Therapeutics Systematic review and meta-analysis
Long-term antibiotic therapy reduces exacerbation frequency in patients with COPD but it remains unclear which patients to target 10.1136/eb-2013-101711
James P Allinson, Gavin C Donaldson Centre for Respiratory Medicine, University College London, London, UK Correspondence to: Dr Gavin C Donaldson, Centre for Respiratory Medicine, University College London, Rowland Hill Street, London NW3 2PF, UK; [email protected]
Commentary on: Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev 2013;11:CD009764.
Context Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease. Acute exacerbations of COPD are key events that inflict significant morbidity, mortality and healthcare utilisation costs.1 Exacerbation prevention is a key strategy by which health-related quality of life and disease prognosis could be improved. There is currently an unmet need for therapeutics which effectively target exacerbations and their consequences. Historically, long-term antibiotics have been used to treat COPD.2 Herath and Poole’s review examines whether or not this therapy reduces COPD exacerbations and improves clinical outcomes. The limitations of the evidence and the potential therapeutic drawbacks are discussed.
Methods This systematic review considered randomised control trials (RCTs) published before August 2013 of orally administered, appropriately dosed, antibiotics given for at least 3 months to adult patients, with COPD confirmed by spirometry according to international guidelines. The authors describe their search methods clearly and the analysis is undertaken according to the Cochrane guidelines. The primary outcomes examined included the number of exacerbations and health-related quality of life. Secondary outcomes included exacerbation duration and severity, days of disability, frequency and duration of hospital admissions, lung function decline, microbial resistance, adverse events, and respiratory and all-cause mortality.
Findings Seven RCTs fulfilled inclusion criteria (3170 patients with a mean age of 66 years and moderate-to-severe COPD). Meta-analysis of three trials (n=1262) using continuous macrolide therapy found a reduction of
patients reporting at least one exacerbation per year (odds ratio=0.55, 95% CI 0.39 to 0.77) with a number needed to treat of 8 (95% CI 5 to 18). Continuous therapy reduced exacerbation frequency (relative risk=0.73, 95% CI 0.58 to 0.91). The one trial using a pulsed quinolone did not reduce the number of patients reporting at least one exacerbation. Meta-analysis of two trials (n=1926, one continuous, one pulsed) for improvements in quality of life showed mean difference of −1.78 (95% CI −2.95 to −0.61), although the authors considered a mean difference of 4 to be clinically significant. Both antibiotic-specific adverse events (hearing loss with azithromycin and gastrointestinal disturbance with moxifloxacin) and increased bacterial resistance (eg, the development of moxifloxacin-resistant pseudomonas) were detected but meta-analysis of these data was not possible.
Commentary Although the meta-analysis concluded that continuous prophylactic macrolide therapy reduces COPD exacerbation frequency, this outcome relied on combining just three clinical trials. There was no clinically significant health status improvement or reduced lung function decline. The heterogeneity of antibiotics and methods made it difficult to draw any conclusions regarding side-effects or bacterial resistance beyond those reported in the original trials. These risks prevent prophylaxis from being recommended by the major COPD guidelines. Unsurprisingly, the authors do not suggest that this stance should change, but the manuscript does highlight the need for further well-conducted clinical trials. Fundamentally, we do not know which patients will benefit from long-term antibiotic therapy, and in whom the risks might be worth taking. It is possible that post hoc analysis could reveal which patient groups experience the most benefit and whether or not patient characteristics, such as chronic bronchitis, or inflammatory biomarkers could be used to select patients for future trials. An analysis of blood markers in one trial using azithromycin3 found that the decline in soluble tumour necrosis factor receptor 75 predicted time to the first exacerbation differently between the placebo and azithromycin groups.4 Improved understanding of the mechanisms by which long-term antibiotics reduce exacerbation rate might also help guide their use. This review highlights the paucity of good-quality studies of longterm antibiotic therapy in COPD, but by identifying the good studies it will help move the field forward. Competing interests None. References 1. Wedzicha JA, Brill SE, Allinson JP, et al. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med 2013;11:181. 2. James GD, Petersen I, Nazareth I, et al. Use of long-term antibiotic treatment in COPD patients in the UK: a retrospective cohort study. Prim Care Respir J 2013;22:271–7. 3. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689–98. 4. Prescott GW, Richard KA, Wissam C, et al. Analysis of blood biomarkers in the NIH-sponsored Azithromycin in COPD study. A13 Advances in COPD pathogenesis and exacerbation susceptibility. Am J Resp Crit Care Med 185:2012:A1007.
