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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 T Schaberg, I Ballin, G Huchon, H Bassaris, B Hampel, P Reimnitz and The AECB Study Group Journal of International Medical Research 2001 29: 314 DOI: 10.1177/147323000102900408 The online version of this article can be found at: http://imr.sagepub.com/content/29/4/314

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The Journal of International Medical Research 2001; 29: 314 – 328

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 T SCHABERG1, I BALLIN2, G HUCHON3, H BASSARIS4, B HAMPEL5, P REIMNITZ5 AND THE AECB STUDY GROUP 1

Lungenklinik, Diakoniekrankenhaus, Rotenburg, Germany; 2Pendlebury Health Centre, Pendlebury, Manchester, UK; 3Hotel-Dieu, Notre Dame, Paris, France; 4 University Hospital Medical School, Rion GR, Patras, Greece; 5Bayer Vital GmbH & Co KG, Leverkusen, Germany

The aim of this study was to compare the efficacy and safety of once daily dosing with moxifloxacin (BAY 12-8039) with that of coamoxiclav given three times daily for the treatment of acute exacerbation of chronic bronchitis (AECB). Moxifloxacin (one 400 mg tablet daily) was administered orally for 5 days and co-amoxiclav (three 625 mg tablets daily) was given orally for 7 days. The study was randomized, non-blinded, multinational (12 countries) and multicentre (68 centres). A total of 575 patients, all with clear signs of AECB, were treated, 292 with moxifloxacin and 283 with co-amoxiclav. Of these, 512 patients were evaluable for efficacy (261 in the moxifloxacin group and 251 in the co-amoxiclav group). The primary efficacy parameter was clinical response at 14 days in the evaluable population. A clinical success was classified as resolution or

improvement of symptoms. Variables used to assess clinical response included wheeze, cough, dyspnoea, sputum volume, rales and rhonchi. The success rate for moxifloxacin in the evaluable patients was 96.2% and that for co-amoxiclav was 91.6%. The 95% confidence intervals for this difference (0.4%; 8.7%) indicate equivalence in the treatments. Sputum samples were taken from patients and 140 of these contained a pathogen, Haemophilus influenzae being the most frequently isolated. Moraxella catarrhalis and Streptococcus pneumoniae were also commonly isolated pathogens. The eradication rate at 14 days in the evaluable patients was 87.7% in the moxifloxacin group and 89.6% in the coamoxiclav group. Both drugs were well tolerated with no significant differences in the numbers of drug-related adverse events or the numbers of patients

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T Schaberg, I Ballin, G Huchon et al. Moxifloxacin versus co-amoxiclav in AECB

withdrawing because of an adverse event. These results and the broad spectrum of antibacterial activity make moxifloxacin a

promising and safe alternative to conventional therapy for the empirical treatment of AECB.

KEY WORDS: MOXIFLOXACIN; CO-AMOXICLAV; CHRONIC BRONCHITIS; BACTERIAL ORAL THERAPY; SAFETY

Introduction Chronic bronchitis is a major cause of morbidity and mortality worldwide, with considerable economic impact.1,2 In addition, the disease has a considerable physical and psychological impact on patients, with adverse effects on their quality of life.3 Despite the prevalence of the disease, the pathophysiological mechanisms underlying chronic bronchitis are not understood completely.4,5 The disease is characterized by an inflammation of the bronchial mucosa and a remodelling of the peripheral airways. This can be initiated and aggravated by various factors, including smoking, exposure to pollutants and allergens in the atmosphere and microbial infection.1,4 The inflammation leads to ciliary dysfunction, which in turn triggers excessive bronchial secretions. Smoking and pollutants have also been shown to inhibit ciliary function6 and various respiratory pathogens, including Haemophilus influenzae and Streptococcus pneumoniae, can impair mucosal clearance mechanisms, both directly and indirectly.2,7 Acute respiratory infections and exacerbations of chronic bronchitis can accelerate declining respiratory function in already damaged airways,8,9 and can cause acute or chronic lung injury.5 Chronic bronchitis is defined clinically as ‘chronic or recurrent cough with excess sputum production’ and epidemiologically as a minimum of ‘cough and sputum persisting for 3 months in the previous 2 years’.10 Patients with chronic bronchitis

