Azithromycin versus Pivampicillin in the Treatment of Acute Exacerbations of Chronic Bronchitis: a Single-blind, Doubledummy, Multicentre Study

Transcription

1 M Nomura, S Kida, J Yamashita The Journal et al. of International Medical Research Endovascular 2000; 28: Embolization of Unruptured Vertebral Dissection Azithromycin versus Pivampicillin in the Treatment of Acute Exacerbations of Chronic Bronchitis: a Single-blind, Doubledummy, Multicentre Study P SCHOUENBORG 1, N GERDES 2, HH RASMUSSEN 3, N WICKERS-NIELSEN 4 AND E MATHIASSEN 5 1 Department of Microbiology, Vejle Hospital, Vejle, Denmark; 2 Gothersgade 59, Frederica, Denmark; 3 Sæbyvej 17, Asaa, Denmark; 4 sterå 17, Aalborg, Denmark; 5 Rådhustorvet 4, Vejle, Denmark This single-blind, double-dummy, multicentre study compared oral azithromycin, administered as tablets, 500 mg once daily for 3 days, versus oral pivampicillin, 700 mg twice daily for 10 days, in adults with acute exacerbations of chronic bronchitis (not needing parenteral antibiotic therapy, hospitalization or oxygen support). Clinical success (cure + improvement) rates were similar for both groups at the end of treatment (day 10; azithromycin, 124 of 133 [93%]; pivampicillin, 79 of 92 [86%]) and at follow-up (day 52; 98 of 126 [78%] versus 66 of 81 [81%]). The treatments produced similar levels of pathogen eradication at the end of treatment (49 of 54 [91%] versus 32 of 37 [86%]). Azithromycin-treated patients had significantly reduced chest discomfort at the end of treatment, and a trend towards improved lung function. The two groups were similar with respect to improvements in other clinical symptoms and patient well-being, and to the incidences of adverse events and treatment discontinuations. This oral azithromycin regime is an effective treatment for acute exacerbations of chronic bronchitis, similar in efficacy to the longer pivampicillin regime and may offer superior patient compliance. KEY WORDS: AZITHROMYCIN; PIVAMPICILLIN; ANTIBACTERIAL DRUGS; EXACERBATIONS OF CHRONIC BRONCHITIS; CHRONIC BRONCHITIS; PATIENT COMPLIANCE 101

2 INTRODUCTION The incidence of chronic obstructive pulmonary disease (COPD) in developed countries has increased sharply in recent decades. This disease is now the fifth leading cause of mortality and, with acute lower respiratory tract infections, the leading burden of disease among member states of the World Health Organization. 1 Chronic bronchitis is an important element of COPD and occurs frequently in both male and female patients of all ages. The clinical course of chronic bronchitis includes periodic exacerbations, which may be of infective (e.g. bacterial, viral) or noninfective (e.g. chemical agent) origin. Patients typically experience a median of three acute exacerbations per year, 2,3 up to 50% of which are bacterial in origin. 4,5 The most frequently reported causative organisms in acute bacterial exacerbations of chronic bronchitis (AECB) include Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, 6,7 which account for 85 95% of cases. 6 Other pathogens include haemolytic streptococci, Staphylococcus aureus and Gram-negative enteric bacilli. 7 Recent years have witnessed an increased awareness of the involvement of the atypical pathogens, Mycoplasma pneumoniae, Legionella species and Chlamydia pneumoniae, in AECB 6 and, to a greater extent, in community-acquired pneumonia. 8,9 A meta-analysis of randomized trials published up to 1994 indicated that there are significant advantages to be gained from the use of antimicrobial therapy in patients with AECB. 10 Patients classified as having AECB of Anthonisen Type 1 severity (defined as increases in dyspnoea, sputum volume and sputum purulence) were shown to benefit from treatment. 11 A 7 10-day course of broad-spectrum antibiotic therapy is normally recommended for AECB. 11 Conventional treatment options include trimethoprim/sulfamethoxazole and aminopenicillins (ampicillin, amoxycillin or amoxycillin/clavulanic acid) or erythromycin (in patients hypersensitive to penicillins). 