Randomized, double-blind, double-dummy study comparing the efficacy and safety of amoxycillin 1 g bd with amoxycillin 500 mg tds in the treatment of acute exacerbations of chronic bronchitis

A. Georgopoulosa, M. Borekb,*, W. Ridlb and The Amoxycillin Bronchitis Study Group{dagger}

a Department of Internal Medicine I, Division of Infectious Diseases and Chemotherapy, University of Vienna, Währinger Gürtel 18–20, A-1090 Vienna; b International Medical Department, Biochemie GmbH, A-6250 Kundl, Austria


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This randomized, multicentre, double-blind, double-dummy study compared the efficacy and safety of amoxycillin 1 g bd with amoxycillin 500 mg tds in 395 patients with a clinical diag- nosis of acute exacerbation of chronic bronchitis (AECB). Patients were treated for 10 days and were assessed during therapy (days 3–5), after the end of therapy (days 12–15) and at follow up (days 28–35). In the intention-to-treat (ITT) population, clinical success rates at the end of therapy were 86.6% (162/187 patients) and 85.6% (161/188 patients) in the bd and tds group, respectively. In the per-protocol (PP) subgroup, the success rates were 89.1% (156/175) and 92.6% (150/162), respectively. The clinical recurrence rates at follow up were, in the ITT and PP populations, respectively, 14.2% (20/141) and 13.4% (18/134) in the bd group, and 12.6% (18/143) and 13.7% (18/131) in the tds group. The 95% confidence intervals (CI) confirmed the clinical equivalence of the two dosage regimens in the ITT and PP populations. Two hundred and nineteen patients from the clinically evaluable ITT population had at least one pathogen isolated at baseline and were evaluable for bacteriological efficacy. Bacteriological success at the end of therapy was obtained in 76.2% (83/109) of patients in the bd group, and 73.7% (81/110) of patients in the tds group (95% CI: –9 to 14%). The most frequently reported drug-related adverse events in the safety evaluable patients were gastrointestinal symptoms, which occurred in 11.2% (22/197) in the bd group and 11.6% (23/198) in the tds group. Amoxycillin 1 g bd is clinically and bacteriologically as effective as amoxycillin 500 mg tds in the treatment of AECB, and the two dosage regimens show a similar safety profile.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Chronic bronchitis is a clinical diagnosis based upon the presence of a productive cough on most days for a minimum of 3 months per year for at least two consecutive years. It is a slowly progressive disease, punctuated by acute exacerbations, which are associated with increased morbidity and mortality.1 The cause of an exacerbation may be multifactorial. It is estimated that bacterial infection plays a part in between half and two-thirds of exacerbations.2 Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae are the bacteria most frequently isolated from patients' sputum during acute exacerbations of chronic bronchitis (AECB).1,2 Several studies have shown that as lung function deteriorates, other Gram-negative bacteria may be recovered more frequently from the respiratory tract.2,3 Antimicrobial therapy, when compared with placebo, has been associated with a significant clinical improvement in patients with AECB, especially in patients with low baseline peak expiratory flow rates.4 However, no clear benefit in clinical efficacy has been shown for newer antibacterial agents in comparison with standard agents such as amoxycillin, despite microbiological and pharmacokinetic properties that might be thought to be superior.5–7