INFECTION;

may experience several acute infectious exacerbations of their disease in a year, particularly during the winter months. The commonest cause of an infectious exacerbation is of bacterial origin, although viral infections may also occur.5,11 Acute exacerbations are characterized by an increase in coughing, a change in the purulence of the sputum, an increase in the volume of sputum and worsening dyspnoea.2,5,12 In acute bacterial exacerbations of chronic bronchitis, bacteria are present in the sputum in large numbers.1 The organism most commonly occurring in these exacerbations is H. influenzae, with Moraxella catarrhalis and S. pneumoniae also frequently being implicated.1,4,5,9,13 It is standard practice in most countries to prescribe antibiotics for acute bacterial exacerbations of chronic bronchitis; however, this practice is controversial as benefits from antibacterial therapy cannot always be demonstrated1,13,14 and organisms can be isolated frequently from the sputum of patients between exacerbations.15 More detailed studies, however, have indicated the type of patients who may benefit from antibacterial therapy. Anthonisen et al.16 treated over 362 cases of AECB and showed a significant benefit associated with antibiotics. The benefit was greatest in those patients with increased sputum volume, increased dyspnoea and increased sputum purulence. When only one of these symptoms was present, the success rates for antibiotic and placebo were less pronounced.

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T Schaberg, I Ballin, G Huchon et al. Moxifloxacin versus co-amoxiclav in AECB Similarly, Saint et al.17 concluded from a meta-analysis of a number of studies that the use of antibacterials produced a slight, but clinically significant effect which was most marked in hospitalized and the more seriously ill patient. These findings have led to the generally accepted view that mildly ill patients with AECB should not be included in clinical trials of antibacterials as they are unlikely to benefit from therapy. Effective treatment of the more severe acute bacterial exacerbations seems to decrease their severity, to shorten the period of morbidity and hospital stay, to improve airway flow rates and to provide longer periods between exacerbations.12,15 Some patients can resolve these infections without treatment; however, their illness may be prolonged and some patients may go on to develop pneumonia or other complications.15 The efficacy of antimicrobials depends on their pharmacokinetics, spectrum of antimicrobial activity and their ability to produce therapeutic levels at the site of infection without unacceptable adverse events (AEs). Currently, there is a wide range of antimicrobial agents available that are effective in the treatment of acute bacterial exacerbations of chronic bronchitis. The increasing emergence of drug-resistant and β-lactamase producing organisms has, however, reduced the efficacy of many of the agents currently available. More recently, fluoroquinolones have found favour for the treatments of acute exacerbation of chronic bronchitis (AECB).14 The excellent in vitro activity of moxifloxacin (BAY 12-8039), a new 8-methoxyfluoroquinolone, against all important pathogens in AECB,18 together with its good pharmacokinetics, which allow for oncedaily dosing,19 and its excellent penetration into bronchial tissues make it a good candidate for use in this area.20

This multicentre study was designed to compare the effect of moxifloxacin dosed once daily for 5 days with that of coamoxiclav dosed three times daily for 7 days for the treatment of patients with AECB.

Patients and methods STUDY DESIGN The study was a multinational, multicentre, non-blinded, randomized comparison of moxifloxacin (BAY 12-8039) 400 mg oral tablets, given once daily for 5 days, and co-amoxiclav 625 mg oral tablets, given three times daily for 7 days in the treatment of AECB. A total of 68 centres in 12 countries were involved in the study. The majority of centres were in Germany (16), France (14) and the UK (14), with one, two or three centres in the remaining countries. The study took place between 1 December 1998 and 9 June 1999. Randomly assigned numbers per centre were assigned sequentially to the patients according to their date of inclusion. The study protocol was prepared in accordance with the European Guidelines for Good Clinical Practice (1991) and national rules and regulations and was reviewed by the appropriate national and regional ethics committees. The study was conducted in accordance with the ‘Good Clinical Practice Guidelines for Trials on Medicinal Products in the European Community’ as issued by the Committee for Proprietary Medicinal Products (July 1990) and other applicable guidelines. To ensure compliance with these guidelines, the study was subject to inspection by authorized personnel and investigators agreed in writing to co-operate fully with compliance checks.