7 Alternative treatments include various oral cephalosporins (such as cefuroxime axetil and cefprozil) and newer macrolides (azithromycin and clarithromycin), 7 which, unlike β-lactam antibiotics, are effective against atypical pathogens. Pivampicillin, an ampicillin ester, is better absorbed than ampicillin 12 and attains higher serum levels at comparable doses. 13 Clinical studies have demonstrated that the clinical efficacy of pivampicillin, administered twice or three times daily, is comparable with that of oral ofloxacin in treating purulent AECB, 14 and superior to that of amoxycillin in treating acute bronchitis. 15,16 Multiple daily doses 17 and longer (> 7 days) duration of treatment 18 are risk factors for poor patient compliance with medication, however, so the need remains for antibiotic agents that afford effective therapy with once-daily dosing and a short duration of treatment. The azalide azithromycin is structurally related to erythromycin. 19,20 The in vitro antimicrobial spectrum of azithromycin is superior to that of erythromycin and includes S. pneumoniae, H. influenzae and M. catarrhalis, as well as the atypical respiratory pathogens. 21 In addition, the unique pharmacokinetic profile of azithromycin, which includes phagocytemediated delivery to sites of infection, 22 leads to high respiratory tissue concentrations. 23,24 As a result, the intracellular levels of azithromycin exceed its minimum inhibitory concentrations against respiratory pathogens for up to 8 days, 25 enabling effective, short-duration therapy with once-daily dosing. 20 Clinical 102

3 studies have shown that a 3-day course of once-daily oral azithromycin is as effective clinically as other more frequently administered antibacterial agents across a range of indications, including respiratory tract infections. 20 In addition, azithromycin has an excellent tolerability/safety profile in adults and children. 26 A study was therefore conducted to compare oral azithromycin, 500 mg once daily for 3 days, versus oral pivampicillin, 700 mg twice daily for 10 days, in the treatment of patients with AECB. The study drugs were evaluated for clinical and microbiological efficacy, frequency of relapse within 6 weeks of initiation of therapy, and safety and tolerability. PATIENTS AND METHODS STUDY DESIGN This randomized, single-blind, doubledummy, comparative study was performed in 47 Danish general practices. Written informed consent was obtained from all patients entering the study. Eligible patients comprised ambulatory men or women, 18 years old (with no upper age limit), with chronic bronchitis (defined as daily coughing and expectoration for more than 3 months within a 1-year period, and for 2 consecutive years without any other proven pulmonary disease) 27 and with an acute exacerbation (indicated by two or more of the following: increase in dyspnoea, increase in coughing and expectoration, body temperature > 38.5 C). Before initiation, the study was approved by the Danish National Board of Health and the Scientific Ethical Committee of Funen and Vejle. Criteria for exclusion from study entry included: suspected pneumonia; need for parenteral antibiotic therapy; need for hospitalization and/or oxygen support; terminal illness or other conditions precluding completion of the study or clinical evaluation; known hypersensitivity to macrolides or penicillins; pregnancy or lactation (women of child-bearing potential were required to use adequate contraception); treatment with another antimicrobial agent within 2 weeks (or with any investigational drug within 4 weeks) of study entry; concomitant treatment with carbamazepine, cyclosporine, digoxin or ergotamine; clinically significant hepatic or renal diseases (liver function tests more than twice the upper limit of normal, and serum creatinine level > 200 µmol/l); and any gastrointestinal disturbance that might affect study drug absorption. Eligible patients who entered the study at baseline (day 0) were randomized, using Geigy s random numbers, to receive one of two treatments: azithromycin 500 mg active tablets, once daily for 3 days, plus pivampicillin placebo tablets, twice daily for 10 days; or pivampicillin 700 mg active tablets, twice daily for 10 days, plus azithromycin placebo tablets, once