FL; Michael Collins, Hoover, AL; Clark Cullen, Medford, OR; Indravadan Dattani, Saskatoon, Saskatchewan; Charles DeBusk, New Tazewell, TN; Donald Denmark, Oklahoma City, OK; Anthony DiMarco, Chardon, OH; Nicholas Doll, Baton Rouge, LA; Joel Epstein, Lakewood, CA; Neil Ettinger, Chesterfield, MO; Gary Ferguson, Livonia, MI; Chester Fisher, Newport News, VA; Mark Fraley, Colorado Springs, CO; John Gezon, Salt Lake City, UT; Wayne Gilbert, Johnson City, TN; Philip Giordano, Orlando, FL; Miguel Gomez, Glendale, AZ; Mark Gotfried, Phoenix, AZ; Janette Gray, San Diego, CA; Robert Grindstaff, Johnson City, TN; Theodore Gronski, Milwaukee, WI; Ronald Grossman, Mississauga, Ontario; Richard Guzzetta, Clovis, CA; Eric Hermansen, Chester, MD; Darrell Herrington, San Angelo, TX; David Hill, Waterbury, CT; Jerry Hutchinson, Tucson, AZ; Ronald Intelisano, Blackwood, NJ; John Jacobsen, Omaha, NE; Amal Jubran, Hines, IL; Jatin Kadakia, Clarksville, TN; Kambiz Karimi, Indianapolis, IN; Edward Kerwin, Medford, OR; Hany Khalil, Toledo, OH; Richard Krause, Chattanooga, TN; Ben Lasko, Toronto, Ontario; James Lawless, Camillus, NY; Daniel Lorch Jr., Brandon, FL; Tad Lowdermilk, Winston-Salem, NC; Frank Maggiacomo, Cranston, RI; George Mark, Elkhart, IN; Harris McLJwain, Tampa, FL; Lothar McMillian, Rancho Cucamonga, CA; Donald McNicol Jr., Astoria, NY; Mia Moon, Temecula, CA; Greg Moran, Sylmar, CA; Alexander Murray, Greensboro, NC; Thomas Nolen, Columbiana, AL; Dan Olson, Toledo, OH; Frank Onuska, Kitchener, Ontario; Douglas Owens, Greer, SC; Robert Piasecki, St Joseph, MI; Terry Poling, Wichita, KS; Mark Radbill, Bensalem, PA; Marina Raikhel, Torrance, CA; Albert Razzetti, Deland, FL; William Renaudin, Metairie, LA; Gary Richmond, Fort Lauderdale, FL; Mark Ringold, Christiansburg, VA; William Rodriguez-Cintron, San Juan, Puerto Rico; Melvin Russell, Tallassee, AL; David Schneider, Metairie, LA; Allan Seibert Iy Mobile, AL; Daniel Shu, Coquitlam, British Columbia; John Sibille, Sunset, LA; Henry Sideropoulos, Pasadena, CA; Stuart Simon, Marietta, GA; Wayne Sinclair, Missoula, MT; Emil Skobeloff, Ridley Park, PA; Michael Smith, Savannah, TN; Philip Snell, Greer, SC; Julie Son, San Diego, CA; Malcolm Sperling, Fountain Valley, CA; Claude St. Pierre, Sherbrooke, Quebec; Robert Strzinek, Colleyville, TX; Javier Szwarcberg, St. Louis, MO; Raymond Tidman, Blue Ridge, GA; Miguel Trevino, Largo, FL; Stephen Ulrich, Zanesville, OH; Paul Wagner, San Diego, CA; Brian Walls, Merritt Island, FL; Tony Warren, Rome, GA; Steven Weinstein, Huntington Beach, CA; Kenneth Wiley, Metairie, LA; and David Wilhelm, Birmingham, AL.

* The data in support of this paper were presented at the 6th European Congress of Chemotherapy and Infection, 1-3 December 2004, Paris, France

References

1. National Institutes of Health, NHLBI. Morbidity and mortality: 2004 chart book on cardiovascular, lung, and blood diseases. Available from URL: http://www.nhlbi.nih.gov/resources/docs/ cht- book.htm [accessed November 2004]

2. Anthonisen NR, Manfreda J, Warren CPW, Hershfield ES, Harding GKM, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196-204

3. Sethi S. Infectious etiology of acute exacerbations of chronic bronchitis. Chest 2000;117:3803-3855

4. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:1418-22

5. Doll H, Grey-Amante P, Duprat-Lomon I, et al. Quality of life in acute exacerbation of chronic bronchitis: results from a German population study. Respir Med 2002;96:39-51

6. McCrory DC, Brown C, Gelfand SE, Bach PB. Management of acute exacerbations of COPD: a summary and appraisal of published evidence. Chest 2001;119:1190-209