PATIENT SELECTION Patients gave their written informed consent before participating in this trial, as required by the Declaration of Helsinki. Patients included

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T Schaberg, I Ballin, G Huchon et al. Moxifloxacin versus co-amoxiclav in AECB were male or female, aged at least 18 years, and judged by clinical criteria to be suffering from chronic bronchitis. Chronic bronchitis was defined as a sputum-productive cough present for 3 consecutive months in 2 consecutive years (World Health Organization criteria). For inclusion patients had to have clinical symptoms of AECB, of the Anthonisen type I and II1 with purulent/mucopurulent sputum, together with increasing dyspnoea and/or increasing sputum volume. Patients with a known hypersensitivity to either of the study drugs or their related compounds, female patients who were pregnant, lactating or using inadequate contraception and patients with known significant liver impairment or renal insufficiency were excluded. Other exclusion criteria included: patients known to have congenital or sporadic syndromes of QTc prolongation, or receiving concomitant medication reported to increase the QTc interval; those with a previous history of tendinopathy following therapy with quinolones; and any patients requiring any concomitant systemic antibacterial agent or who had received prior therapy with an antibacterial agent within 48 h of screening or participated in any clinical study within 2 months of screening.

with a follow-up evaluation at 28 – 35 days after completion of treatment. The following variables were used to assess clinical response: wheeze, dyspnoea, cough, volume of sputum, auscultation: rales and rhonchi. These signs and symptoms at the posttreatment examinations were compared with those present at baseline and categorized as ‘the same’, ‘slightly decreased’ or ‘greatly decreased’ as appropriate. At the 14-day evaluation, clinical response (using the above criteria) was defined as: ‘success’ (i.e. resolution or improvement of symptoms, no further antibacterial therapy necessary); ‘failure’ (i.e. no change or worsening of symptoms, antibacterial therapy required); or ‘indeterminate’ (i.e. patients in whom clinical evaluation was not possible). At the follow-up evaluation (28 – 35 days post-treatment) clinical responses were categorized as ‘continued resolution’ (i.e. success), ‘recurrence or relapse’ (i.e. reappearance of signs and symptoms and need for antibacterial therapy) or ‘indeterminate’. If, after or during the 5- or 7-day course of therapy, the investigator decided that the patient was a treatment failure, then the patient was evaluated fully before being given other antimicrobial drugs.

DETERMINATION OF EFFICACY TREATMENT Each patient received the study medication for 5 or 7 days. Moxifloxacin tablets (400 mg) were administered once daily for 5 days and the comparator, co-amoxiclav tablets (625 mg) three times daily for 7 days. The medication was oral and not blinded. Co-amoxiclav was administered with meals and 100 ml water.

The primary efficacy parameter was the clinical response at 14 days in the evaluable population. Secondary efficacy parameters were clinical responses at follow-up, bacterial responses at 14 days and clinical responses at 14 days and at follow-up in those patients from whom a bacterial pathogen had been isolated (bacteriologically valid patients).

CLINICAL ASSESSMENT

BACTERIOLOGICAL RESPONSE

Patients were screened prior to therapy. The primary evaluation was made at 14 days,

Sputum samples were obtained prior to treatment and on day 14 and at the

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T Schaberg, I Ballin, G Huchon et al. Moxifloxacin versus co-amoxiclav in AECB follow-up examination (days 28 – 35) on the sub-group of bacteriologically valid patients. The samples were examined using a Gram stain, cultured, identified to species level and, where appropriate, their susceptibility to the drugs determined by use of the E-test. The bacteriological response at 14 days was assessed as ‘eradication’ (causative organisms not present at end of therapy), ‘presumed eradication’ (culture not taken from patients classified as ‘clinical resolution’), ‘persistence’ (causative organism still present), ‘presumed persistence’ (clinical failures from whom cultures were not available), ‘super-infection’ (a new pathogen present during therapy or up to 7 days post-therapy and associated with signs and symptoms), ‘indeterminate’ (bacteriological response not evaluable). The overall bacteriological response was categorized as ‘success’ or ‘failure’. A bacteriological failure was a patient with a bacteriological response classified as ‘persistence’, ‘presumed persistence’ or ‘super-infection’. A bacteriological success was a patient with a bacteriological response classified as ‘eradication’ or ‘presumed eradication’ without the occurrence of a super-infection, re-infection or recurrence.

