a Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece; b Department of Pediatrics, George Washington University School of Medicine, Washington, DC 20010; c Division of Clinical Care Research, New England Medical Center, Department of Medicine, Tufts University School of Medicine, Boston, MA 02111, USA
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Abstract |
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Introduction |
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In the last decade, many clinical efficacy trials have been conducted evaluating short courses of azithromycin versus other antibiotics that require typically longer courses in various lower respiratory tract infections. Interpretation of the results is difficult due to the small number of patients in many of the studies. Therefore, we conducted a metaanalysis of evidence on the treatment of acute bronchitis, acute exacerbation of chronic bronchitis and community-acquired pneumonia. A companion meta-analysis of azithromycin's comparative efficacy for upper respiratory tract infections was also conducted.8
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Materials and methods |
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We carried out a literature search of the MEDLINE and EMBASE databases for pertinent randomized controlled trials (RCTs) published from 1990 to March 21, 2000. We used the text word and medical subject heading azithromycin. We included trials that assessed the use of azithromycin in the treatment of acute bronchitis, acute exacerbation of chronic bronchitis and community-acquired pneumonia. We also examined the Cochrane Controlled Trials Registry for additional studies, but none were found. Besides types of infection, eligibility criteria were similar to those used in a companion meta-analysis of azithromycin in upper respiratory tract infections.8
Primary outcome
The primary outcome was the clinical failure rate in patients receiving azithromycin versus comparator antibiotics. We selected as time for evaluation of the clinical outcome the day closest to day 10 (all studies carried out primary outcome evaluations between days 6 and 21). Relapses at the time of primary evaluation were counted as failures.
Data extraction
The type of data extracted was similar to what has been described in a companion meta-analysis8 and included information on the study population, types and diagnosis of eligible infections, efficacy and safety outcomes and study design characteristics.
Statistical analysis
We calculated pooled odds ratios, risk ratios, risk differences and 95% confidence intervals (CIs) for clinical failures for each lower respiratory infection of interest. Between-study heterogeneity was assessed using the 2-based Q statistic.9 We used both the MantelHaenszel fixed effects10 and DerSimonianLaird random effects11 models. For evaluation of toxicity, we pooled and compared rates of discontinuations due to side effects for each agent across all cases of lower respiratory tract infection. In the main analysis, study-specific rates were weighted simply by the sample size of each study. Weighting by the inverse of the fixed or random effects variance yielded qualitatively similar results (not shown).
Subgroup analyses were carried out to evaluate differences in comparative efficacy when different comparator antibiotics were used and for different types of community-acquired pneumonia. Analyses based on source of funding were also conducted. Bias diagnostics included: (i) inverse funnel plots;9 (ii) recursive cumulative meta-analysis12 and (iii) control-rate meta-regression13 as described also in a companion meta-analysis.8
Analyses were conducted in Meta-Analyst (Joseph Lau, Boston, MA, USA) and in SPSS version 9.0 (SPSS Inc., Chicago, IL, USA). All P-values are two-tailed.
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Results |
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The literature search strategy yielded 39 independent studies that were pertinent for the conditions of interest.1452 Four of these studies19,22,28,51 had two RCTs reported each, resulting in 43 comparisons where an oral azithromycin regimen was involved.
Twenty-one trials14,17,19,21,25,28,32,33,36,3841,4346,4851 studied only one type of lower respiratory tract infection. Four of them were excluded, because they simply compared different azithromycin doses (n = 3),25,45,46 or they were not truly randomized (n = 1).48 The other 17 trials studied more than one lower respiratory tract infection of interest. Articles that described more than one condition were evaluated for eligibility for each condition separately. Nine studies were excluded from all relevant analyses because they did not separate the outcome data for the conditions of interest (n = 8)15,24,26,29,31,35,37,42 or they had fewer than 10 patients per condition of interest (n = 1).47 Five studies20,22,27,30,52 that were excluded from the analysis of one or two condition(s), were eligible for the analysis of the other condition(s).
Acute bronchitis
A total of 16 independent studies15,18,20,22,24,26,27,2931,34,35,4749,52 were identified. One study22 reported two separate RCTs and, therefore, there were a total of 17 comparisons. Eleven studies (12 comparisons) were excluded from the meta-analysis because they did not provide separate outcome data for acute bronchitis (n = 6 involving 501 patients);15,24,26,29,31,35 did not provide data on improvement rates but only on cure rates (n = 1; two comparisons involving 233 patients);22 had fewer than 10 patients per treatment arm (n = 3 involving 37 patients);27,30,47 or used envelope randomization although the investigators were free to choose treatment options (n = 1 with 131 patients).48 In total, clinical outcome data on 902 patients with acute bronchitis treated with azithromycin versus a comparator antibiotic were excluded from the analysis for these reasons. Finally, from one study that categorized patients according to presence or absence of underlying pulmonary disease, only data from patients without underlying pulmonary disease were included in this meta-analysis.49
The five eligible studies, involving 1372 patients18,20,34,49,52 were all in the English language, published between 1993 and 1996 and were all multicentre studies conducted exclusively in Europe except for one that was also conducted in Argentina.34 One study18 was sponsored by Pfizer, while another trial49 was sponsored by a different pharmaceutical company. Three studies20,34,52 did not state their source of funding. All studies were conducted in adults. The mean ages of the study populations ranged from 43 to 57 years, and the percentage of males ranged from 47% to 59% (Table 1).