Amoxycillin is a broad-spectrum amino-penicillin that has been often used as standard comparator in clinical trials evaluating new drugs developed for the treatment of AECB,6–11 with a usual oral dosage of 500 mg tds. Pharmacodynamic studies have shown that for ß-lactam antibiotics, the time for which the serum concentration exceeds the MIC of the pathogen (t > MIC) is a key parameter in predicting a successful clinical and bacteriological outcome.12 New dosage regimens should, therefore, aim to maximize both t > MIC and compliance, because of the possibility of increased doses and reduced dosing frequency.13,14 Studies of pharmacokinetic/pharmacodynamic data from healthy volunteers have shown that oral administration of 1 g amoxycillin every 12 h resulted in a t > MIC similar to that reached after a dose of 500 mg amoxycillin given every 8 h (data on file, Biochemie GmbH, Kundl, Austria). For penicillins, it is thought that the t > MIC only needs to be 40–50% of a dose interval to achieve maximum bacteriological cure.12,15 This has led recently to the use of pharmacodynamic breakpoints defined by serum concentrations exceeding the MIC for >=40% of the dose interval.16 The pharmacokinetic/pharmacodynamic data obtained for the amoxycillin 1 g bd regimen support a pharmacodynamic breakpoint of 2 mg/L (t > MIC for 2 mg/L, 43% (95% CI 39–47%), which is in accordance with the data reported for the 500 mg tds17 and 875 mg bd18 dosage regimens. In a multicentre survey of European lower respiratory pathogens, 82.2% of M. catarrhalis, 84.2% of H. influenzae and 97.5% of S. pneumoniae isolates had an MIC <= 2 mg/L,19 suggesting that amoxycillin 1 g bd might have acceptable efficacy. The objective of this trial was to determine whether the clinical efficacy of the 1 g bd regimen was equivalent to that of the standard 500 mg tds regimen in the treatment of AECB in adults.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This double-blind, double-dummy, randomized, multicentre trial on two parallel groups was conducted at 12 centres in Austria. The study protocol was approved by each local ethics committee. Signed informed consent was obtained from each patient before inclusion.

Patient selection

Adult male and female out-patients (or in-patients for whom oral therapy was indicated), aged >=18 years, with a clinical diagnosis of AECB, without signs and symptoms of bacterial pneumonia and willing to comply with the protocol were included in the study. AECB was defined as a history of chronic or recurrent cough present on most days of the week for three consecutive months in each of the two preceding years, with any combination of at least two of the following symptoms with or without fever: recent onset (<7 days) of increased cough and/or dyspnoea, increased sputum volume or increased sputum purulence.

Patients with known hypersensitivity to ß-lactams, or with infectious mononucleosis, lymphatic leukaemia, clinical and/or radiological diagnosis of pneumonia, suspected localized lung disease (such as tuberculosis or bronchial carcinoma), severe chronic or terminal disease, severe renal or hepatic dysfunction or alcoholism or those in a poor general state, and those who had received previous antibiotic therapy within the last 4 weeks or participated in a clinical trial within the last 12 weeks were excluded from study participation. Pregnant or lactating females and females of child-bearing age without sufficient contraceptive protection were also excluded.

Study treatments

Patients were randomized to a double-blind, double-dummy treatment for 10 days with amoxycillin 1 g film-coated tablets bd (Biochemie GmbH) (with placebo 500 mg capsules tds) or 500 mg capsules tds (with placebo 1 g film-coated tablets bd).

Clinical and bacteriological assessments

Clinical and bacteriological assessments were made at inclusion, during therapy (days 3–5), after the end of therapy (days 12–15) and at the follow-up visit (days 28–35). Clinical assessments were made on the basis of severity of cough, dyspnoea, rales/rhonchi, subjective impairment of general state and sputum appearance. The volume of sputum produced in a 24 h period was recorded during the first 24 h of the study (day 1) and after the end of therapy (day 11). The temperature was recorded and lung function measurements (FEV1, vital capacity and peak flow spirometry) were performed at each visit.

Expectorated sputum samples were collected at the inclusion visit and from those patients able to produce sputum at the subsequent visits, and were sent within 48 h (depending on the study centre) to a central laboratory (University Hospital, Vienna). Gram's stain, bacterial culture and susceptibility testing were performed according to standard NCCLS methods.

