clavulanate tablets in the treatment of acute exacerbation of chronic bronchitis

CLINICAL THERAPEUTICWVOL.

23, NO. I, 200 1

Comparison of the Efficacy of Extended-Release Clarithromycin Tablets and AmoxicillinKlavulanate Tablets in the Treatment of Acute Exacerbation of Chronic Bronchitis Antonio Anzueto, MD,’ Chester L. Fisher, Jr., MD, MPH,2 Todd Busman, MS,3 and Carol A. Olson, MD, PhD3 ‘University of Texas Health Science Center at San Antonio, San Antonio, Texas, 2Health Research of Hampton Roads, Inc, Newport News, Virginia, and -‘Abbott Laboratories, Abbott Park. Illinois

ABSTRACT Background: Clarithromycin has established efficacy and safety in the treatment of respiratory infections. Objective: This study examined the efficacy and safety of a new extended-release formulation of clarithromycin compared with amoxicillinklavulanate in the treatment of acute exacerbation of chronic bronchitis (AECB). Methods: This phase IIIB, multicenter, randomized, parallel-group, investigator-blinded study in patients with AECB and productive cough with purulent sputum compared treatment with extended-release clarithromycin (two 500-mg tablets once daily for 7 days) and amoxicillinklavulanate (one 875-mg tablet twice daily for 10 days). Assessments were performed before treatment, between study days 10 and 12 (or within 48 hours after premature discontinuation), and between study days 17 and 21 (test of cure). Results: Of 287 patients randomized and treated, 270 were clinically evaluable (137 clarithromycin, 133 amoxicillinklavulanate). Treatment groups were well matched in terms of demographic characteristics, medical condition, and history. Among clinically evaluable patients at test of cure, 85% and 87% of clarithromycinand amoxicillinklavulanatetreated patients, respectively, demonstrated clinical cure (as defined in 1998 draft US Food and Drug Administration guidelines); among clinically and bacteriologically evaluable patients, 92% versus 89%, respectively, demonstrated bacteriologic cure. Overall pathogen eradication rates were similar in the 2 groups (88% clarithromycin, 89% amoxicillinklavulanate). Rates of premature discontinuation of study drug for any reason differed between Accepted for publication

November

Printed in the USA. Reproduction

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1.5, 2000. in whole or part is not permitted.

0149-2918/01/$19.00

A. ANZUETO ET AL.

treatments: 3% (4/142) of clarithromycintreated patients versus 12% (17/145) of amoxicillin/clavulanate-treated patients (P = 0.005). One percent (2/142) and 6% (8/145) of the respective treatment groups discontinued study drug because of adverse events. Adverse events generally occurred with a similar frequency in the 2 groups; however, taste alteration was more common with clarithromycin (9/142 [6%]) than with amoxicillin/clavulanate (l/145 [l%]; P = 0.01). Mean severity scores for gastrointestinal adverse events showed a significant difference between groups (1.16 for clarithromycin-treated patients and 1.58 for amoxicillin/clavulanatetreated patients; P = 0.016). Conclusions: The results of this study demonstrate the clinical and bacteriologic equivalence and improved gastrointestinal tolerability of a 7-day course of once-daily extended-release clarithromycin relative to a lo-day course of twice-daily amoxicillin/clavulanate in the treatment of AECB. Key words: acute exacerbation of chronic bronchitis, clarithromycin, extendedrelease, amoxicillin/clavulanate. (Clin Ther: 2001;23:72-86)

INTRODUCTION Chronic bronchitis is a common condition, affecting 10% to 25% of the adult population of the United States, or -12.5 million people.‘** It is characterized by cough and excessive production of mucus and is the cause of significant morbidity, mortality, and use of health care resources.3,4 The prevalence of chronic obstructive pulmonary disease (COPD), which includes both chronic bronchitis and emphysema, is increasing both in the United States and worldwide, and appears

to be correlated with smoking and environmental pollution. In the United States, COPD is now the fourth leading cause of death and the only common cause of death that is increasing in incidence.4 The World Health Organization has predicted that by the year 2020, COPD will rank as the third leading cause of death worldwide.5 Acute exacerbation of chronic bronchitis (AECB) may be triggered by a variety of environmental factors and infectious agent@; bacterial and viral exacerbations may be recurrent.’ The most commonly isolated pathogens in AECB are Haemophilus injluenzae, Streptococcus pneumoniae, and Moraxella catarrhaliss-‘O; Haemophilus