daily for 3 days. Treatment was followed by a period of 42 days during which no antibiotic treatment was allowed. The study drugs were supplied to the investigators in study-specific medicine dispenser boxes, each labelled in accordance with Danish Health Authority Regulations for clinical drug supplies. A difference in the colour of pivampicillin active (white) and placebo (yellow white) tablets meant that treatment was blinded only with respect to the patients. Patients were assessed at baseline, at the end of treatment (day 10) and at follow-up (day 52) for medical history (baseline only), lung function, and clinical signs and symptoms of AECB (dyspnoea, cough, chest pain, expectoration, stethoscopic auscultation, body temperature and sputum colour and/or consistency). Venous blood samples were obtained at baseline and at the end of treatment. 103

4 Sputum samples were obtained at baseline, at the end of treatment and at follow-up. Patient compliance with medication was monitored at the end of treatment by counting tablets and recording patient information on tablet intake. Patients with < 80% compliance were excluded from the assessment of clinical efficacy, but were included in safety and tolerability evaluations. ASSESSMENT OF CLINICAL EFFICACY Clinical efficacy at the end of treatment and at follow-up was classified as cure (resolution of signs and symptoms to levels that existed before the exacerbation), improvement (resolution of fever but incomplete resolution of the other signs and symptoms of the exacerbation), failure (lack of resolution of any signs or symptoms or a need for additional antibiotic therapy), relapse (follow-up only; failure in a patient classified as cure or improvement at the end of treatment) or unevaluable. Lung function was evaluated by measuring the peak expiratory flow rate (PEFR; best of three measurements) using the Wright Peak Flow Meter (Clement Clarke, UK). Dyspnoea, cough, chest pain and expectoration were each assessed using a four-point scale (0 = not present, 1 = mild, 2 = moderate and 3 = severe). Sputum colour and/or consistency was graded as clear, white, purulent or brownish/reddish. Each patient was asked to complete two diaries (one for the treatment period and one for the follow-up period), and was trained in the use of the Wright Peak Flow Meter. Patients were asked to record their PEFR (twice daily during treatment, once weekly during followup; best result of three measurements), body temperature (once daily), expectoration (once daily, assessed as normal, improved, unchanged or worse) and well-being (once daily, assessed as normal, improved, unchanged or worse). Patient well-being was evaluated according to the time between baseline and the patient s first report of normal well-being (10 days, if no report of normal wellbeing was recorded at the end of treatment). ASSESSMENT OF BACTERIOLOGICAL EFFICACY Sputum samples were examined microscopically for the presence of bacteria, columnar cells and leucocytes, and by culture (2 days, 35 C) using 5% blood agar plates. Bacteriological efficacy at the end of treatment was classified as: eradication (absence of baseline pathogen); presumptive eradication (absence of adequate culturable material from a patient exhibiting clinical cure or improvement); improvement (eradication of some but not all baseline pathogens); persistence (presence of baseline pathogen); colonization (presence of pathogen not identified at baseline); superinfection (presence of pathogen not identified at baseline, associated with emergence or worsening of infection requiring antibiotic therapy); or unevaluable. No serology tests were performed. SAFETY ASSESSMENT Details of all adverse events, treatment discontinuations and clinical laboratory test results were recorded for patients receiving at least one dose of study drug. Venous blood samples were assayed for alkaline phosphatase, aspartate aminotransferase, bilirubin, creatinine, haemoglobin and leucocytes. STATISTICAL ANALYSIS Baseline, efficacy and safety data were analysed for differences between treatment groups. All statistical analyses were performed on an intention-to-treat basis and with a significance level of 5%. Patients who did not attend assessment at the end of treatment were excluded from primary evaluation. For quantitative data that were apparently normally distributed, the null hypothesis of no difference between means was tested using 104