Clinical and bacteriological responses

Clinical response at the end of therapy was assessed by the investigator as: (i) cure (complete resolution of signs and symptoms, including fever, with clinical condition identical to pretherapy disease-free interval); (ii) improvement (reduction in the severity of all signs and symptoms with resolution of fever; patient did not need any further antibiotic therapy); (iii) failure (absence of improvement or worsening of symptoms at days 3–5 and/or end-of-therapy visit and/or need for additional antibiotic therapy). Evaluation of clinical response at follow-up assessed the absence or presence of clinical recurrence defined as: patient cured or improved at end of therapy with recurrent signs and symptoms of acute exacerbation at any time between the end of therapy and follow-up visits. The ‘cure’ and ‘improvement’ outcomes were defined as clinical success.

The bacteriological response at end of therapy was assessed for each microbiologically evaluable patient according to the following definitions: (i) eradication (absence of the initial causative pathogen in subsequent culture at end of therapy); (ii) presumed eradication (patient with clinical success at end of therapy and no sputum available); (iii) eradication with colonization (absence of the initial causative pathogen and presence of another organism at end of therapy in a patient with clinical success); (iv) eradication with reinfection (absence of the initial causative pathogen and presence of another organism in a patient with clinical failure); (v) persistence (presence of the initial causative pathogen in culture at end of therapy); (vi) presumed persistence (clinical failure at end-of-therapy visit but no sputum available or evaluable). The bacteriological response at follow-up was assessed according to definitions corresponding to those used for end-of-therapy assessment, with the following additional outcomes: (vii) colonization (presence of a new organism at follow-up, in the absence of clinical recurrence, when no pathogen was found at end of therapy); (viii) superinfection (presence of a new organism in the presence of clinical recurrence); (ix) relapse (absence of the initial causative pathogen at end of therapy but reappearance at follow up).

To be microbiologically evaluable, patients had to have at least one organism isolated at baseline. In the case of more than one pre-treatment causative pathogen, each bacterial isolate was evaluated separately and the bacteriological response of a patient was assessed as the worst bacteriological outcome for each of the causative organisms.

Microbiological responses of eradication, presumed eradication, eradication with colonization (or colonization at follow-up assessment) were combined as overall bacteriological success since, in all of these cases, the original infection had been eradicated.6 Eradication with reinfection, persistence, presumed persistence, relapse and superinfection (at follow-up assessment) were combined as bacteriological failure.

Safety assessments

Adverse events were recorded at each visit and assessed with regard to seriousness, severity, event causality (e.g. study indication, coexistent disease, study medication), relationship to study medication, duration, frequency, outcome and required therapeutic measures. No laboratory tests were required by the study protocol.

Statistical analysis

The primary objective of this trial was to determine whether the clinical success rates of the 500 mg tds and 1 g bd dosage regimens were equivalent at end of therapy. Assuming a success rate of 85% for the 500 mg tds regimen, ß = 20% and an equivalence {delta} of 10%, it was estimated that 180 patients would have to be enrolled in each treatment group. The equivalence between the treatment groups for the primary clinical efficacy outcome was considered to be established if the lower limit of the two-tailed 95% CI around the difference in clinical success (bd minus tds) was not below –10% and if the CI included the value of zero.

The primary efficacy endpoint was the clinical response at the end-of-therapy visit; secondary efficacy endpoints were the bacteriological response at end of therapy and the clinical recurrence rate at follow-up.

All patients randomized, receiving >=3 days of medication and who did not violate the inclusion/exclusion criteria in any way liable to influence the efficacy outcome were considered as the intention-to-treat (ITT) population. Patients who were not evaluated at the end of therapy were regarded as treatment failures. The per-protocol (PP) subgroup was defined as those patients who remained in the study at each scheduled time-point, did not violate the protocol in any way liable to influence the efficacy outcome, had a valid evaluation of efficacy and were compliant with the treatment regimen (i.e. <=20% of study medication returned unused and/or documented intake of study medication for >7 days). All determinations of evaluability were made before unblinding.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Disposition of patients

A total of 395 patients were enrolled from March 1997 to March 1998. Most patients (95%) were treated as out-patients. The disposition of study patients evaluable for clinical efficacy and microbiological efficacy is shown in the FigureGo. Compliance was monitored by tracking trial medication usage at the end-of-therapy visit for 173 patients in the bd group and 174 in the tds group.