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Four studies used a 3 day azithromycin regimen and one study49 used a 5 day regimen. The comparator drugs were co-amoxiclav (n = 2), clarithromycin (n = 2) and roxithromycin (n = 1). The randomization method and efforts for allocation concealment were not clarified in any of the studies. There were three open-label studies and two double blind studies.49,52
The total number of evaluable patients in the five eligible studies was 1372; sample size ranged from 48 to 617 patients. In all studies the outcome evaluation was carried out between 6 and 21 days. Overall, there were 50 clinical failures in 765 (6.5%) evaluable patients in the azithromycin treatment arms and 39 clinical failures in 607 (6.4%) evaluable patients in the comparator arms. There was no significant heterogeneity between the studies. There was no statistically significant difference between azithromycin and comparators (random effects odds ratio 0.84, 95% CI 0.541.31) (Figure 1). The results were similar with the fixed and random effect models.
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A total of 18 independent studies were identified (19 comparisons). Five studies (six comparisons) were excluded from the meta-analysis. One study (n = 8 patients)47 had fewer than 10 patients per treatment arm with acute exacerbation of chronic bronchitis, three studies (n = 179 patients)15,29,37 did not separate the clinical outcome of interest for specific lower respiratory tract infections and another study (n = 152 patients)22 with two comparisons, did not provide data on improvement rates, but only on cure rates. In total, 339 patients with acute exacerbation of chronic bronchitis who were treated with azithromycin versus a comparator antibiotic were excluded from the analysis.
The 13 eligible studies with 1342 patients (Table 2) were all in the English language, published between 1992 and 1999. Ten of them were conducted exclusively in Europe, two in the USA and one in Argentina and Europe. Four studies18,23,30,36 were sponsored by Pfizer and one study16 was sponsored by another pharmaceutical company. Seven other studies17,20,27,34,39,50,52 did not specify their source of funding. All studies were conducted in adults. The mean age of the study population ranged from 45 to 66 years and males ranged from 55% to 86%.
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Eleven studies used a 3 day azithromycin regimen and two studies23,50 used a 5 day regimen. The comparator drugs were amoxicillin (n = 1), co-amoxiclav (n = 6), cefaclor (n = 2), clarithromycin (n = 2), dirithromycin (n = 1) and roxithromycin (n = 1).
There were four double blind studies27,30,36,52 and two single blind studies.21,50 The other seven trials were unmasked. The randomization method was specified and appears to have been adequately concealed in two studies.30,36
The total number of evaluable patients in the 13 eligible studies was 1342; trial sample size ranged from 47 to 205 patients with acute exacerbation of chronic bronchitis. Outcome evaluation was carried out around day 12 (range: 821 days). Overall, there were 53 clinical failures (7.3%) in 726 evaluable patients in the azithromycin group and 59 clinical failures in 616 (9.6%) evaluable patients in the comparator arms. The combined estimate (random effects odds ratio 0.64, 95% CI 0.311.32) showed no statistically significant difference between azithromycin and its comparators (Figure 2). There was significant between-study heterogeneity, with one particular outlier study, favouring the comparator arm.17 This study also included cases with radiographic failures and had unusually low efficacy rates for azithromycin-treated cases of S. pneumoniae and H. influenzae without reporting antibiotic susceptibility profiles of the isolates. Sensitivity analysis, after removing this outlier, resulted in a statistically significant reduction of clinical failures in azithromycin-treated patients (random effects odds ratio 0.50, 95% CI 0.300.82, fixed effect odds ratio 0.47, 95% CI 0.310.74). In the remaining 12 studies, there was no significant between-study heterogeneity.
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We identified 30 independent studies with a total of 34 comparisons. Fifteen studies and one of the two trials included in another study22 were excluded. Nine comparisons (n = 64 patients)15,20,22,27,29,30,37,47,52 had fewer than 10 patients in a treatment arm; the clinical outcomes were not given for specific lower respiratory tract infections in four trials (n = 111 patients);24,26,31,35 the study arms compared different azithromycin treatment schedules in three comparisons.25,45,46 In total, fewer than 175 patients with pneumonia treated with azithromycin versus a comparator antibiotic were excluded from the analysis.