and Staphyisolated.“~‘* Given that episodes of AECB tend to predispose patients to subsequent episodes and carry the potential for a downward clinical course, rapid initiation of effective antimicrobial therapy is crucial.” Nonetheless, optimal antimicrobial therapy for patients with AECB remains undefined, although the trend in recent years has been toward shorter durations of therapy requiring fewer daily doses (ie, once or twice daily).“~” This study compared the safety and efficacy of a 7-day course of extendedrelease clarithromycin with those of a loday course of amoxicillin/clavulanate in the treatment of AECB. A 7-day course of extended-release clarithromycin administered as two 500-mg tablets once daily is the regimen approved by the US Food and Drug Administration (FDA) for this indication, based on the results of a previous study showing clinical equivalence between the extended-release and immediate-release formulations. I4 The 1O-day course of amoxicillin/clavulanate administered as one 875-mg tablet twice daily is lococcus

parainjluenzae

aureus are also commonly

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CLINICAL THERAPEUTICS@

the FDA-approved dose and duration for this indication.‘” This paper presents the primary end points of the study (rates of clinical cure, bacteriologic cure, and pathogen eradication).

PATIENTS

AND METHODS

This phase BIB, multicenter, randomized, parallel-group, investigator-blinded study enrolled patients at 55 sites throughout the United States between October 1999 and April 2000. The study protocol was approved by the institutional review board of each participating institution, and all patients or their legal guardians provided written informed consent before any study-related procedures were performed.

Inclusion and Exclusion Criteria Men and women were eligible for the study if they were ~40 years of age and had a presumptive diagnosis of AECB (Anthonisen type 1 criteriai6-increased dyspnea, increased sputum volume, increased sputum purulence) plus ~1 of the following: fever 238’C not attributable to another cause, increased wheezing, or increased respiratory rate. Patients were required to have a productive cough with purulent sputum (~25 white blood cells [WBC] and ~10 squamous epithelial cells per lowpower field). A positive culture for a protocol-specified pathogen was not required for study inclusion but was required for inclusion in the analyses of bacteriologic efficacy. Patients were not discontinued from the study if the laboratory identified a bacterial isolate classified as resistant to 1 or both of the study medications, unless the patient’s clinical condition warranted this. Patients were required to be ambulatory, to have a history of chronic bronchi-

74

tis (cough with sputum production in >2 consecutive years and for most days in a consecutive 3-month period),2 and to have evidence of COPD (airflow obstruction due to chronic bronchitis or emphysema, forced expiratory volume at 1 second ~70% of the predicted value). Use of corticosteroids was permitted. Among the exclusion criteria was a history of hypersensitivity to penicillin or macrolide antibiotics. Also excluded were pregnant or lactating women; patients with a history of amoxicillin/clavulanateassociated cholestatic jaundice or hepatic dysfunction; residents of chronic care facilities; patients with suspected infectious mononucleosis (potential adverse reaction to amoxicillin); patients with severe or complicated lower respiratory tract infection, pneumonia, or positive radiographic evidence of tuberculosis or other mycobacterial infection, empyema, pulmonary embolism, lung abscess or tumor, pleural effusion or consolidation, or other significant pulmonary disease; and patients with severely compromised respiratory status (ie, oxygen dependent, requiring hospitalization). Patients who had received a systemic antibiotic within 14 days before initiation of study treatment, who required parenteral antibiotic therapy, or who were currently receiving or were likely to require other systemic antimicrobial therapy between the pretreatment and test-of-cure visits (study days 17-21) were also excluded. Additional exclusion criteria have been published previously.i4

Antimicrobial

Therapy

At each investigational site, patients satisfying inclusion criteria were randomly assigned in a 1: 1 ratio to receive

A. ANZUETO ET AL.

either a 7-day course of extended-release clarithromycin (two 500-mg tablets once daily) or a lo-day course of amoxicillin/clavulanate (one 875mg tablet twice daily). Medication was supplied to patients in bottles that were similar in size and appearance, with instructions for administration. Medication was to be taken with food. To maintain investigator blinding, a designated person at each site dispensed study drug, instructed patients on dosing procedures, and contacted patients by telephone on study days 2 and 3 to administer a questionnaire on clinical signs and symptoms. The designated person and patient were instructed not to discuss the assigned treatment with the investigator or other study personnel at any time during the trial, and the person dispensing treatment could not participate in the clinical or safety evaluations. To document adherence with therapeutic regimens, patients were instructed to return bottles of study medication (empty or otherwise) to the study site at the follow-up visit (between study days 10 and 12).