5 Student s t-test. For data that were not normally distributed, the null hypothesis that the two samples were derived from the same population was tested using the Mann Whitney U-test. Treatment effect on PEFR was assessed by analysis of variance for repeated measures with unstructured covariances. 6 A null hypothesis for no difference between treatments was tested using the χ 2 test with a row-effects model. For qualitative data with two levels of outcome, a standard χ 2 test in 2 2 tables was used to test the null hypothesis that outcome was independent of treatment. Response categories were analysed by combining categories to generate 2 2 tables (clinical efficacy at end of treatment: cure versus improvement + failure; clinical efficacy at follow-up: cure versus improvement + relapse + failure; bacteriological efficacy at end of treatment: eradication or eradication + presumed eradication versus improvement + persistence + colonization). If one or more of the expected cell counts was less than five, Fisher s exact test was used. For outcomes with c (> 2) ordered levels, a log-likelihood test for independence, given that a row-effects model holds, was applied. 28 Patient well-being data were analysed using the log-rank test for survival data. RESULTS BASELINE CHARACTERISTICS Of 239 patients enrolled, 236 were randomized to treatment. Baseline characteristics and prognostic factors were generally similar in the two treatment groups (Table 1). A high proportion of patients in each treatment group had increased dyspnoea and increased coughing and expectoration; fewer patients in each group had an elevation in body temperature. The randomization of patients was skewed, however, due to intercentre variations in patient enrolment (azithromycin, 138; pivampicillin, 98; P = 0.011). In addition, the proportion of patients who were atopic was statistically TABLE 1 Characteristics and prognostic factors at baseline assessment in patients with acute exacerbations of chronic bronchitis Azithromycin a Pivampicillin b (n = 138) (n = 98) Mean age (range, years) 59.4 (26 87) 61.0 (20 85) Male (%) Weight (kg) Increase in dyspnoea (%) Increase in coughing and expectoration (%) Body temperature > 38.5 C (%) Peak expiratory flow rate (l/min) a 500 mg once daily. b 700 mg twice daily. 105

6 significantly lower for the azithromycin group than for the pivampicillin group (1.5% versus 12.1%; P < 0.001). CLINICAL EFFICACY The clinical success (cure or improvement) rate for azithromycin-treated patients (124 of 133, 93%) did not differ from that for pivampicillintreated patients (79 of 92, 86%) at the end of treatment (P > 0.05; Table 2). The clinical efficacy outcome for atopic patients was no different from that for non-atopic patients (data not shown). At follow-up, there was no statistically significant difference in clinical success rate between treatment groups (azithromycin, 98 of 126, 78%; pivampicillin, 66 of 81, 81%; P > 0.5; Table 2). The frequency of clinical relapse at follow-up was comparable for the two treatment groups (azithromycin, 22 of 126, 17%; pivampicillin, 11 of 81, 14%; P > 0.5). BACTERIOLOGICAL EFFICACY At the end of treatment, no statistically significant differences between treatment groups were observed with regard to bacteriological efficacy (eradication versus improvement + persistence + colonization, P > 0.05; eradication + presumed eradication versus improvement + persistence + colonization, P > 0.05; Table 3). Very few patients were able to produce a sputum specimen at follow-up; therefore, no analysis for this timepoint was performed. CLINICAL SIGNS AND SYMPTOMS For dyspnoea, cough, expectoration, sputum colour, sputum consistency and body temperature, no statistically significant differences between groups in the change in severity from baseline were observed, either at the end of treatment or at the end of the study (P > 0.05). The