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Duration of antibiotic treatment and symptom recovery in community-acquired
pneumonia
El Moussaoui, R.
Publication date
2006
Link to publication
Citation for published version (APA):
El Moussaoui, R. (2006). Duration of antibiotic treatment and symptom recovery in
community-acquired pneumonia.
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CHAPTER
Short Course Antibiotic Treatment in Acute Exacerbations of chronic bronchitis and COPD: a meta-analysis of double-blind studies
R. el Moussaoui', B.M. Roede', P. Speelman', P. Bresser, LM. Prins', P.M.M. Bossuyt3
'Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, and
Center for Infection and Immunity Amsterdam (CINIMA), 2 Department of Pulmonology and
Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands
Abstract
Objective: To determine whether a short course of antibiotic treatment is as effective as the
conventional longer treatment in patients with acute exacerbations of chronic bronchitis and COPD.
Method: Systematic review of the available literature and meta-analysis.
Data Sources: MEDLINE, EMBASE and the Cochrane central register of controlled trials on
the Cochrane library were searched to July 2006.
Review Methods: Eligible were double-blind randomized clinical trials including adult
patients > 18 years of age with clinical diagnosis of exacerbation of chronic bronchitis and COPD or pulmonary emphysema, no antimicrobial therapy at the time of diagnosis and random assignment to antibiotic treatment up to 5 days versus longer than 5 days.
Main outcome measures: Primary outcome measure was clinical treatment failure at early
follow-up, on intention to treat basis. Secondary outcome measures were clinical failure at late follow-up and the bacteriological failure rate.
Results: 21 studies with a total of 10698 patients were included. The average quality of the
studies was high: the mean Jadad score was 3.9 (SD 0.9). At early follow-up (<25 days) the summary odds ratio (OR) for clinical treatment failure with short treatment versus conventional treatment was 1.01 (95% CI 0.92 to 1.11). At late follow-up the summary OR was 1.0 (95% CI 0.91 to 1.10) and the summary OR for bacteriological failure was 0.96 (95% CI 0.80 to 1.15). Similar summary ORs were observed for early failure in studies grouped by the antibiotic class used in the short arm.
Conclusions: A short course (5 days) of antibiotic treatment is as effective as the traditional
Short Course Antibiotic Treatment in Acute Exacerbations of chronic bronchitis and COPD
Introduction
Chronic bronchitis affects 3% to 17% of the adult population in developed countries '. Acute exacerbations of chronic bronchitis (AECB) occur frequently. Causes include air pollutants, allergens and viruses, as well as bacterial pathogens. The predominant bacterial pathogen implicated in AECB is Haemophilus influenzae, which is present in 50% of all bacterial exacerbations, with approximately a further third of isolates being either Streptococcus
pneumoniae or Moraxella catarrhalis .
Most patients with AECB are treated with antibiotics but the benefit of antibiotic therapy remains controversial. This controversy is fuelled by data suggesting that at least one third of exacerbations is non-infectious in origin 3"5. In addition, clinical trials of antibiotics have
yielded conflicting data, with several large studies failing to demonstrate superiority of antibiotic therapy above placebo 6;7. Other trials indicated that antibiotic therapy is effective in
patients who have at least two of the following symptoms: increased dyspnoea, increased sputum volume and increased sputum purulence (i.e. a type 1 or 2 exacerbation) , and in those with more severe chronic obstructive pulmonary disease (COPD) . A meta-analysis recently included in the Cochrane Library confirms these findings in COPD patients. In acute exacerbations with increased cough and sputum purulence the use of antibiotics reduces the risk of short-term mortality by 77% and decreases the risk of treatment failure by 53% . This raises the question how long the duration of antibiotic therapy should be. Antibiotic consumption in AECB occurs on large scale and this may contribute to increasing resistance rates of the relevant pathogens li:l2. Up to 35% of//, influenzae and > 90% of M. catarrhalis
produce p-lactamases l3"16. Worldwide, the prevalence of penicillin resistance among strains
of S. pneumoniae ranges from 1% to 59%17. A shorter duration of treatment might help
contain these growing resistance rates, but a shorter treatment can only be recommended if this is equally efficacious.
We performed a systematic review and meta-analysis of published randomized double-blind studies to answer the question whether a short course of antibiotic treatment is as effective as a long course in patients with a type 1 or 2 exacerbation of chronic bronchitis and COPD.
Methods
Criteria for considering studies for this review and primary outcomes
Eligible for inclusion were randomized trials of antibiotic intervention involving adult patients > 18 years of age with a diagnosis of chronic bronchitis or COPD. We excluded studies not published in the English language.