Clinical and Bacteriologic

Assessments

At the pretreatment visit (within 48 hours before administration of study medication), each patient’s medical history was obtained and a physical examination was performed. Clinical signs and symptoms (cough, sputum production, dyspnea, rhonchilwheezing, pleuritic or substernal pain, headache, fever 838OC) and the patient’s baseline (pre-acute episode) signs and symptoms and current condition were documented. Cough, sputum production, and dyspnea were rated as mild, moderate, or severe. A sputum sample was obtained (by spontaneous expec-

toration or transtracheal aspiration) for Gram’s staining, culture, and susceptibility testing. The volume of sputum production during the previous 24 hours, as estimated by the patient, was also recorded (~1 oz, l-2 oz, 2-3 oz, >3 oz), and sputum appearance was assessed (eg, purulent, mucopurulent). Purulent sputum (>25 WBC and ~10 squamous epithelial cells per low-power field) was required for enrollment. Patients who met all other inclusion/exclusion criteria were allowed to begin taking study medication before culture results were known. Clinical and bacteriologic evaluations were conducted between study days 10 and 12 (or within 48 hours after premature discontinuation) and between study days 17 and 21 (test-of-cure visit). The clinical response was evaluated in accordance with 1998 FDA draft guidelines for antimicrobial use in the treatment of AECB.” These guidelines eliminated the previously used improvement category of clinical response. Consequently, it was anticipated that efficacy rates in this trial would be lower than those in trials that did not use the draft FDA guidelines. For the evaluation of clinical response, clinical cure was defined as resolution or improvement (return to baseline condition) of pretreatment signs and symptoms of infection at the test-of-cure visit and no further need for antimicrobial therapy. Clinical failure was defined as lack of improvement or worsening (new symptoms may have appeared) of pretreatment signs and symptoms of infection and a need for additional antimicrobial therapy at the test-of-cure visit. Sputum samples for Gram’s staining and culture were obtained at the pretreatment (baseline) visit to determine the presence and antimicrobial susceptibility of

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S pneumoniae, H influenzae, M catarrhalis, S aureus, H parainfluenzae, or other pathogens. If the patient was producing purulent sputum at the 2 follow-up visits, occurring between study days 10 and 12 and between study days 17 and 21, repeat cultures were performed for bacteriologic analysis. Sputum samples were obtained by spontaneous or induced expectoration. In vitro susceptibility to clarithromycin and amoxicillin/clavulanate was determined by use of break points established by the National Committee for Clinical Laboratory Standards. l* The diskdiffusion method, with measurement of the zone of inhibition (mm), and the dilution method, with measurement of minimum inhibitory concentrations @g/mL), were used to determine susceptibility. For the evaluation of bacteriologic response, the following definitions were used: presumed eradication-in the absence of a repeat sputum culture, eradication was assumed if the definition of clinical cure was met; eradication-absence of the pathogen(s) identified at study entry on repeat sputum culture performed between study days 17 and 21; presumed persistence-in the absence of a repeat sputum culture, the initial pathogen was assumed to be persistent if the definition of clinical failure was met; persistencepresence of the original pathogen(s) on sputum culture performed between study days 17 and 21 or at the time of discontinuation of study therapy; superinfectionpresence of new pathogen(s) on sputum culture performed between study days 7 and 10 or study days 17 and 2 1 in a symptomatic patient; and indetenninate-evaluation was not possible. The bacteriologic cure rate was defined as the percentage of bacteriologically evaluable patients (ie, those with ~1 evalu-

76

able pathogen at study entry) with eradication or presumed eradication of all evaluable pathogens. The bacteriologic failure rate was defined as the percentage of bacteriologically evaluable patients with presumed persistence, persistence, or superinfection. The pathogen eradication rate was determined using 2 measures: the percentage of patients in whom each pretreatment pathogen was eradicated, and the percentage of evaluable pretreatment pathogens eradicated, regardless of the number of patients.

Safety Assessments Patients were monitored by telephone follow-up on study days 2 and 3, as well as by physical examination (including vital signs) and laboratory assessments at follow-up visits, to determine the occurrence of adverse events. Patients were instructed to contact the investigator or return to the study site at any time during the treatment period if they experienced any adverse event, if their condition had not improved, or if signs and symptoms of infection had worsened. The investigator assessed each adverse event with regard to its severity, relationship to study drug, and actions taken. Investigators were instructed to use the following scale to rate the severity of adverse events: 1 = mild (transient and easily tolerated); 2 = moderate (caused discomfort and interrupted usual activities); and 3 = severe (caused considerable interference with usual activities and could have been incapacitating or life threatening).