STATISTICAL ANALYSIS Demographic and baseline characteristics of each treatment group were compared using quantitative data or frequency counts (qualitative/categorical data) as appropriate. Efficacy parameters were calculated on the clinical and bacteriological responses at day 14 and follow-up. A 95% confidence interval of the difference between the success rates in the treatment groups was calculated using Mantel–Haenszel weights. This test is designed to determine equivalence between the two treatments, and if the lower limit of this confidence interval was > –10%, it indicates no difference in the treatments.21

SAFETY PARAMETERS All AEs, including clinically relevant abnormalities in laboratory values, were recorded and documented in detail. Their severity and possible relation to the trial drug was assessed. Each patient was monitored by the investigator for AEs (including clinically significant deviations from normal laboratory values) and patients were encouraged to report any AE(s) experienced. Any patient experiencing an AE received appropriate treatment and observation until the event was resolved or the patient’s condition was stabilized. Adverse events occurring up to 7 days after stopping medication, and any serious AEs occurring up to 30 days after stopping medication, were also reported. A safety analysis was performed on all patients who had received at least one dose of the trial drug or comparator. Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) were used for the description of all AEs. The incidence and severity of AEs and abnormal laboratory values were examined and compared descriptively. All AEs were tabulated. All laboratory data were analysed by descriptive statistics, including identification of laboratory data outside normal ranges.

Results A total of 577 patients were enrolled in the study. All 577 were randomized, although two patients (one in each treatment group) did not receive treatment with the study drugs. A total of 575 patients (292 in the moxifloxacin group and 283 in the coamoxiclav group) were therefore valid for safety (intent-to-treat [ITT] population) and 512 patients (261 in the moxifloxacin group and 251 in the co-amoxiclav group) fulfilled all the criteria for efficacy analysis (efficacy evaluable population). The major reasons

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T Schaberg, I Ballin, G Huchon et al. Moxifloxacin versus co-amoxiclav in AECB for exclusion from the efficacy analysis are listed in Table 1. A total of 22 patients discontinued therapy prematurely, eight in the moxifloxacin group and 14 in the co-amoxiclav group; 16 of these discontinuations (seven and nine, respectively) were because of an AE.

DEMOGRAPHICS AND BASELINE CHARACTERISTICS The demographic and baseline characteristics of patients in the ITT and efficacy-evaluable populations are listed in Table 2. Baseline data included the severity of the current exacerbation, the numbers of exacerbations patients had experienced during the previous year, co-existing cardiopulmonary diseases, episodes of pulmonary failure and whether they were smokers. The majority of patients had an Anthonisen type I exacerbation and had co-existing cardiopulmonary disease. All differences between the two groups were slight and were not statistically significant (P-values between 1.0 and 0.05). The signs and symptoms of AECB of patients in the ITT and efficacy-evaluable populations at the entry to the study are listed

in more detail in Table 3. Rales and rhonchi were present in the majority of patients, and most were producing mucopurulent sputum. Sputum volume, dyspnoea, cough and wheeze were increased in most patients. All differences between the two groups were slight and were not statistically significant (P-values of between 1.0 and 0.05). A total of 140 patients (27.3%) were valid for microbiological evaluation in the efficacy evaluable population and 155 in the intent-totreat patients. The organisms most frequently isolated before therapy are listed in Table 4. The most commonly isolated pathogen was H. influenzae, present in 42.9% of the culturepositive cases (60). The less frequently isolated pathogens included Klebsiella pneumoniae (five) and Pseudomonas aeruginosa (seven).

CLINICAL EFFICACY The clinical responses at 14 days (the primary efficacy parameter) and at followup in the evaluable and bacteriologically valid patients (secondary efficacy parameters) for the efficacy-evaluable populations are shown in Table 5. In the moxifloxacin group, 251/261 patients were classified as a success

TABLE 1: Reasons for exclusions from efficacy analysisa Moxifloxacin (n = 293)

Co-amoxiclav (n = 284)

Violation of inclusion/exclusion criteria

18

14

Essential data missing or invalid

10

17

Insufficient duration of therapy

8

12

Non-compliance with study drug

1

8

Violation of time schedule

4

6

Use of prohibited concomitant medication

2

3

No study medication

1

1

Informed consent withdrawn

1

1

32

33

Total excluded (any reason) aMore

than one reason may apply to an individual patient.