The primary outcome was clinical treatment failure at early follow-up (the latter as defined by the authors of the studies), which included lack of clinical resolution or improvement, and indeterminate outcome: clinical response to the study drug could not be assessed for any reason. Clinical cure was defined as resolution or improvement of the clinical symptoms of the exacerbation. Secondary outcomes were (1) the rate of clinical treatment failures, recurrences, relapses and indeterminate cases reported from the time of diagnosis to the final evaluation point, and (2) the bacteriological failure rate, which included persistence of the causative pathogen, presumed persistence (no material was available in a patient considered a
clinical failure), and indeterminate outcome: if the bacteriological response to the study drug was not evaluable for any reason.
Search strategy for identification of studies
We searched the Cochrane central register of controlled trials on the Cochrane library (issue 2, 2006), Medline (1966-July 2006) and Embase (1988-July 2006), using the following search terms: chronic bronchitis or COPD, antibiotic treatment, and clinical trials (see appendix A for details of the search strategy). We also searched the reference lists of included studies for additional studies.
Data extraction
Studies were included in the meta-analysis if they satisfied the following criteria: (1) adult patients > 18 years of age, (2) clinical diagnosis of exacerbation of chronic bronchitis or COPD or pulmonary emphysema, (3) no antimicrobial therapy at the time of diagnosis, (4) random assignment to antibiotic treatment up to 5 days versus treatment longer than 5 days, (5) study design with double blinding. Double-blind studies with azithromycin in the short arm were excluded. This antibiotic has a very long half-life, and 3 days of azithromycin can therefore not be regarded as a short therapy.
Two authors independently rated abstracts identified by the electronic searches for inclusion in the meta-analysis. Inter-rater reliability for trial selection was assessed with Cohen's K. In case of disagreement between raters the full original article was retrieved for data extraction. Differences in opinion over inclusion of studies were resolved through discussions and consensus.
Hard copies of the full article of all potentially eligible studies were obtained. Two reviewers independently extracted the following data from each study: the author, year of publication, sample size, mean age of subjects, percentage of smokers, hospitalized or outpatient status of the subjects, antibiotic regimen used, antibiotic treatment duration, criteria used to define exacerbation of chronic bronchitis or COPD, and the major outcome measure(s) for each study.
Assessment of study quality
The internal validity of included trials was assessed by the same reviewers using the Jadad scale '8. The scale assigns scores from 0 to 5 (best quality trial), based on the following items:
(1) the study is randomized, (2) the intervention is double-blind, (3) an accounting and description of study withdrawals is done, (4) the randomization procedure is adequately performed using an appropriate method such as computer generated random numbers, and (5) the blindness is also adequately performed using identical looking placebo.
Concealment of treatment allocation was also evaluated for adequacy: if trialists were unaware of each participant's allocation when they were recruited, the allocation was said to be adequately concealed.
Statistical analysis
Meta-analyses were performed with the Cochrane collaboration's Revman 4.1 progam (Cochrane Collaboration, Oxford, UK). From each study the clinical and bacterial failure rates were calculated and the risk of treatment failure with a short course of antibiotics (< 5
Short Course Antibiotic Treatment in Acute Exacerbations of chronic bronchitis and COPD
days), as compared to a longer course (> 5 days), was expressed as an Odds Ratio (OR) with 95% confidence intervals (CIs). An OR > 1 indicates a greater number of failures with the short course of antibiotics and superiority of the long course of antibiotics.
Summary Odds Ratios (OR) were calculated based on the individual trial outcomes using the fixed-effects model. In additional analyses, studies were grouped by the classes of the antibiotic used in the short-course arm: cephalosporins, macrolides (other than azithromycin) and fluoroquinolones. Statistical heterogeneity among trials was assessed by chi-square analysis. The presence of publication bias was assessed by a funnel plot.
Sensitivity analyses were conducted to assess the robustness of the study by comparing summary ORs among groups redefined by (1) excluding trials of a lower methodological quality (Jadad score < 4), (2) excluding trials with inadequate or unknown concealment, and (3) excluding trials of comparisons between different antibiotics.
Results
Literature search and trial inclusion
The search strategy identified 885 studies. A total of 30 full hard copies were selected for further data extraction (figure 1). There was 94% agreement about which abstracts to include for retrieval of hard copies (K 0.79, 95% CI 0.66 to 0.92).