Study Analyses The primary population for analysis was the clinically evaluable population: those

A. ANZUETO ET AL.

who met all selection criteria, including a confirmed diagnosis of AECB, and had taken 280% of study drug to qualify as a clinical cure. For classification as a clinical failure, patients had to have taken study drug for ~3 full days. With the exception of those who had been classified as clinical failures before a scheduled visit, clinically evaluable patients returned to the study site for the test-of-cure visit. In addition, clinically evaluable patients could take no nonstudy systemic antimicrobial agents for other infections or report any other potentially confounding interventions during the study period. The clinically and bacteriologically evaluable population met the same criteria as those for the clinically evaluable population. In addition, clinically and bacteriologically evaluable patients had ~1 target pathogen (H injluenzae, S pneumoniae, A4 catarrhalis, H parainjluenzae, or S aureus) isolated before treatment. The intentto-treat population consisted of all patients who had a clinical diagnosis of AECB and took 21 dose of study drug. All patients who received ~1 dose of study medication were included in the safety analysis.

Statistical Analyses Based on data from previous studies of clarithromycin versus amoxicillin/clavulanate and of immediate-release versus extended-release clarithromycin conducted by Abbott Laboratories, as well as on information available for amoxicillin/clavulanate 87.5mg tablets, the expected difference in gastrointestinal adverse events between the 2 treatments would be -15%. Approximately 300 patients (- 150 per treatment group) would provide -80% power to detect a significant difference at the 0.05 (2-tailed) level.

Assuming an 80% evaluability rate, -300 patients would provide -80% power to demonstrate equivalence in clinical cure, assuming an expected cure rate of 85% in each treatment group and a lower limit of -0.15 for the 95% CI. The primary efficacy variables were rates of clinical cure, bacteriologic cure, and pathogen eradication. All statistical tests between treatment groups were 2tailed, with an 0.05 significance level. Descriptive statistics were used to summarize patients’ demographic characteristicssex, race (white, black, other), age (~40 years, 40-65 years, %5 years), and body weight (~70 kg, 270 kg)-by treatment group. Treatment groups were compared with respect to sex and race using the Fisher exact test; age and body weight were analyzed using l-way analysis of variance.i9 The efficacy variables were summarized by treatment group and analyzed using the Fisher exact test to compare treatment groups. Binomial CIs were computed for the difference in efficacy variables between treatment groups (extended-release clarithromycin - amoxicillin/clavulanate). Changes in each clinical sign and symptom from pretreatment to posttreatment were summarized by treatment group, compared with respect to the percentage of patients showing either resolution or improvement, and analyzed using the Fisher exact test. Efficacy variables were further summarized and compared according to subgroup variables (eg, investigator site, sex, race, age, tobacco use, target pathogen) using the Cochran-MantelHaenszel test. The protocol specified performance of a secondary analysis based on stratification by corticosteroid use. Treatment-emergent adverse events were mapped using the Coding Symbols for Thesaurus of Adverse Reaction Terms

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CLINICAL THERAPEUTICS’

system.20 The incidence of drug-related adverse events was summarized by treatment group and compared using the Fisher exact test. Events associated with concurrent conditions were excluded.

RESULTS Patient Populations A total of 287 patients were randomized and treated. Of these, 142 patients were treated with extended-release claritbromycin and 145 patients were treated with amoxicillinklavulanate. There were no statistically significant differences between treatment groups in demographic characteristics (Table I). A small number of patients aged ~40 years (5 in the ex-

Table I. Baseline demographic

tended-release clarithromycin group and 6 in the amoxicillinklavulanate group) were approved for trial entry based on medical history. The protocol allowed enrollment of such patients as protocol variations, and inclusion of each of these patients was approved by the sponsor. Patients were well matched with respect to pretreatment presenting conditions, medical history, use of corticosteroids and other concomitant medications, and signs and symptoms of AECB. All patients presented with cough, and all but 1 presented with purulent or mucopurulent sputum; 98% of subjects presented with dyspnea and 86% with rhonchilwheezing. All patients had a history of COPD, and 30% had a history of asthma.

characteristics. Extended-Release Clarithromycin

Total treated Sex, no. (%) Female Male Age (Y) Mean f SD Range Weight (kg) Mean + SD Range Race, no. (%) White Other Smoking status, no. (%) Current smoker Former smoker Number of AECB episodes Mean + SD Range

in past

142

145

68 (48) 74 (52)

68 (47) 77 (53)

58.3 + 13.1 36-91

57.2+ 11.8 31-85

81.1 * 18.5 41-137

81.1 + 21.0 39-149

132 (93) 10 (7)

136 (94) 9 (6)

73 (51) 55 (39)

75 (52) 52 (36)

2.7 + 1.3 1-7

2.8 * 1.5

12 months

AECB = acute exacerbation of chronic bronchitis.