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TABLE 2: Baseline demographics and characteristics of the two treatment groups Efficacy-evaluable population

Intent-to-treat population

Variable

Moxifloxacin (n = 261)




Sex Male Female

164 97

154 97

179 113

170 113

Age ± SD (years)

61.3 ± 13.5

59.3 ± 14.6

61.4 ± 13.3

59.6 ± 14.6

Weight ± SD (kg)

75.9 ± 17.0

73.1 ± 15.6

75.4 ± 16.8

73 ± 15.5

Severity of present exacerbation Anthonisen I Anthonisen II

244 17

233 18

267 25

262 20

Duration of present exacerbation > 7 days 67 4 – 7 days 63 < 4 days 129 Not reported –

73 67 110 –

81 69 140 2

87 72 123 1

Episodes of respiratory failure No 254 Yes 7

235 16

283 9

264 19

Co-existing cardiopulmonary disease 202

185

230

214

Exacerbations in previous year ≥3 118 2% are summarized in Table 9. Dizziness and nausea were more frequent in the moxifloxacin group, and diarrhoea and headache in the co-amoxiclav group. More patients in the co-amoxiclav group (11/283; 3.9%) withdrew from the study because of an AE than in the moxifloxacin group (eight of 292; 2.7%). The majority of the drug-related AEs in both treatment arms were mild to moderate in severity. Fewer severe AEs were reported in the moxifloxacin patients, five of 52 (9.6%) compared with co-amoxiclav, eight of 55 (14.5%).

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TABLE 7: Bacteriological response in efficacy-evaluable and intent-to-treat patients Moxifloxacin Bacteriological response

No.

Efficacy-evaluable patients Bacteriological success rate Eradication Presumed eradication Bacteriological failure rate Eradication with super-infection Persistencea Presumed persistence

Percentage

Co-amoxiclav No.

(n = 73)

Percentage (n = 67)

64 10 54

87.7 13.7 74.0

60 13 47

89.6 19.4 70.1

9 2 5 2

12.3 2.7 6.8 2.7

7 3 2 2

10.4 4.5 3.0 3.0

Intent-to-treat patients

(n = 87)

(n = 77)

Bacteriological success rate Eradication Presumed eradication

68 13 55

78.2 14.9 63.2

62 14 48

80.5 18.2 62.3

Bacteriological failure rate Eradication with super-infection Persistencea Presumed persistence Indeterminate/missing

19 2 9 2 6

21.8 2.3 10.3 2.3 6.9

15 3 5 2 5

19.5 3.9 6.5 2.6 6.5

a

Including persistence with super-infection.

Discussion Acute exacerbation of chronic bronchitis is a common and debilitating disease and treatment is normally empirical as it is not always practical to collect samples and identify the causative agent. Diagnosis is normally made using clinical criteria, which include an increase in coughing and sputum volume, mucopurulent sputum, worsening dyspnoea and the presence of rhonchi and rales. As treatment is empirical, it is essential that the agent used has good activity against the most common aetiological agents; H. influenzae, M. catarrhalis and S. pneumoniae. Other organisms implicated can include Haemophilus parainfluenzae, S. aureus and atypical bacteria. Moxifloxacin has activity against all of these species and

its activity is unaffected by resistance mechanisms found now with increasing frequency in these species to β-lactams and macrolides. An additional feature of moxifloxacin likely to favour its activity in respiratory tract infections is its ability to penetrate bronchial tissues.20 As already noted, for various reasons, antibacterial therapy has not always been shown to be of benefit in AECB. Ball1 points out that a possible contributing factor to this apparent lack of clear benefit may be a consequence of the methods used to assess a ‘cure’. Frequently, a criterion used is the eradication of the pathogen from the sputum sample, but it has been shown that the common aetiological agents of AECB can persist in bronchial secretions between exacerbations, albeit at lower levels.22 In this

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TABLE 8: Clinical failuresa in the efficacy-evaluable population at 14 days in various prognostic sub-groups Prognostic sub-group

Moxifloxacin

Age < 60 years > 60 years

3/109 (2.8%) 7/152 (4.6%)

6/114 (5.3%) 15/137 (10.9%)b

Number of acute exacerbation of chronic bronchitis in previous year 3

3/142 (2.1%) 7/118 (5.9%)