Of these potentially eligible studies, 21 met the criteria for inclusion in the meta-analysis (shown in table 1). Three trials had three treatment arms l9~21. In these cases the comparison of
the short and long duration with the same antibiotic was chosen above the comparison between different antibiotics. Two trials were reported in a single paper . As sufficient information could be extracted from this paper, they were included in the meta-analysis. Methodological quality
The mean quality score for the trials was 3.9 (standard deviation (SD) 0.9) on the Jadad scale. Seventy-one percent were of very high quality (Jadad score > 4) (table 1). Substantial inter-rater agreement for assignment of this score was reached (K 0.75, 95% CI 0.60 to 0.90). Seventeen studies (81%) described the reasons for patient withdrawal. Six trials (29%) were judged as having adequate allocation concealment (table 1); the remaining studies did not
describe the concealment of treatment allocation. Description of trials
The 21 included studies included a total of 10698 patients (table 1), of which 5348 patients were allocated to short treatment groups and 5350 to long treatment groups. Four trials did not specify how exacerbation was defined. All other trials included only patients satisfying at least two of the following criteria: increased cough and/or dyspnea, increased sputum volume and increased purulence (i.e., a type 1 or 2 exacerbation as defined by Anthonisen8). The mean age of study patients was 57.4 years (SD 4.3) in the short treatment
groups versus 58 (SD 4.4) in the long treatment groups. The percentage of smokers was 71.8 (SD 16.3) versus 71.8 (SD 16.3). A majority of the studies had included outpatients. The mean duration of treatment was 4.9 days (SD 0.4) in the short treatment groups versus 8.3 (SD 1.5) in the long treatment groups (table 1).
All trials defined clinical cure as the disappearance of AECB-related signs and symptoms, return to the pre-infection state, or sufficient improvement such that additional or alternative antimicrobial therapy was not required. The mean early follow-up evaluation moment was after 15 days (SD 3.5) and the mean late evaluation moment was at day 31 (SD 5.3). In all but one trial 20 clinical failure rates at early follow-up could be extracted or calculated. Four
studies ~ " did not report clinical failure rates at late follow-up. Three studies 23;26;27 did not
report bacteriological failure rates.
Total number of abstracts screened by electronic search n= 1112
i '
Potentially relevant studies retrieved n=147
• r
Duplicates n-227
Excluded
Not meeting inclusion criteria n=738
Excluded
- Duration of therapy:
- Equivalent in both study arms n= 92 - < 5 days in both study arms n=7 - > 5 days in both study arms n=6 - Open or single blind study design n=12 Trials considered for meta-analvsis n=30
Trials included in meta-analvsis n=21
Excluded:
- Azithromycin in the short arm n=4 - Insufficient data n=l
- Short treatment is 5-7 days n=l - Included non-COPD patients n=2 - Meta-analysis n=l
Figure 1 Flowchart of stages of the systematic review of shorter duration of antibiotic therapy in exacerbations of COPD or chronic bronchitis
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The primary outcome analyzed was the clinical failure rate at the early follow-up in an intention to treat (ITT) analysis. Early follow-up was in all studies before day 25. Tests for statistical heterogeneity were performed for all analyses. Statistically significant heterogeneity was not observed in the primary outcome of early clinical failure (p=0.8), nor in the secondary outcomes of late clinical failure (p=0.34) or bacteriological failure (p=0.2). A funnel plot did not suggest any form of publication bias.
The summary odds ratio (OR) for early treatment failure was 1.01 (95% CI 0.92 to 1.11) (figure 2). The summary odds ratio for failures, relapses, recurrences and indeterminate cases at late follow-up was 1.0 (95% CI 0.91 to 1.10). The summary OR for bacteriological failure was 0.96 (95% CI 0.80 to 1.15) (figure 3).
Similar summary ORs were observed for early clinical failure in studies grouped by the antibiotic class used in the short arm. The summary OR was 0.97 (95% CI 0.81 to 1.16) for cephalosporines, 1.04 (95% CI 0.86 to 1.24) for macrolides and 1.06 (95% CI 0.91 to 1.23) for fluoroquinolones (figure 4).
Sensitivity analysis
Sensitivity analyses were conducted for the primary outcome, i.e. clinical failure rate at the early follow-up. Treatment failure rates were not significantly more likely with shorter duration in very high quality trials (summary OR, 1.0; 95% CI 0.84 to 1.18), trials with adequate concealment (summary OR 0.96; 95% CI 0.8 to 1.15), or trials with the same antibiotic in both arms (summary OR 1.08; 95% CI 0.90 to 1.29).