reduction in severity of chest discomfort was statistically significantly greater for azithromycin than for pivampicillin at the end of treatment (P = ); the two groups were comparable at follow-up (P = 0.22). Diary-card analysis showed that there was no significant difference in subjective improvement in patient TABLE 2 Clinical efficacy at end of treatment and at follow-up 42 days later (evaluable patients) in patients with acute exacerbations of chronic bronchitis treated with azithromycin (500 mg once daily) or pivampicillin (700 mg twice daily) No. (%) of patients End of treatment Follow-up Azithromycin Pivampicillin Azithromycin Pivampicillin (n = 133) (n = 92) (n = 126) (n = 81) Cure 40 (30%) 32 (35%) 63 (50%) 42 (52%) Improvement 84 (63%) 47 (51%) 35 (28%) 24 (30%) Success (cure + improvement) 124 (93%) 79 (86%) 98 (78%) 66 (81%) Relapse NA NA 22 (17%) 11 (14%) Failure 9 (7%) 13 (14%) 6 (5%) 4 (5%) NA, not applicable. 106

7 TABLE 3 Bacteriological efficacy at end of treatment (day 10; evaluable patients) in patients with acute exacerbations of chronic bronchitis treated with azithromycin (500 mg once daily) or pivampicillin (700 mg twice daily) No. (%) of patients Azithromycin Pivampicillin (n = 54) (n = 37) Eradication 36 (67%) 26 (70%) Presumed eradication 13 (24%) 6 (16%) Eradication + presumed eradication 49 (91%) 32 (86%) Improvement 0 1 (3%) Persistence 3 (6%) 3 (8%) Colonization 1 (2%) 1 (3%) Superinfection 1 (2%) 0 well-being (time to normalization) between the two treatments (P = 0.95). A trend (P = 0.052) towards a higher PEFR for azithromycin-treated patients compared with pivampicillin-treated patients was observed throughout the study; no significant differences in response were noted between treatment groups. SAFETY AND TOLERABILITY A total of 15 azithromycin- and 19 pivampicillin-treated patients withdrew from the study. Reasons for withdrawal included: adverse events (azithromycin, four patients; pivampicillin, five patients); conflicting concomitant medication (two and three patients, respectively); poor compliance (one patient in each group); loss to follow-up (two and four patients, respectively); and clinical failure (three patients in each group). There was no significant difference in withdrawal rates between the two treatment groups. The incidences of adverse events and treatment discontinuations were comparable for the two treatment groups. Of 138 patients randomized to treatment with azithromycin, 54 (39%) experienced at least one adverse event of any causality and 20 (14%) experienced at least one treatment-related adverse event. The corresponding values for pivampicillin-treated patients (n = 98) were 46 (47%) and 22 (22%). The most frequently reported treatment-related adverse events were diarrhoea (5%) and abdominal pain (5%) in the azithromycin group, and diarrhoea (11%) and nausea (3%) in the pivampicillin group. The rates of treatment discontinuation due to treatment-related adverse events were three of 138 (2%) for azithromycin and five of 98 (5%) for pivampicillin; the difference between treatment groups was not statistically significant. The treatment-related adverse events leading to withdrawal were rash, vomiting and diarrhoea for the azithromycin group, and diarrhoea, nausea, vomiting, stomatitis, weakness, gastritis and urticaria for the pivamipicillin group. 107

8 DISCUSSION β-lactam antibiotics have been used extensively to treat AECB. Their usefulness as empirical therapy is limited by increased β-lactamase production among causative pathogens, and by poor activity against the atypical respiratory pathogens. 29 In Denmark, there is a low incidence (< 1%) of penicillin resistance among S. pneumoniae strains. 