Fifteen studies including 1664 patients were eligible for the quantitative data synthesis (Table 3). Three studies19,28,51 reported two qualifying randomized trials each (two independent comparisons in two different patient populations each); thus, 18 independent comparisons were included (Table 3
).
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The majority of the studies (n = 10) used traditional clinical signs and symptoms for the definition of pneumonia (Table 3). The clinical criteria used were not defined in four studies (Table 3
). Twelve studies also specifically required or considered new pulmonary infiltrates in chest radiograph as an additional inclusion criterion. Purulent sputum, Gram's stain, leucocytosis, elevated erythrocyte sedimentation rate, neutrophilia and age were used to target patients with either atypical pneumonia or bacterial pneumonia in most comparisons (n = 13), while five studies did not attempt to separate these syndromes. Few studies specifically excluded special categories of patients, such as patients with leucopenia (n = 2), cystic fibrosis (n = 3), high-risk patients (n = 5), immunocompromised patients (n = 1), patients requiring intravenous or additional antibiotics (n = 3) or cases with pathogens resistant to the study drugs (n = 3). It is conceivable that such categories were also not included in other studies as well, although this was not specifically stated.
Based on eligibility criteria and pathogens detected, typical bacterial pneumonias predominated in five comparisons, atypical pneumonias predominated in seven comparisons, while both bacterial and atypical pneumonias were targeted in another six studies (Table 3). Of course, some contamination with atypical pneumonias would be unavoidable in trials targeting typical pneumonias and vice versa.
Eight studies used a 3 day azithromycin regimen,16,32,34,38,4043 and the other seven studies used a 5 day regimen. All the adult studies used 1500 mg total dose of azithromycin, except for one19 where 3000 mg were used. In the paediatric studies the maximal azithromycin dose used was also 1500 mg, when mentioned. The comparator drugs were erythromycin (n = 6), roxithromycin (n = 2), josamycin (n = 2), clarithromycin (n = 3), cefaclor (n = 2), co-amoxiclav (n = 2) and benzylpenicillin (n = 1).
The randomization method was described in detail in three cases.22,42,51 The majority of the studies were open-label (n = 12), but there were three double blind studies (four comparisons)28,32,33 and masking was unclear in two other studies.14,22 The methods ensuring allocation concealment were not described in detail in any of the studies.
The total number of patients in the 18 eligible comparisons was 1664. The largest study had 407 patients, but the largest sample size in a comparison was only 219. In all studies, outcome evaluation was carried out at around day 10 (range, 520 days). Overall there were 56 clinical failures in 928 (6.0%) evaluable patients treated with azithromycin and 72 clinical failures in 736 (9.8%) evaluable patients in the comparator arms. There was no significant between-study heterogeneity. A significant reduction in the risk of clinical failures was noted with azithromycin therapy (random effects odds ratio 0.63, 95% CI 0.420.95) (Figure 3). The fixed effects and random effects results were similar.
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Table 4 shows the pooled estimates for each of the three conditions and subgroup analyses according to type of antibiotic and, in the case of community-acquired pneumonia, type of syndrome involved. We observed no significant heterogeneity for different comparators or between atypical and typical pneumonias. Nevertheless, subtle differences in subgroups could have been missed due to type II error.
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There were limited data from double blind studies and their pooled results were inconclusive. The random effects odds ratios for acute bronchitis, acute exacerbations of chronic bronchitis and community-acquired pneumonia were 1.50 (95% CI, 0.514.43), 0.75 (95% CI, 0.321.75) and 1.12 (95% CI, 0.323.88), respectively. The respective fixed effects point estimates were 1.50, 0.71 and 1.05.
There was no evidence of publication bias and inverted funnel plots were symmetrical for all three conditions of interest. Similarly, there was no evidence that the treatment effect changed over time in more recent publications and for all three conditions the clinical failure rate in the comparator antibiotic was not significantly related to the treatment effect.
Adverse events
All 39 trials were considered in the analysis of safety. Data on discontinuation due to side effects per study arm were available in 33 trials. Data were not available in six trials, for a total of 458 patients with lower respiratory tract infections receiving azithromycin.17,25,32,42,49,51 Overall, there were 23 discontinuations due to adverse events among 3487 patients receiving azithromycin (discontinuation rate 0.7%). The respective discontinuation rates for the other antibiotics were 4.0% for co-amoxiclav, 0.9% for clarithromycin, 2.2% for erythromycin and 2.8% for cefaclor. The side effects that led to discontinuation of azithromycin included gastrointestinal tract side effects (n = 8), rash (n = 3), paraesthesia (n = 1), hyperkinesia and urticaria (n = 1) and unstated reasons (n = 10). In indirect comparisons, therapy was more often discontinued because of adverse events when antibiotics other than azithromycin were used (Table 5). In direct comparisons, discontinuations were significantly fewer with azithromycin versus co-amoxiclav, while direct comparison data with other specific antibiotics were sparse.