78

Amoxicillin/ Clavulanate

I-IO

A. ANZUETO ET AL.

Nine percent of patients (25/283) took oral corticosteroids before treatment, and 25% (721283) used inhaled corticosteroids before treatment. During treatment, 10% (28/283) took oral corticosteroids and 5% (141283) used inhaled corticosteroids. The treatment groups were comparable with respect to use of corticosteroids before and during treatment. Clinical outcomes were also comparable between patients who received inhaled or oral corticosteroids before or during treatment. The intent-to-treat population included 283 patients, 140 in the extended-release clarithromycin group and 143 in the amoxicillin/clavulanate group. Four patients (2 in each group) were excluded because they did not meet the criteria for AECB. A total of 270 patients were included in the clinically evaluable population, 137 in the extendedrelease clarithromycin group and 133 in the amoxicillin/clavulanate group. Three patients in the extended-release clarithromytin group and 10 in the amoxicillin/clavulanate group were excluded for confounding use of medications or occurrence of a confounding illness during the study, protocol violations, or mistiming or missing the endof-therapy or test-of-cure visit. A total of 121 patients were included in the clinically and bacteriologically evaluable population, 59 in the extended-release clarithromycin group and 62 in the amoxicillin/clavulanate group. Of the excluded patients, 153 (79 extended-release clarithromycin, 74 amoxicillin/clavulanate) had no protocol-defined target pathogen isolated at the pretreatment visit. Patients may have been excluded for >l reason.

Duration of Treatment and Adherence Seven percent (21/287) of treated patients discontinued treatment prematurely

for any reason. A between-group difference was observed with respect to discontinuation-3% (4/142) had been randomized to extended-release clarithromycin and 12% (17045) had been randomized to amoxicillin/clavulanate (P = 0.005). The most frequently reported reason for discontinuation of study drug was development of an adverse event (cited by 1% [2/142] of clarithromycin-treated patients and 6% [8/145] of amoxicillin/clavulanate-treated patients). The mean (2 SD) duration of therapy in patients receiving extended-release clarithromycin was 7.0 + 0.75 days; in patients receiving amoxicillin/clavulanate, it was 9.6 f 2.25 days. A statistically significantly higher percentage of patients treated with extended-release clarithromycin took ~80% of the prescribed medication compared with patients treated with amoxicillin/clavulanate (98% vs 88%, respectively; P = 0.001).

Clinical Response Among clinically evaluable patients, 85% (1171137) of those treated with extended-release clarithromycin and 87% (116/l 33) of those treated with amoxicillin/clavulanate were considered clinically cured. The 95% CI (-10.0 to 6.4) for the difference between clinical cure rates (extended-release clarithromycin - amoxicillin/clavulanate) among clinically evaluable patients demonstrated equivalence between the 2 treatments. Among clinically and bacteriologically evaluable patients, 86% (5 l/59) of the extended-release clarithromycin group and 87% (54/62) of the amoxicillin/clavulanate group were classified as clinically cured at the testof-cure visit (Table II). The results for the intent-to-treat population were similar to

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CLINICAL THERAPEUTICS”

Table II. Clinical

and bacteriologic

cure rates at the test-of-cure Extended-Release Clarithromycin, % (n/N)

Clinical cure rate Clinically evaluable 95% CI Clinically and bacteriologically evaluable 95% CI Bacteriologic cure rate Clinically and bacteriologically evaluable 95% CI

Amoxicillin/ Clavulanate, % (n/N)

85 (I 17/137) 78.4 to 90.8

87 (I 16/133) 80.3 to 92.4

86 (51/59) 75.0 to 94.0

87 (54/62) 76.1 to 94.3

92 (54159) 81.3 to 97.2

89 (55/62) 78. I to 95.3

those for the clinically evaluable population, although the absolute numbers were lower due to the counting as failures of patients with no data at the test-of-cure visit. Clinical cure rates at the test-of-cure visit were 84% (117/140) in the extendedrelease clarithromycin group and 81% (116/143) in the amoxicillinklavulanate group. After adjustment for subgroup variables (investigator, sex, race, age, body weight, overall clinical condition, infection status, number of AECB episodes in the past 12 months, study drug adherence, tobacco use, alcohol use), no statistically significant differences were noted between treatment groups. In addition, no statistically significant between-treatment differences were observed in clinically evaluable patients at the end-of-therapy or test-of-cure visit in terms of the percentage of patients showing resolution or improvement in pretreatment signs and symptoms of AECB (with the exception of volume of sputum production). At the end-of-therapy visit, there was a statistically significant difference in resolution or improvement

80

visit.