30 The emergence of multiple daily dosing as a risk factor for patient non-compliance with medication 17,31 has increased the interest in finding simplified courses of antibiotic therapy that allow patient compliance to be optimized. Pivampicillin has a pharmacokinetic profile superior to that of ampicillin, and has demonstrated good clinical and bacteriological efficacy in the treatment of AECB. It must, however, be administered two or three times daily In contrast, azithromycin is notable for its good clinical efficacy achievable with a simple dosing regimen, comprising once-daily dosing for only 3 days. A study to provide a direct comparison between pivampicillin and azithromycin treatment regimens was therefore considered both useful and appropriate. The study was designed to have two treatment arms with equal numbers of patients. In fact, randomization was skewed such that more patients were treated with azithromycin. This reflected inter-centre variations in the numbers of patients enrolled and the distribution of patients between treatments in these centres, but it did not prevent statistical analysis of the difference in efficacy and/or safety between the two treatments. The two treatments were comparable with respect to clinical efficacy at the end of treatment and at follow-up. The clinical success rate for azithromycin at the end of treatment, which was in excess of 90%, is consistent with that observed across a number of published, comparator-controlled studies of azithromycin in the treatment of approximately 1000 patients with AECB (Pfizer Inc., data on file). The success rate for pivampicillin at end of treatment in the present study is lower than that reported previously among patients receiving pivampicillin 700 mg administered three times daily. 14 The present study used a dosing regimen of pivampicillin 700 mg administered twice daily, as recommended by the manufacturer. This study is noteworthy for its long follow-up period of 42 days after treatment. The clinical success rates recorded for both drugs at follow-up are impressive, given the considerable opportunity for relapse between the end-of-treatment and follow-up assessments. Azithromycin and pivampicillin also exhibited comparable bacteriological efficacy at the end of treatment. The pathogen eradication rate for azithromycin compares favourably with that observed in previously reported studies (79%; Pfizer Inc., data on file). The eradication rate for pivampicillin is lower than that reported 14 for patients receiving pivampicillin three times daily. In the present study, lung function and the clinical signs and symptoms of AECB tended to improve more rapidly for patients receiving azithromycin. This trend reached statistical significance for chest pain at end of treatment but not at follow-up. The subjective assessment of patient well-being using patient diary cards was an unusual feature of the study protocol, and provided a measure of the rate of improvement in clinical symptoms with time. In this study, its use was limited to the treatment period but extensions of the assessment to the full study period would be worth considering for future studies. Both treatment groups exhibited a high incidence of adverse events due to all causes, as expected for a study involving a long follow-up period. The adverse-event profile of azithromycin reported in this study is in agreement with the safety database drawn 108

9 from clinical trials with azithromycin. 26 Overall, the results of this study indicate that oral azithromycin is equivalent to oral pivampicillin in terms of clinical and bacteriological efficacy, as well as safety, and is an effective treatment for AECB. The simple, short-duration dosing regimen of azithromycin may, however, offer the opportunity to optimize patient compliance. ACKNOWLEDGEMENT This study was supported by a grant from Pfizer A/S, Denmark. REFERENCES 1 World Health Organization: The World Health Report 1999 Making a Difference. Geneva: World Health Organization, Niederman MS: Acute exacerbations of chronic bronchitis: the role of infection and the selection of appropriate therapy. Pulm Crit Care Update 1996; 11: Ball P, Harris J, Lowson D, et al: Acute infective exacerbations of chronic bronchitis. QJM 1995; 88: Chodosh S: Treatment of acute exacerbations of chronic bronchitis: state of the art. Am J Med 1991; 91: 87S 92S. 5 Fagon J, Chastre J, Trouillet J, et al: Characterization of distal bronchial microflora during acute exacerbation of chronic bronchitis. Use of the protected specimen brush technique in 54 mechanically ventilated patients. Am Rev Respir Dis 