Discussion
In this systematic review of randomized double-blind studies we found that short courses of antibiotic therapy (up to 5 days) are as effective as the conventional courses of longer than 5 days in the treatment of AECB. The clinical cure rates at both early and late follow-up as well as the bacteriological cure rates were comparable for both treatment strategies.
The overall methodological quality of studies was found to be high or very high, with 71% of the studies having a Jadad score of at least 4. Sensitivity analyses showed no differences between both treatment groups, enhancing the statistical robustness of the overall analysis and strengthening the appropriateness of combining all studies into a single meta-analysis. Statistically significant heterogeneity was not present, suggesting homogeneity of the patient populations.
A potential weakness of meta-analyses is the incorporation of existing biases and introduction of new biases " . To minimize bias during trial selection, we used predetermined inclusion criteria. Language bias must be considered, since this meta-analysis included only trials published in the English language. No signs of publication bias were detected.
Antibiotics are widely prescribed for respiratory tract infections (RTIs). RTIs account for 75% of community prescriptions 1;32. Tonsillopharyngitis is the most frequent indication,
followed by bronchitis. It has already been demonstrated that a short course (4-5 days) of cephalosporin therapy is at least as effective as 10 days of penicillin treatment in group A streptococcal tonsillopharyngitis , and that a short course (5 days) of short acting antibiotics is an effective treatment for uncomplicated acute otitis media in children 34. Studies
investigating the effectiveness of shorter courses in community-acquired pneumonia show 35"
Short Course Antibiotic Treatment in Acute Exacerbations of chronic bronchitis and COPD S t u d y Short c o u r s e C o n v e n t i o n a l c o u r s e n i l n i l OR (95%CI Fixed) Lorenz 1998 Langan 1998 Langan 1999 Wilson 1999 Wasilewski 1999b Wasilewski 1999a Fogarty 2000 Paster 2000 File 2000 Chodosh 2000 Masterton 2001 Aubier 2002 Wilson 2002 Soler 2003 Zervos 2003 Sethi 2004 Gotfried 2005 Fogarty 2005 Sethi 2005 Alvarez-Sala 2006 3 1 / 1 0 8 61 / 3 4 0 1 3 2 / 2 7 3 8 7 / 3 7 4 6 3 / 2 8 2 4 3 / 2 4 9 61 / 278 1 5 3 / 2 9 1 5 7 / 3 0 4 1 4 / 2 8 8 71 / 2 6 8 30 / 1 6 0 7 2 / 3 5 1 2 8 / 1 3 6 6 1 / 1 8 2 2 7 / 1 8 2 6 0 / 2 1 8 4 6 / 2 7 0 51 / 4 4 3 5 3 / 2 6 4 3 6 / 1 0 9 63 / 344 119 / 268 8 2 / 3 7 1 7 0 / 2 7 6 12 1 250 7 0 / 2 7 0 154 / 295 4 9 / 2 9 6 1 5 / 2 8 1 55 / 262 3 5 / 1 6 0 7 8 / 3 5 8 23 / 1 2 6 5 3 / 1 9 1 3 9 / 1 7 8 5 4 / 2 2 6 4 6 / 2 8 2 61 / 4 5 0 48 / 277 Total(9S%CI) 1201/5261 1 1 9 2 / 5 2 7 0 Test tor heterogeneity chi-square=1374 dt=19 p=0.8
Test for overall effect 1=0.28 p=0.8
W e i g h t % 3.0 6 0 12 7.4 6.4 4.0 6.5 8 4 4.7 1.7 4.8 3.3 7.1 2.2 4 0 3.9 4.5 4 3 6.2 4.4 100.0 OR (95%CI Fixed) 0.82(0.46,1.45] 0.98(066,1 44] 1.17(0.84,1.641 1.07(0.76,1.51] 0.85(0.57,1.25] 1 .03(0.65,1.65] 0.80(0.54,1.19] 1.02(0.73,1.40] 1.16(0.76,1.77] 0.91(0.43,1.91] 1.36(0.91,2.03] 0.82(0.48,1.42] 0.93(0.65,1.33] 1.16(0.63,2.15] 1.31(0.84,2.04] 0.62(0.36,1.07] 1.21(0.79,1.85] 1.05(0.67,1.65] 0.83(0.56,1.23] i 20(0 7:3.! 