in the volume of sputum production between clinically evaluable patients treated with extended-release clarithromycin and those treated with amoxicillinklavulanate (85% vs 75%, respectively; P = 0.045). Bacteriologic

Response

In the intent-to-treat population, pretreatment cultures were positive for 21 of the protocol-defined target pathogens in 79 isolates from 61 clarithromycintreated patients and 81 isolates from 68 amoxicillinklavulanate-treated patients. Among clarithromycin-treated patients, 27% (21/79) of isolates were H influenzae, 27%

(21/79)

M catarrhalis,

19%

(15/79) S pneumoniae, 18% (14/79) H parainjkenzae, and 10% (W79) S aureus. Among amoxicillinklavulanate-

treated patients, 25% (20/81) of isolates were H influenzae, 19% (15/8 1) M catarrhalis, 20% (1618 1) S pneumoniae, 32% (26/S]) H parainfluenzae, and 5% (4/S]) S aureus.

Among clinically and bacteriologically evaluable patients, 92% (54/59) of those

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Table III. Bacterial eradication at the test-of-cure evaluable population).

visit (clinically

Extended-Release Clarithromycin, % (n/N) Pathogen eradication rate 95% CI Eradication rate, by protocol-defined Haemophilus influenzae Moraxella catarrhalis Streptococcus pneumoniae Haemophilus parainfluenzae Staphylococcus aureus

and bacteriologically

Amoxicillinl Clavulanate, % (n/N)

88 (68/77) 79.0 to 94.5

89 (67/75) 80.1 to 95.3

85 90 73 IO0 I00

95 86 79 96 67

pathogen

who received extended-release clarithromytin and 89% (W62) of those who received amoxicillinklavulanate had achieved bacteriologic cure at the test-of-cure visit (Table II). The overall pathogen eradication rate was similar in the 2 treatment groups: 88% (68/77) of isolates from patients treated with extended-release clarithromycin and 89% (67/75) of those from patients treated with amoxicillinklavulanate (Table III). The 95% CIs for the difference between bacteriologic cure rates (-7.8 to 13.4) and pathogen eradication rates (-11.0 to 9.0) demonstrated equivalence between the 2 treatments. After adjustment for subgroup efficacy variables, no statistically significant differences were noted between treatment groups. Isolates of H influenzue that had demonstrated pretreatment resistance to clarithromycin in vitro were eradicated, and patients achieved clinical cure. No isolate demonstrated resistance to amoxicillin/ clavulanate before treatment. In addition, 4 persistent isolates (3 from extended-release clarithromycin-treated patients, 1 from an amoxicillinklavulanate-treated patient) did not demonstrate resistance after treatment.

(17/20) ( 18/20) (I l/15) (14/14) (8/8)

(18/19) (12/14) (I l/14) (24/25) (2/3)

Bacteriologic failures among patients infected with S pneumoniae also were not the result of in vitro resistance, as all isolates of this organism were susceptible to both study drugs. Failures to achieve a bacteriologic response (4 in the extendedrelease clarithromycin group, 3 in the amoxicillinklavulanate group) were the result of superinfection or the persistence of a susceptible organism. Patients whose pretreatment isolates had demonstrated in vitro resistance achieved both clinical and bacteriologic cure in both treatment groups.

Safety Excluding events judged not related or probably not related to study drug, 21 adverse event was reported by 20% (28/142) of patients who received extended-release clarithromycin and 24% (35/145) of patients who received amoxicillinklavulanate. The most frequently occurring study drug-related adverse event in the 2 treatment groups was diarrhea, reported by 8% (12/142) of patients who received extended-release clarithromycin and 12%

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Table IV. Incidence

and severity of drug-related

treatment-emergent

Extended-Release Clarithromycin (n = 142) Adverse Event Diarrhea Altered taste Nausea Vaginitis Headache

Mild

Moderate

adverse events.

Amoxicillin/Clavulanate (n = 145)

Severe

Total (%)

Mild

Moderate

Severe

Total (%)

11

I

0

l2(8)

10

5

3

18 (12)

7 4 2 0

2 3 0 0

0 0 0 0

9 7 2 0

1 2 3 2

0 0 3 3

0 2 0 0

4 (3) 6 (4) 5 (3)

(6)* (5) (1) (0)

1 (1)

*P = 0.01 versus amoxicillin/clavulanate.