13/140 (9.3%)c 7/110 (6.4%)

Co-existing cardiopulmonary disease Yes No

10/202 (5%) 0/59 (0%)

Co-amoxiclav

19/185 (10.3%)d 2/66 (3%)

Concomitant steroid therapy Systemic Inhaled None

2/50 (4%) 5/64 (7.8%) 3/147 (2%)

7/44 (15.9%) 8/77 (10.4%) 6/130 (4.6%)

Anthonisen Type I Type II

9/244 (3.7%) 1/17 (5.9%)

19/233 (8.2%)e 2/18 (11.1%)

Airways obstruction FEV1 < 35% FEV1 35 – 50% FEV1 > 50%

2/23 (8.7%) 1/46 (2.2%) 0/173 (0%)

1/35 (2.9%) 1/34 (2.9%) 3/159 (1.9%)

a

Number of failures/number in stated category. P = 0.048. c P = 0.01. d P = 0.054. e P = 0.05. b

TABLE 9: Summary of drug-related adverse events by symptom reported at a frequency of at least 2% No. of patients (%) Adverse event


Total (n = 575)

9 (3.1%)

21 (7.4%)

30 (5.2%)

11 (3.8%)

5 (1.8%)

16 (2.8%)

Headache

4 (1.4%)

8 (2.8%)

12 (2.1%)

Abdominal pain

6 (2.1%)

4 (1.4%)

10 (1.7%)

Dizziness

7 (2.4%)

1 (0.4%)

8 (1.4%)

Diarrhoea Nausea


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T Schaberg, I Ballin, G Huchon et al. Moxifloxacin versus co-amoxiclav in AECB study, only those patients with Anthonisen type I and II exacerbations of AECB were recruited as these are the patients thought to be most likely to benefit from antibacterial therapy.16,17 Moxifloxacin produces high and sustained plasma and tissue levels with only one daily dose of 400 mg19 and has already been shown to be effective in the treatment of AECB when dosed for only 5 days.23,24 In these studies, it was at least equal in activity to clarithromycin dosed for 10 days. Moxifloxacin has also been shown to be effective when dosed for 5 days in the treatment of sinusitis, comparing favourably with trovafloxacin25 and cefuroxime axetil.26 In this study, co-amoxiclav was chosen as the comparator as it is a widely used and effective agent for the treatment of AECB.4 Co-amoxiclav was dosed at 625 mg three times daily for 7 days and moxifloxacin was dosed at 400 mg once daily for 5 days. The primary efficacy criterion was clinical response in the efficacy-evaluable groups at 14 days. Both treatments produced a high success rate in these groups at 14 days (moxifloxacin 96.2%; co-amoxiclav 91.6%) and the 95% confidence intervals indicated that the two treatments were no different. Secondary efficacy parameters also showed no significant differences between the two treatments. At the follow-up assessment, the clinical success in the moxifloxacin group was 89.4% and in the co-amoxiclav group 87.5%. Clinical responses in the bacteriologically valid patients were high in both groups (moxifloxacin 93.2%, co-amoxiclav 91.0%) and equivalence was achieved. No differences were seen in the clinical cure rates in the different countries taking part in the study. Analyses were made of the failure rates in certain sub-populations with known risk factors for AECB. There were slight

differences in some groups, with moxifloxacin patients having fewer failures, but as the numbers in these sub-groups were fewer than in the total population, these differences were generally not highly significant. Groups in which co-amoxiclav therapy was slightly less effective included those with co-existing cardiopulmonary diseases, those aged > 60 years and those with Anthonisen type I disease. The numbers of patients from whom a causative organism could be isolated in this study were low, only 140/512 (27.3%) in the efficacy-evaluable patients and 155/575 (27.0%) in the intent-to-treat patients. The study was carried out in 12 countries and there were marked differences in the rate of recovery of organisms in the different countries; Greece, for example, had the highest rate of isolation (47.5%). All samples in Greece were handled at one local hospital laboratory, whereas in a number of countries a central testing laboratory was used and it is possible that the transport of specimens may have affected the results adversely. In view of the low rate of isolation, no attempts have been made to estimate eradication rates for the two agents. Both agents were well tolerated and there were no significant differences between the groups in the numbers of AEs attributed to the drug or to the numbers of severe AEs. In conclusion, this study has shown that a short course of moxifloxacin, dosed at 400 mg once daily for 5 days, is at least equal in efficacy to and as well tolerated as co-amoxiclav, dosed at 625 mg three times daily for 7 days in the treatment of AECB.