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Long-term antibiotic therapy reduces exacerbation frequency in patients with COPD but it remains unclear which patients to target 10.1136/eb-2013-101711
James P Allinson, Gavin C Donaldson Centre for Respiratory Medicine, University College London, London, UK Correspondence to: Dr Gavin C Donaldson, Centre for Respiratory Medicine, University College London, Rowland Hill Street, London NW3 2PF, UK; [email protected]
Commentary on: Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev 2013;11:CD009764.
Context Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease. Acute exacerbations of COPD are key events that inflict significant morbidity, mortality and healthcare utilisation costs.1 Exacerbation prevention is a key strategy by which health-related quality of life and disease prognosis could be improved. There is currently an unmet need for therapeutics which effectively target exacerbations and their consequences. Historically, long-term antibiotics have been used to treat COPD.2 Herath and Poole’s review examines whether or not this therapy reduces COPD exacerbations and improves clinical outcomes. The limitations of the evidence and the potential therapeutic drawbacks are discussed.
Methods This systematic review considered randomised control trials (RCTs) published before August 2013 of orally administered, appropriately dosed, antibiotics given for at least 3 months to adult patients, with COPD confirmed by spirometry according to international guidelines. The authors describe their search methods clearly and the analysis is undertaken according to the Cochrane guidelines. The primary outcomes examined included the number of exacerbations and health-related quality of life. Secondary outcomes included exacerbation duration and severity, days of disability, frequency and duration of hospital admissions, lung function decline, microbial resistance, adverse events, and respiratory and all-cause mortality.
Findings Seven RCTs fulfilled inclusion criteria (3170 patients with a mean age of 66 years and moderate-to-severe COPD). Meta-analysis of three trials (n=1262) using continuous macrolide therapy found a reduction of
patients reporting at least one exacerbation per year (odds ratio=0.55, 95% CI 0.39 to 0.77) with a number needed to treat of 8 (95% CI 5 to 18). Continuous therapy reduced exacerbation frequency (relative risk=0.73, 95% CI 0.58 to 0.91). The one trial using a pulsed quinolone did not reduce the number of patients reporting at least one exacerbation. Meta-analysis of two trials (n=1926, one continuous, one pulsed) for improvements in quality of life showed mean difference of −1.78 (95% CI −2.95 to −0.61), although the authors considered a mean difference of 4 to be clinically significant. Both antibiotic-specific adverse events (hearing loss with azithromycin and gastrointestinal disturbance with moxifloxacin) and increased bacterial resistance (eg, the development of moxifloxacin-resistant pseudomonas) were detected but meta-analysis of these data was not possible.
Commentary Although the meta-analysis concluded that continuous prophylactic macrolide therapy reduces COPD exacerbation frequency, this outcome relied on combining just three clinical trials. There was no clinically significant health status improvement or reduced lung function decline. The heterogeneity of antibiotics and methods made it difficult to draw any conclusions regarding side-effects or bacterial resistance beyond those reported in the original trials. These risks prevent prophylaxis from being recommended by the major COPD guidelines. Unsurprisingly, the authors do not suggest that this stance should change, but the manuscript does highlight the need for further well-conducted clinical trials. Fundamentally, we do not know which patients will benefit from long-term antibiotic therapy, and in whom the risks might be worth taking. It is possible that post hoc analysis could reveal which patient groups experience the most benefit and whether or not patient characteristics, such as chronic bronchitis, or inflammatory biomarkers could be used to select patients for future trials. An analysis of blood markers in one trial using azithromycin3 found that the decline in soluble tumour necrosis factor receptor 75 predicted time to the first exacerbation differently between the placebo and azithromycin groups.4 Improved understanding of the mechanisms by which long-term antibiotics reduce exacerbation rate might also help guide their use. This review highlights the paucity of good-quality studies of longterm antibiotic therapy in COPD, but by identifying the good studies it will help move the field forward. Competing interests None. References 1. Wedzicha JA, Brill SE, Allinson JP, et al. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med 2013;11:181. 2. James GD, Petersen I, Nazareth I, et al. Use of long-term antibiotic treatment in COPD patients in the UK: a retrospective cohort study. Prim Care Respir J 2013;22:271–7. 3. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689–98. 4. Prescott GW, Richard KA, Wissam C, et al. Analysis of blood biomarkers in the NIH-sponsored Azithromycin in COPD study. A13 Advances in COPD pathogenesis and exacerbation susceptibility. Am J Resp Crit Care Med 185:2012:A1007.
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