7. Grossman RF. Guidelines for the treatment of acute exacerbations of chronic bronchitis. Chest 1997;112(Suppl 6):310S- 313S

8. Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease exacerbations: a meta- analysis. J Am Med Assoc 1995;273:957-60

9. Chodosh S. Bronchitis and asthma. In: Gorbach SL, Bartlett JL, Blacklow NR, editors. Infectious diseases. Philadelphia (PA): WB. Saunders Co; 1992. p. 476-85

10. Niederman MS. Antibiotic therapy of exacerbations of chronic bronchitis. Semin Resp Infect 2000; 15:59-70

11. Lorenz J. Comparison of 5-day and 10-day cefixime in the treatment of acute exacerbation of chronic bronchitis. Chemotherapy 1998;44(Suppl l):15-8

12. Langan C, Clecner B, Cazzola CM, Brambilla C, Holmes CY, Staley H. Short-course cefuroxime axetil therapy in the treatment of acute exacerbations of chronic bronchitis. Int J Clin Prac 1998;52:289-97

13. McCarty JM, Pierce PF. Five days of cefprozil versus lOdays of clarithromycin in the treatment of an acute exacerbation of chronic bronchitis. Ann Allergy Asthma Immunol 2001;87:327-34

14. Schaberg T, Ballin I, Huchon G, Bassaris H, Hampel B, Reimnitz P, The Bronchitis Study Group. A multinational, multicentre, non-blinded, randomized study of moxifloxacin oral tablets compared with co-amoxiclav oral tablets in the treatment of acute exacerbation of chronic bronchitis. J Intern Med Res 2001;29:314-28

15. Chodosh S, DeAbate CA, Haverstock D, Aneiro L, Church D, The Bronchitis Study Group. Short-course moxifloxacin therapy for treatment of acute bacterial exacerbations of chronic bronchitis. Respir Med 2000;94:18-27

16. DeAbate CA, Mathew CP, Warner JH, Heyd A, Church D. The safety and efficacy of short course (5-day) moxifloxacin vs. azithromycin in the treatment of patients with acute exacerbation of chronic bronchitis. Respir Med 2000;94:1029-37

17. Paster RZ, McAdoo MA, Keyserling CH, Nemeth MA, Tack KJ, Griffin TJ. A comparison of a five-day regimen of cefdinir with a seven-day regimen of loracarbef for the treatment of acute exacerbations of chronic bronchitis. Int J CIn Prac 2000;54:293-9

18. File T, Schlemmer B, Garau J, Lode H, Lynch S, Young C. Gemifloxacin versus amoxicillin/clavulanate in the treatment of acute exacerbations of chronic bronchitis [The 070 Clinical Study group]. J Chemother 2002;12:314-25

19. Masterton RG, Burley CJ. Randomized, double-blind study comparing 5- and 7-day regimens of oral levofloxacin in patients with acute exacerbation of chronic bronchitis. Int J Antimicrob Agents 2001; 18:503-12

20. Fogarty CM, Bettis RB, Griffin TJ, Keyserling CH, Nemeth MA, Tack KJ. Comparison of a 5-day regimen of cefdinir with a 10day regimen of cefprozil for treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother 2000;45:851-8

21. Wilson R, Schentag JJ, Ball P, Mandell L, 068 Study Group. A comparison of gemifloxacin and clarithromycin in acute exacerbations of chronic bronchitis and long-term clinical outcomes. Clin Ther 2002;24:639-52

22. Langan CE, Zuck P, Vogel F, et al. Randomized, doubleblind study of short-course (5 day) grepafloxacin versus 10 day clarithromycin in patients with acute bacterial exacerbations of chronic bronchitis. J Antimicrob Chemother 1999;44:515-23

23. Nalepa P, Dobryniewska M, Busman T, Notario G. Short-course therapy of acute exacerbation of chronic bronchitis: a double- blind, randomized, multicenter comparison of extended-release versus immediate-release clarithromycin. Curr Med Res Opin 2003;19:411-20

24. Guillemot D, Carbon C, Balkau B, et al. Low dosage and long treatment duration of beta-lactam: risk factors for carriage of penicillin-resistant Streptococcus pneumoniae. J Am Med Assoc 1998;279:365-70

25. Reyes H, Guiscafre H, Munoz O, Perez-Cuevas R, Martinez H, Gutierrez G. Antibiotic noncompliance and waste in upper respiratory tract infections and acute diarrhea. J Clin Epidemiol 1997;50:1297- 304

26. Weiss K, Vanjaka A, Canadian Study Group on Bronchitis. An open-label, randomized, multicenter, comparative study of the efficacy and safety of 7 days of treatment with clarithromycin extended-release tablets versus clarithromycin immediate-release tablets for the treatment of patients with acute bacterial exacerbation of chronic bronchitis. Clin Ther 2002;24:2105-22