Acknowledgements The authors acknowledge the contribution of Pamela A Hunter in the preparation of the manuscript. This study was supported by funding from Bayer AG, Germany.

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Appendix ACUTE EXACERBATION OF CHRONIC BRONCHITIS STUDY GROUP MEMBERS Centre Investigators Austria: F Kummer, N Wetter (Wien); Belgium: P Delpire (Charleroi); M Deruyttere (Leuven); J-B Martinot (Namur); France: P-L Llorens (Aureille); F Albesa (Beaucaire); F Bart (Bethune); L Bernabeu (Chauny); F Royer (Essey les Nancy); L Foquert (Grasse); A Simmons (Linas); Y Martinat (Lyon); G Meridjen (Mallemort); R Francon (Marseille); P Zuck (Metz); P Godard (Montpellier); GR Boyer (Nice); Germany: O Cerwicz (Dossenheim); K Colberg (Bad Segeberg); A Linnehoff, A McDaniel, W Mitlehner, R Schnorr, T Schultz, U Szerdahelyi, L-H von Versen, U Westerhausen (Berlin); K Todoroff (Bad Dürrheim);

V Janekovic (Frankfurt); H Leiner (Kiel); F Käßner (Groß Gaglow); E Beck (Rüdersdorf); Greece: E Papadakis (Athens); P Nikolaidis, P Kollaras (Thessaloniki); Hungary: E Ludwig (Budapest); S Ferenczi (Gyor Vasvári Pál); S Tímár (Kecskemét Nyíri); Israel: A Eliraz (Rehovat); The Netherlands: AJM Schreurs (Amsterdam); ThA Bantje (Breda); R Aalbers (Groningen); Poland: A Dmoch (Kielce); T Plusa, J Zielinski (Warszawa); B Halawa (Wroclaw); Russia: A Solomatin, S Yakovlev (Moscow); V Trofimov (Saint Petersburg); Switzerland: M Schmitz (Davos Wolfgang); E Kohler (Liesetal); UK: I Ballin (Manchester); I Battye (Beccles); D Allin (Birmingham); C Allenby, S Edwards (Cardiff); WD Carr (Fife); DM Reid, I McColl (Glasgow); M Kansagra, J Zachariah (Milton Keynes); D Morgan (Mountain Ash); WRC Aitchison (Paisley); K Garg (Preston); DA Keating (Sheffield).

• Received for publication 3 January 2001 • Accepted 15 January 2001 ©2001 Cambridge Medical Publications References 1 Ball P: Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest 1995; 108 (Suppl): 43S – 52S. 2 Read R: Infection in acute exacerbations of chronic bronchitis: a clinical perspective. Respir Med 1999; 93: 845 – 850. 3 Nicolson P, Anderson P: The patient’s burden: physical and psychological effects of acute exacerbations of chronic bronchitis. J Antimicrob Chemother 2000; 45: 25 – 32. 4 Chodosh S: Role of antimicrobials in the management of acute exacerbations of chronic bronchitis. Infect Med 1999; 16 (Suppl A): 8 – 20. 5 Sethi S: Infectious exacerbations of chronic bronchitis: diagnosis and management (see comments). J Antimicrob Chemother 1999; 43 (Suppl A): 97 – 105. 6 Green GM, Kass EH: Factors influencing clearance of bacteria by the lung. J Clin Invest 1964; 43: 769 – 776. 7 Cole P: The damaging role of bacteria in chronic lung infection. J Antimicrob Chemother 1997; 40 (Suppl A): 5 – 10. 8 Colley JRT, Mill DL: Acute respiratory infections. Chest 1989; 96 (Suppl): 355 – 360. 9 Grossman R: Management of acute exacerbation of chronic bronchitis. Can Respir J 1999; 6 (Suppl A): 40A – 45A.

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Address for correspondence Professor T Schaberg Head of Lungenklinik, Unterstedt, Diakoniekrankenhaus, 27342, Rotenburg Wümme, Germany.

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