85] 1.01(0.92,1.11] F i g u r e 2 C l i n i c a l failure a t e a r l y f o l l o w - u p Favours s h o r t c o u r s e Favours c o n v e n t i o n a l c o u r s e Study Short c o u r s e C o n v e n t i o n a l c o u r s e n i l n i l OR (95%CI Fixed) W e i g h t % 5.2 1.2 14.2 3.0 9.6 6.1 3.4 3.5 6.2 2.2 7 I 4.5 5.0 1.8 3.2 12.8 6.4 4.4 100.0 OR (95%CI Fixed) 1.75(0.87,3.50] 1.87(0.44,7.93] 0.48(0.27,0.86) 1.38(0.52,3.60] 0.71(0.38,1.34] 1.56(0.81,3.01] 1.22(0.48,3.09] 0.39(0.11,1.37] 1.07(0.53,2.19] 0.35(0.07,1.87] 0.57(0.26,1.25] 1 14(0.50,2.59] 0.55(0.21,1.42] 1.16(0.32,4.20] 1.33(0.53,3.38] 0.88(0.52,1.47] 1.28(065,2.49] 1.37(0.62,3.05] 0 96(0.80,1.15] Langan 1998 Lorenz 1998 Wilson 1999 Langan 1999 W a s i l e w s k i 1999b W a s i l e w s k i 1999a Chodosh 2000 File 2000 Masterton 2001 Gotfried 2001 Wilson 2002 Aubier 2002 Soler 2003 Z e r v o s 2003 Sethi 2004 Sethi 2005 Gotfried 2005 Fogarty 2005 2 8 / 1 0 2 1 0 / 3 5 2 6 / 1 1 5 11 / 8 9 2 3 / 1 2 5 27 / 1 0 3 1 0 / 1 5 2 4 / 4 4 2 0 / 1 1 2 2 / 8 7 1 4 / 5 7 3 0 / 5 0 8 / 6 3 6 / 2 5 11 / 4 4 3 9 / 1 4 1 2 3 / 1 0 5 1 6 / 8 6 1 6 / 9 0 3/17 43/114 8/86 26/108 2 0 / 1 0 8 9/165 9 / 4 4 1 7 / 1 0 1 5 / 8 0 2 4 / 6 6 2 5 / 4 4 14/67 6/28 1 2 / 6 0 41 / 1 3 5 20/111 13/91 Total(95%CI) 3 0 8 / 1 5 3 5 3 1 1 / 1 5 1 5 Test for heterogeneity chi-square=21.69 df=17 p=0.2
Test for overall effect z=-0.48 p = 0 6
F a v o u r s ; course Favours conventional course F i g u r e s B a c t e r i o l o g i c a l f a i l u r e 27
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;ts é 13 8 « " i t ï H S t n s 3 CÜ o u o *• *-i ; 0) *-i 2 0) i E en J « o o S • ï ~ L^ ^ fM /VÏ ^n Ï : « . CO 5 Ö ï Z ° V I) - rShort Course Antibiotic Treatment in Acute Exacerbations of chronic bronchitis and COPD
According to most COPD-guidelines 3" 39 antibiotic treatment is only indicated in patients
with acute exacerbations of COPD characterized by increased sputum volume and purulence. The issue of the appropriate duration of antibiotic therapy, however, is not addressed in any of these guidelines.
Shorter courses of antibiotic treatment have several potential advantages compared to long course therapy. Poor compliance appears to be more common with longer treatment courses, so shorter courses of antibiotic treatment may enhance compliance. The compliance rate in tonsillopharyngitis, in which penicillin therapy is typically prescribed for 10 days, is inversely related to the duration of therapy and has been observed to be as low as 8% by the ninth day of treatment 40"42. It is to be expected that a short course will also reduce antibiotic costs.
More important is the effect of unnecessarily lengthy courses on the development of resistant organisms. On a population level there is a clear relationship between total antibiotic consumption and resistance rates of the pathogens ' ' ' . Decreasing the duration of antibiotic courses in respiratory tract infection might contribute to decrease these resistance rates 44.
Our meta-analysis convincingly demonstrates the effectiveness of short course treatment in exacerbations of chronic bronchitis or COPD characterized by at least two of the following criteria: increased cough and/or dyspnea, increased sputum volume and increased purulence. Based on the included studies, it seems that the duration of antibiotic treatment can be safely reduced. We therefore propose that the guidelines of chronic bronchitis and COPD should recommend antibiotic treatment duration of no longer than 5 days, regardless of antibiotic class.
Acknowledgment
We thank Heleen C. Dyserinck for her magnificent support with the search strategy.
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