(18/145) of patients who received amoxicillin/clavulanate (Table IV). Altered taste, a known effect of clarithromycin, was more common (P = 0.01) among patients treated with extended-release clarithromycin (9/142 [6%]) than among those who received amoxicillin/clavulanate (l/l45 [l%]). There were, however, no premature discontinuations from the trial due to altered taste. The majority of adverse events were mild to moderate in severity. However, mean severity scores for gastrointestinal adverse events were statistically significantly different between treatment groups: the mean severity score in the extended-release clarithromycin group was 1.16, compared with 1.58 in the amoxicillin/clavulanate treatment group (P = 0.016) (Table IV). Adverse events accounted for a total of 10 premature discontinuations of study treatment, 6 (60%) due to gastrointestinal events. Two patients who had received extended-release clarithromycin discontinued treatment because of a gastrointestinal adverse event. Eight patients who had received amoxicillin/clavulanate discontinued treatment because of an adverse event: 4 with gastrointestinal adverse events, 1 with worsening bronchitis, 1

82

with chest pain and headache, 1 with dizziness and vertigo, and 1 with pruritus and urticaria. Eight patients reported serious adverse events that required hospitalization. Five of these patients had received extendedrelease clarithromycin and 3 had received amoxicillin/clavulanate. None of these serious adverse events were considered related to study drug.

DISCUSSION The present study was conducted to compare the rates of clinical cure, bacteriologic cure, and pathogen eradication achieved with 7 days’ treatment with extended-release clarithromycin versus 10 days’ treatment with amoxicillin/clavulanate. As anticipated, clinical cure, bacteriologic cure, and pathogen eradication rates were comparable in the 2 treatment groups. The 95% CI demonstrated that the 2 treatments were equivalent in terms of clinical and bacteriologic response and overall pathogen eradication. Interestingly, all isolates of H i&enzaethat had exhibited in vitro resistance before treatment were eradicated with clarithromycin treatment, and the patients

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achieved clinical cure. Persistent isolates of H influenzae did not demonstrate in vitro resistance to either study drug before or after treatment, and clarithromytin-treated patients with H injhenzae isolates that had demonstrated in vitro resistance before treatment were considered clinically cured. No patient in the amoxicillin/clavulanate group had a pretreatment isolate of H influenzae that was considered resistant to study drug. Similar results were noted for S pneumoniae isolates, as the patients who were considered bacteriologic failures had susceptible organisms pretreatment and failed treatment because of superinfection or persistence of susceptible organisms, whereas patients who had isolates that demonstrated resistance before treatment were clinically cured. Thus, in vitro susceptibility did not correlate with clinical outcome in this study. A statistically significant difference in adherence (280% of study drug taken) was observed between treatment groups. More patients in the extended-release clarithromycin group were adherent to their therapeutic regimen than were patients in the amoxicillin/clavulanate treatment group (98% vs 88%, respectively; P = 0.001). This measure of adherence to study regimen was required for inclusion in the clinically evaluable population. A minimum of 3 full days of therapy was required before a patient could be considered a clinical failure; less than this duration of therapy resulted in exclusion from the clinically evaluable population. Adverse events were generally mild to moderate with both extended-release clarithromycin and amoxicillin/clavulanate and occurred at comparable rates in the 2 groups. Most of the adverse events were related to the gastrointestinal tract. There

was a statistically significant difference in the severity of gastrointestinal adverse events, with extended-release clarithromytin-treated patients reporting a mean severity score of 1.16, compared with 1.58 in amoxicillin/clavulanate-treated patients (P = 0.016). As expected, altered taste was reported by a greater number of patients in the extended-release clarithromycin group, but this effect did not lead to premature discontinuation of treatment. Relative to those who received extended-release clarithromycin, 4 times as many patients in the amoxicillin/clavulanate treatment group discontinued treatment prematurely because of a drug-related adverse event (2 vs 8). The majority (60%) of these discontinuations were due to gastrointestinal adverse events (2/2 in the extended-release clarithromycin group, 4/8 in the amoxicillin/clavulanate group). It has been shown that gastrointestinal adverse events are less severe with the extended-release formulation of clarithromycin than with the original immediate-release, twice-daily formulation.‘” Similarly, the 875-mg, twice-daily formulation of amoxicillin/clavulanate has been shown to cause less-severe gastrointestinal adverse events than the 500-mg, three-times-daily formulation2’ Macrolide antibiotics are considered the first-line treatment for AECB. The immediate-release, twice-daily formulation of clarithromycin, an expanded-spectrum macrolide agent, has long been used for the treatment of a variety of infectious diseases, including upper respiratory tract infections, community acquired pneumonia, and AECB. This study evaluated a new matrix-type, extended-release formulation of clarithromycin requiring only once-daily administration, which has been developed and recently approved for use in treatment of AECB and acute maxillary