1990; 142: Ball P: Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest 1995; 108: 43S 52S. 7 Reynolds HY: Chronic bronchitis and acute infectious exacerbations. In: X. Principles and Practice of Infectious Diseases, 4th edn (Mandell GL, Bennett JE, Dollin R, eds). New York: Churchill Livingstone, 1995; pp File TM, Jr, Tan JS: Incidence, etiologic pathogens, and diagnostic testing of community-acquired pneumonia. Curr Opin Pulm Med 1997; 3: Feldman C: Severe community-acquired pneumonia. Curr Opin Pulm Med 1997; 3: Saint S, Bent S, Vittinghoff E, et al: Antibiotics in chronic obstructive pulmonary disease exacerbations: a metaanalysis. JAMA 1995; 273: Anthonisen N, Manfreda J, Warren C, et al: Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987; 106: Maesen F, Davies B: A clinical comparison of ampicillin, ampicillin esters (bacampicillin and pivampicillin) and amoxycillin in acute exacerbations of chronic bronchitis. Infection 1979; 7: S483 S Neu H: Aminopenicillins clinical pharmacology and use in disease states. Int J Clin Pharmacol Biopharm 1975; 11: Egede F, Kristensen I: A clinical comparative study of ofloxacin and pivampicillin in acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1988; 22: Moran D: A multicentre general practice study comparing pivampicillin (Pondocillin) and amoxycillin (Amoxil) in respiratory tract infections. J Int Med Res 1983; 11: Admani A, Somasundrum U, Singh I: The management of elderly patients with acute lower respiratory tract infections: a comparison of pivampicillin and 109

10 amoxycillin. Curr Med Res Opin 1985; 9: Ballow CH: Cost considerations in oral antibiotic therapy. Adv Ther 1995; 12: Grob PR: Antibiotic prescribing practices and patient compliance in the community. Scand J Infect Dis Suppl 1992; 83: Fiese EF, Steffen SH: Comparison of the acid stability of azithromycin and erythromycin A. J Antimicrob Chemother 1990; 25: Dunn C, Barradell L: Azithromycin: a review of its pharmacological properties and use as 3-day therapy in respiratory tract infections. Drugs 1996; 51: Pontani D, Washton H, Bouchillon S, et al: Susceptibility of European respiratory tract isolates to trovafloxacin, ciprofloxacin, clarithromycin, azithromycin and ampicillin. Eur J Clin Microbiol Infect Dis 1998; 17: Gladue RP, Bright GM, Isaacson RE, et al: In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection. Antimicrob Agents Chemother 1989; 33: Gemmell C: Macrolides and host defences to respiratory tract pathogens. J Hosp Infect 1991; 19: Andrews JM, Honeybourne D, Brenwald NP, et al: Concentrations of trovafloxacin in bronchial mucosa, epithelial lining fluid, alveolar macrophages and serum after administration of single or multiple oral doses to patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother 1997; 39: Foulds G, Shepard RM, Johnson RB: The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 1990; 25: Hopkins SJ: Clinical toleration and safety of azithromycin in adults and children. Rev Contemp Pharmacother 1994; 5: Medical Research Council s Committee on the Aetiology of Chronic Bronchitis: Definition and classification of chronic bronchitis for clinical and epidemiological purposes. Lancet 1965; i: Diggle PJ, Liang K-Y, Zeger SL, et al: Analysis of Longitudinal Data. Oxford: Clarendon Press, Pechère JC, Gootz TD: Bacteriological activity of trovafloxacin, a new quinolone, against respiratory tract pathogens. Eur J Clin Microbiol Infect Dis 1998; 17: Laursen SB, Konradsen HB: Group B streptococcal infections in adults. Ugeskr Laeger 1997; 159: Cockburn J, Gibberd RW, Reid AL, et al: Determinants of non-compliance with short-term antibiotic regimens. BMJ 1987; 295: P Schouenborg, N HH Rasmussen, N Wickers-Nielsen and E Mathiassen Azithromycin versus Pivampicillin in the Treatment of Acute Exacerbations of Chronic Bronchitis: a Single-blind, Double-dummy, Multicentre Study The Journal of International Medical Research 2000; 28: Received for publication 6 April 2000 Accepted 11 April 2000 Copyright 2000 Cambridge Medical Publications Address for correspondence DR P SCHOUENBORG Department of Microbiology, Vejle Hospital, Kabbeltoft 25, DK-7100, Vejle, Denmark. 110