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Discussion |
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Several possibilities may explain the dissociation of the treatment effects for pneumonia and other lower respiratory tract infections. Random error is one such possibility, given the substantial confidence intervals. Bias also cannot be excluded, as the majority of trials were open-label and, therefore, may not be fully objective in the determination of clinical outcomes. The direction of bias would depend on whether there is a subconscious predilection of the investigators in favour of a particular antibiotic. Furthermore, there is a debate on whether meta-analyses of small trials provide similar results to single large studies.5456 The meta-analysis indicates that small under-powered antibiotic studies may yield results that are very difficult to interpret. Study design in the field can definitely be improved and the meta-analysis shows several deficiencies that would be easy to correct. Careful meta-analyses and well-designed, preferably double blinded and adequately powered large trials should be encouraged in the field of antimicrobial chemotherapy in general.57 We should caution that the few double blind trials are inconclusive about the relative merits of azithromycin for all three types of infection.
Acknowledging these caveats, the superiority of azithromycin for community-acquired pneumonia may also be a true finding. Azithromycin may provide benefits related to its unique pharmacokinetics. Following accumulation in tissue, azithromycin concentrations decline very slowly, remaining in excess of the MICs for many pathogens responsible for respiratory tract infections.7,58 This allows more convenient, short-course dosing, which is valuable for ensuring patient compliance and minimizing the potential for developing antibiotic resistance or re-infection. The optimal duration of treatment for most respiratory tract infections is not known. Acute bronchitis may respond to a few days of antibiotic therapy59 and there is substantial evidence emerging that 5 day regimens of quinolones or ß-lactams may be effective for treating acute exacerbation of chronic bronchitis.36,6064 Conversely, the treatment of pneumonia is likely to require longer courses of antibiotic therapy and prolonged high tissue antibiotic levels may be more important.
Our meta-analysis was limited to studies of oral azithromycin regimens, but recently some randomized evidence has become available for iv azithromycin. Inclusion of two recent trials65,66 where azithromycin was given initially intravenously in patients with community-acquired pneumonia would not change the results: among a total of 2077 randomized patients, the pooled odds ratio for clinical failures is 0.69 (95% CI 0.510.94, P = 0.018) favouring azithromycin against the comparator antibiotics. Neither of the two trials of iv azithromycin was double blind, highlighting again the need for more masked trials. Since the completion of the meta-analysis, one more double blind trial of azithromycin versus co-amoxiclav has been published67 and its results (five clinical failures in 56 patients given azithromycin versus seven failures in 54 given co-amoxiclav) reinforce the superiority of azithromycin.
One should also consider the proportion of spontaneous cures (viral or even bacterial) in each of the three types of lower respiratory tract infections that we examined in this meta-analysis. Spontaneously cured infections are likely to represent a larger proportion of cases of acute bronchitis than of acute exacerbations of chronic bronchitis and community-acquired pneumonia. The inclusion of a large proportion of spontaneously cured infections would diminish the ability of any trial or meta-analysis to show a treatment difference between antibiotic regimens. The same explanation may be offered for the lack of treatment differences we observed in the companion meta-analysis of upper respiratory tract infections,8 where most cases of otitis media and sinusitis resolve spontaneously. Such an explanation would account for the lack of demonstrable superiority in acute bronchitis and for acute exacerbations of chronic bronchitis. A recent meta-analysis has questioned whether antibiotics are generally indicated at all for the treatment of acute bronchitis in otherwise healthy individuals.68 Most patients diagnosed with acute bronchitis in outpatient practice may require no antibiotics at all.
Information on severe-grade side effects was not consistently reported in the trial reports, a deficiency we have observed previously in antibiotic trials.69,70 However, there were largely complete data on discontinuations from adverse events. The available data indicated that azithromycin led to few discontinuations with only one out of c. 150 patients discontinuing the drug because of adverse events. More detailed data on adverse events would be important to record in antibiotic trials, since given the comparable efficacy of various antibiotics, tolerability is an important consideration. The available evidence indicates that azithromycin is safe in patients with lower respiratory tract infections and compares favourably against other commonly used antibiotics.
If the superiority of azithromycin for community-acquired pneumonia is real, the estimated treatment benefit may be clinically meaningful, with approximately a one-third reduction in the rate of clinical failure. The absolute benefit amounts to an estimated one failure prevented per 50 patients with community-acquired pneumonia. These figures need to be considered in conjunction with both the tolerability profile, and the increased cost of this regimen in order to determine whether azithromycin should be a first-line antibiotic for lower respiratory infections.
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Acknowledgements |
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Notes |
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References |
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Received 25 January 2001; returned 19 July 2001; revised 6 August 2001; accepted 23 August 2001