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Figure. Disposition of study patients (% of ITT population) evaluable for clinical efficacy (CE) and microbiological efficacy (ME). EOT, end of therapy; FU, follow up.

 
Demographic and baseline characteristics

The demographic data for the ITT population are shown in Table IGo. Most of the patients were receiving concomitant medication for chronic obstructive pulmonary disease (COPD) and/or cardiovascular disorders. FEV1 values were reported in 345 patients (92% of all ITT patients), with 60% of patients having a FEV1 result <=75% of normal.


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Table I. Demographic data of the intent-to-treat population
 
The most common microorganisms isolated at baseline are listed in Table IIGo. Most patients (77%) had a single pathogen isolated. No strain of M. catarrhalis was resistant to amoxycillin, whereas resistance to amoxycillin was observed in 4.3% of H. influenzae, 13.8% of Escherichia coli and 50% of Staphylococcus aureus strains. All S. pneumoniae isolates were fully susceptible to amoxycillin.


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Table II. Most common organisms isolated at baseline in 219 patients evaluable for microbiological efficacya
 
Compliance was high in both treatment groups: 158 patients (91.3%) in the bd group and 152 patients (87.4%) in the tds group had 100% compliance.

Clinical response

The clinical responses at end of therapy and at follow-up for the ITT and PP populations are shown in Table IIIGo. In the subset of 219 patients evaluable for clinical and microbiological efficacy, the clinical success rates at the end of therapy were 87.2% (95/109 patients) in the bd group and 87.3% (96/110 patients) in the tds group (95% CI for the difference in clinical success rate was –9 to 8.7%). The slightly higher success rate at the end of therapy for the tds group in the PP population may be explained by the fact that more patients with clinical failure (15 in the tds group compared with six in the bd group) had been excluded from PP analysis.


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Table III. Clinical response in the intent-to-treat (ITT) and per-protocol (PP) populations
 
In both treatment groups, there was a marked reduction at the end of therapy in the severity of the initial clinical symptoms of AECB (Table IVGo). The severity of clinical symptoms was already improved at the control visit. Only 31% of patients in the bd group and 35.6% in the tds group still had mucopurulent or purulent sputum at days 3–5 and 26.8% of patients had moderate or severe cough in the bd group compared with 41.5% in the tds group (P = 0.003). Improvement in dyspnoea was also evident, although less pronounced, with 15.5% and 21.3% of bd and tds patients, respectively, having moderate or severe dyspnoea at days 3–5. FEV1 and peak flow spirometry values increased moderately during therapy. No further improvement in lung function was observed until follow-up in the evaluable patients (data not shown).


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Table IV. Clinical symptoms and paraclinical assessments at baseline visit and at end of therapy (days 12–15) in the ITT population
 
Bacteriological response

The overall bacteriological response in the clinically and microbiologically evaluable patients is shown in Table VGo. Analysis of the bacteriological response at the end of therapy according to clinical response is summarized in Table VIGo. In both groups, nearly all patients with clinical failure were also bacteriological failures. The correlation between clinical and bacteriological response at end of therapy was almost identical in both groups ({kappa} = 0.580 in the bd group and {kappa} = 0.579 in the tds group). The bacteriological response by pathogen at the end of therapy is listed in Table VIIGo.


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Table V. Overall bacteriological response at end of therapy and follow-up
 

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Table VI. Bacteriological response at the end of therapy according to clinical response
 

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Table VII. Bacteriological response by pathogen at end of therapy (most common Gram-negative and Gram-positive isolates)
 
Safety evaluation

All randomized patients were included in the safety analysis. One or more adverse events were reported for 46 of 197 patients (23.4%) in the bd group and for 43 of 198 patients (21.7%) in the tds group. The total number of adverse events was 119 (54 in the bd group and 65 in the tds group). The most commonly reported drug-related adverse events are listed in Table VIIIGo. The overall incidence of drug-related gastrointestinal disorders was very similar in the two groups: 11.2% (22/197) in the bd group and 11.6% (23/198) in the tds group. Only three drug-related adverse events were considered severe in each group: one case each of diarrhoea, pneumonia and tiredness in the bd group and one case each of diarrhoea, nausea and dyspnoea in the tds group.