27. Peters DH, Clissold SP. Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential. Drugs 1992;44:117-64

28. Guay DRP, Gustavson LE, Devcich KJ, Zhang J, Cao G, Olson CA. Pharmacokinetics and tolerability of extended-release clarithromycin. CHn Ther 2001;23:566-77

29. Adler JL, Jannetti W, Schneider D, Zhang J, Palmer R, Notario G. Phase III, randomized, double-blind study of clarithromycin extended-release and immediate-release formulations in the treatment of patients with acute exacerbation of chronic bronchitis. Clin Ther 2000;22:1410-20

30. Adam D, Glaser-Caldow E, Wachter J, et al. Comparative efficacy of clarithromycin modified-release and clarithromycin immediate-release formulations in the treatment of lower respiratory tract infections. Clin Ther 2001;23:585-95

31. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 5th ed. Approved Standard NCCLS Document M7AS and 10th Informational Supplement: M100-S10 (M7); 2000

32. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk susceptibility tests, 7th ed. Approved Standard NCCLS Document M2-A7 and 10th Informational Supplement: MlOO-SlO (M2); 2000

33. Reynolds HY. Chronic bronchitis and acute infect\ious exacerbations. In: Mandell GL, Bennett JE, Dolan R, editors. Principles and practice of infectious diseases, 5th ed. New York: Churchill Livingstone; 2000:706-10

34. Chodosh S, Schreurs A, Siami G, et al.; the Bronchitis Study Group. Efficacy of oral ciprofloxacin vs. clarithromycin for treatment of acute bacterial exacerbations of chronic bronchitis. Clin Infect Dis 1998;27:730-8

35. Ziering W, McElvaine P. Randomized comparison of once-daily ceftibuten and twice-daily clarithromycin in the treatment of acute exacerbation of chronic bronchitis. Infection 1998;26:68-75

36. DeAbate CA, Myers D, Henry D, et al. Efficacy and tolerability of once-daily grepafloxacin compared with clarithromycin in the treatment of acute bacterial exacerbations of chronic bronchitis. Clin Drug Invest 1999;17:21-31

37. Langan CE, Zuck P, Vogel F, et al. Randomized, double-blind study of short-course (5 day) grepafloxacin versus 10 day clarithromycin in patients with acute bacterial exacerbations of chronic bronchitis. J Antimicrob Chemother 1999;44:515-23

38. Wilson R, Kubin R, Ballin I, et al. Five day moxifloxacin therapy compared with 7 day clarithromycin therapy for the treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1999;44:501-13

39. Lipsky BA, Unowsky J, Zhang H, Townsend L, Talbot GH. Treating acute bacterial exacerbations of chronic bronchitis in patients unresponsive to previous therapy: sparfloxacin versus clarithromycin. Clin Ther 1999;21:954-65

40. Allin D, James I, Zachariah J, et al. Comparison of once- and twice-daily clarithromycin in the treatment of adults with severe acute lower respiratory tract infections. Clin Ther 2001;23:1958-68

41. Anzueto A, Fisher CL, Busman T, Olson CA. Comparison of the efficacy of extended-release clarithromycin tablets and amoxicillin/ clavulanate tablets in the treatment of acute exacerbation of chronic bronchitis. Clin Ther 2001;23:72-86

42. Gotfried MH, DeAbate CA, Fogarty C, Mathew CP, Sokol WN. Comparison of 5-day, short-course gatifloxacin therapy with 7-day gatifloxacin therapy and 10-day clarithromycin therapy for acute exacerbation of chronic bronchitis. Clin Ther 2001;23:97-107

43. Martinot JB, Carr WD, Cullen S, et al.; The Clarithromycin Once-a-Day Study Group. A comparative study of clarithromycin modified release and amoxicillin/clavulanic acid in the treatment of acute exacerbation of chronic bronchitis. Adv Ther 2001;18:1-11

44. Anzueto A, Morris S. Clarithromycin in 2003: sustained efficacy and safety in an era of rising antibiotic resistance. Int J Antimicrob Agents 2004;24:1-17

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2882_3, Accepted for publication: 12 January 2005

Published Online: 26 January 2005

doi: 10.1185/030079905X26243

Mark Gotfried3, Gerard Notario(b), Joy Spiller(b), Robert Palmer(b) and Todd Busman(b)

a Pulmonary Associates, University of Arizona, Phoenix, AZ, USA

b Abbott Laboratories, North Chicago, IL, USA

Address for correspondence: Dr Mark Gotfried, Pulmonary Associates (PA), 9225 N. Third Street, Ste. 20OB, Phoenix, AZ 85020, USA. Tel.: +1 602 997 7263; Fax: +1 602 944 4553; email gotfriedmd@aol.com

Copyright Librapharm Feb 2005