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sinusitis (AMS). I5 A pharmacokinetic study in adult subjects22 showed, as expected, that the extended-release formulation of clarithromycin had a statistically significantly lower peak concentration (P < 0.001) and a statistically significantly later time to peak plasma concentration (P < 0.001) compared with the immediate-release formulation (one 500-mg tablet twice daily), indicating that the new formulation provided extended release of clarithromycin in vivo. Furthermore, the 24-hour area under the concentration-time curve demonstrated equivalence between the 2 formulations. Two previous studies have assessed the use of the immediate- and extended-release formulations of clarithromycin in patients with AECB or AMS.i4,*” These studies supported the approval for marketing of the extended-release formulation of clarithromycin in the treatment of AECB and AMS.‘” The use of clarithromycin in these contexts is in accordance with the recent trend toward shorter courses of antimicrobial therapy and, when possible, fewer daily doses.“~‘3.24

CONCLUSIONS The results of the present study indicate that the clinical and microbiologic efficacy of 7 days’ treatment with an extended-release formulation of clarithromycin are comparable to those of 10 days’ treatment with amoxicillin/clavulanate in patients with AECB. The incidence of drug-related adverse events was similar in the 2 treatment groups, with the exception of a statistically significantly higher rate of altered taste in the extended-release clarithromycin group. A significantly higher rate of premature discontinuations of study drug and significantly higher

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mean severity scores for gastrointestinal adverse events were observed with amoxicillin/clavulanate compared with extended-release clarithromycin. This study confirms the efficacy of a 7-day course of extended-release clarithromycin and supports its use in the treatment of patients with AECB.

ACKNOWLEDGMENTS Investigators who enrolled patients for this study included the following: Jay Adler, Colorado Springs, Colorado; Jeffrey Aoki, Fresno, California; Jose Armonio, Pawleys Island, South Carolina; Robert Baughman, Cincinnati, Ohio; George Bensch, Stockton, California; Emilio Berberabe, Jr., Las Vegas, Nevada; David Bowton, Winston-Salem, North Carolina; Shari Brazinsky, San Diego, California; Thomas Chiambretti, Dewitt, Michigan; Howard Chipman III, Palm Harbor, Florida; David Claassen, Ozark, Alabama; Naresh Dewan, Omaha, Nebraska; Amin Elashker, Kingston, New York; Robert Emerson, Austin, Texas; Chester Fisher, Newport News, Virginia; Mark Fraley, Colorado Springs, Colorado; Harry Geisberg, Greer, South Carolina; Tadeusz Glinkowski, Houston, Texas; Vina Gohill, Longwood, Florida; W. Manford Gooch III, Salt Lake City, Utah; Richard Hall, Mount Sterling, Kentucky; Mark Harrison, Berrien Center, Michigan; Thomas Hartley, Scottsdale, Arizona; James Hedrick, Bardstown, Kentucky; Joellen Heims, Des Moines, Iowa; William Jannetti, Buena Park, California; Amal Jubran, Hines, Illinois; William Keating, Scotland, Pennsylvania; Richard Krause, Chattanooga, Tennessee; Neil Levine, San Diego, California; Jerry Miller, Kingsport, Tennessee; Timothy Moriarty, Panama

A. ANZUETO ET AL.

City, Florida; William Morowitz, Cherry Hill, New Jersey; Anjulu Nayak, Normal, Illinois; Tom Nolen, Columbiana, Alabama; Douglas Owens, Greer, South Carolina; Mehul Patel, Palm Harbor, Florida; Mahfooz Peshimam, Corona, California; Albert Razzetti, DeLand, Florida; Mark Rosenthal, Miami, Florida; Alan Safdi, Cincinnati, Ohio; Ronald Saff, Tallahassee, Florida; Deepak SantRam, West Grove, Pennsylvania; Eric Schenkel, Easton, Pennsylvania; Jon Schmidt, Lakewood, Washington; David Schneider, Metairie, Louisiana; James Schrenker, Bristol, Tennessee; Sanjay Sethi, Buffalo, New York; William Sokol, Newport Beach, California; Malcolm Sperling, Fountain Valley, California; Roger Steinbrenner, Grants Pass, Oregon; John Sutherland, Waterloo, Iowa; Stuart Topkis, Warminster, Pennsylvania; Charles White, Milan, Tennessee; and Michael Ziter, Cadillac, Michigan.

Address correspondence to: Antonio Anzueto, MD Associate Professor of Medicine Division of Pulmonary Diseases/Critical Care Medicine University of Texas Health Science Center at San Antonio 7703 Floyd Curl Drive San Antonio, TX 78284-7885 E-mail: [email protected]

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