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Table VIII. Most commonly reported drug-relateda adverse events (AEs)
 
Serious adverse events were reported in three patients (1.5%) in the bd group and in two patients (1%) in the tds group. Four patients (2%) in the bd group and six patients (3%) in the tds group discontinued therapy prematurely because of the occurrence of an adverse event.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
To our knowledge, this study is the first adequately powered comparison of two dosage regimens of amoxycillin in the treatment of AECB in adults, showing the clinical and bacteriological equivalence of efficacy between the 1 g bd and the standard 500 mg tds regimens. A similar study, performed in lower respiratory tract infections with the combination of amoxycillin and clavulanic acid, also showed the equivalence between amoxycillin/clavulanic acid 875/125 mg bd and 500/125 mg tds regimens.20 However, none of the published studies that compared bd and tds regimens of amoxycillin (administered as a single substance) in lower respiratory tract infections21–23 or urinary tract infections24 in adults was sufficiently powered to show superiority or equivalence between the regimens tested.25 Only in one recent well-designed study evaluating a 6 day treatment of streptococcal tonsillitis has the 1 g bd regimen been shown to be as effective as the reference 10 day therapy with penicillin V.26 Amoxycillin has nevertheless been used as comparator with 1 g bd or 750 mg bd regimens in a few trials evaluating cephalosporins or clarithromycin in sinusitis27,28 and lower respiratory tract infections.29 This scarcity of published data supporting a twice-daily administration of amoxycillin in respiratory tract infections in adults contrasts with the widely recognized use of amoxycillin 1 g bd in the management of Helicobacter pylori infection.30

The results of this trial indicate that a 1 g bd dosage regimen of amoxycillin is clinically as effective as the standard 500 mg tds regimen in the treatment of AECB. The analysis of the 95% CIs showed a very good consistency of results across all data sets, confirming the equivalence in clinical success at the end of therapy and at follow-up between the two treatment groups. In the subset of ITT patients evaluable for clinical and microbiological efficacy, the clinical success rates at the end of therapy were close to those observed in the overall ITT population, indicating that this subgroup may be considered representative of the overall study population. The mean age of the study population was also in accordance with that reported in other AECB trials.6,8,31 The overall clinical success rates at the end of therapy observed in this study are in accordance with those reported for amoxycillin6,7 and other drugs.31–33 The rapid improvement observed by 3–5 days after initiation of therapy in most clinical symptoms of acute exacerbation has also been reported in other trials.33,34 Our observation of only slight improvements in FEV1 and peak flow spirometry values during therapy is in accordance with the findings reported by others.4,31 Although the present study did not assess exacerbation-free baseline spirometry measurements prospectively, it may be assumed that the values observed at end of therapy and follow-up correspond to the return to actual baseline condition of the underlying airway obstruction related to COPD.35

The most commonly isolated pathogens were H. influenzae and M. catarrhalis, followed by Enterobacteriaceae. An unusual finding in the present study is the very low (<3%) proportion of S. pneumoniae isolates. Nevertheless, incidence rates as low as 7–9% have been reported for S. pneumoniae in other AECB trials.32,33 A possible explanation for the low proportion of S. pneumoniae isolates in our study could be that several study participants had received anti-pneumococcal vaccines. However, assessment of vaccination status was not part of the trial documentation, so this hypothesis has to be considered with caution.

Bacteriological efficacy could be assessed in 219 (58%) of 375 clinically evaluable ITT patients. This proportion compares well with those reported for other AECB trials,31–34 which range from 35 to 59%. The proportion of patients with presumed eradication was also in accordance with those reported for other AECB trials.32,33 Analysis of the 95% CIs showed that the amoxycillin 1 g bd regimen was bacteriologically as effective as the 500 mg tds regimen. Although the overall bacteriological success rate at the end of therapy in the bd group (76.2%) was slightly lower than that reported for amoxycillin 500 mg tds (83%) in another trial using a similar definition of bacteriological success,6 it compares well with those recently published for moxifloxacin31 and clarithromycin.31,34 Most clinical failures in the present study were also bacteriological failures, confirming previous findings31,36 and further supporting a causative role of bacterial infection in AECB.2

The bacteriological success rates by pathogen at the end of therapy in the bd group are in accordance with those reported for the amoxycillin 500 mg tds regimen in other AECB trials in which successful responses ranged from 857 to 89%6 for H. influenzae and from 857 to 90%6 for M. catarrhalis (including ß-lactamase-positive strains). These eradication rates for H. influenzae are higher than those reported for clarithromycin,31,34 a finding that might be related to a lower susceptibility of H. influenzae to clarithromycin on the basis of pharmacodynamic breakpoints.17 The clinical outcome in patients with M. catarrhalis infection was very satisfying, since 32 of 35 patients (91.4%) in our study were assessed as clinical successes at the end of therapy. This observation confirms previous results reported in another AECB trial for the amoxycillin 500 mg tds regimen,7 in which 90% of patients with M. catarrhalis infection had a successful clinical outcome, and is in accordance with retrospective observations of clinical outcomes made in patients with M. catarrhalis infection who were treated with amoxycillin.37 Furthermore, in a European survey, 82% of 376 combined M. catarrhalis isolates had an MIC <= 2 mg/L19 (corresponding to the pharmacodynamic breakpoint for the amoxycillin 1 g bd and 500 mg tds regimens). Taken together, these observations suggest that AECB caused by M. catarrhalis infection remains, at least partly, amenable to therapy with amoxycillin, despite a high frequency of ß-lactamase-producing strains.

Both dosage regimens were generally well tolerated; drug-related adverse events were in accordance with the known safety profile of amoxycillin. The overall incidence of drug-related gastrointestinal disorders was very similar in both groups, indicating that the tolerance of both treatment regimens may be considered equivalent.

The present study supports the use of an amoxycillin 1 g bd dosage regimen as first-line treatment of AECB, especially in geographical regions where the incidence of amoxycillin-resistant respiratory pathogens is considered to be low (such as Austria or Germany), because of its proven efficacy and favourable safety profile. The expected benefit of a 1 g bd administration for amoxycillin is increased patient compliance,14 a parameter that could not be assessed comparatively in this study because of the double-dummy design, but which might become clinically relevant when the bd regimen is used under conditions of daily clinical practice.38


    Acknowledgments
 
The authors thank H. Mailer (GCPL, Vienna) for support in designing the study, selection of investigators and for monitoring of study centres, and A. Millendorfer (Bioconsult, Perchtoldsdorf) for the statistical analysis. The trial was supported by a grant from Biochemie GmbH, Kundl. The members of the Amoxycillin Bronchitis Study Group are as follows: R. Holzer (Wiener Neustadt), I. Thomüller (Graz), N. Vetter (Vienna), H. Artner (St Pölten), G. Wallner, C. Hutter (Vienna), J. Rath (Korneuburg), E. Kohout (Vienna), G. Gitsch (Stockerau), I. Feichtinger (Tulln) and M. Flicker (Leoben).


    Notes
 
* Corresponding author. Tel: +43-5338-200-2868; Fax: +43-5338-200-407; E-mail: michael.borek{at}gx.novartis.com Back

{dagger} Members of the Amoxycillin Bronchitis Study Group are listed in the Acknowledgements. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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Received 5 April 2000; returned 26 June 2000; revised 22 August 2000; accepted 20 September 2000