In Adults With Moderate or Severe COPD Without Bronchiectasis, Continuous Prophylactic Antibiotics Reduce Exacerbations but Azithromycin Increases Risk of Hearing Loss

EBM Focus - Volume 9, Issue 4

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Reference: Cochrane Database Syst Rev 2013 Nov 28;11:CD009764 (level 1 [likely reliable] evidence)

Many patients with COPD will experience acute exacerbations, which often occur after respiratory infections. These exacerbations may require additional treatments, and can lead to reduced quality of life and increased risk of hospitalization or mortality. A recent Cochrane review evaluated the efficacy of prophylactic antibiotics in adults with moderate or severe COPD.

The systematic review identified 7 randomized trials comparing prophylactic oral antibiotics to placebo for at least 3 months in 3,170 adults with moderate or severe COPD. All patients were at least 40 years old and had presented with 1 or more exacerbations in the previous year. Trials evaluating patients with bronchiectasis, asthma, or genetic diseases such as cystic fibrosis were excluded. The administration of antibiotics was continuous in 5 trials and intermittent or pulsed in the other 2 trials. The antibiotics evaluated included erythromycin, azithromycin, clarithromycin, and moxifloxacin. The primary outcomes for the review were the number of exacerbations and quality of life, assessed with the St. George’s Respiratory Questionnaire (0-100 points, with higher scores indicating worse quality of life).

The duration of follow-up was 6 to 12 months in the analysis of exacerbations and 6 to 18 months for the analyses of quality of life and serious adverse events. In a meta-analysis of 4 trials with 2,411 adults, prophylactic antibiotics were associated with reduced risk of exacerbations (odds ratio 0.64, 95% CI 0.45-0.9), with a number needed to treat (NNT) from 5 to 40, given an exacerbation rate of 60% with placebo. A sensitivity analysis showed that the reduction in exacerbations was significant only in trials evaluating continuous administration of antibiotics.

Prophylactic antibiotics (continuous or pulsed) were also associated with greater reductions in symptom scores on the St. George’s Respiratory Questionnaire (mean difference 3.75 points, 95% CI 2-5.5 points) in a meta-analysis of 2 trials with 1,926 adults. However, this difference was below the conventional minimal clinically important difference of 4 points. In addition, prophylactic antibiotics were associated with an increased incidence of gastrointestinal adverse events in a meta-analysis of 4 trials with 2,408 adults (odds ratio 1.58, 95% CI 1.01-2.47).

One high-quality trial evaluating prophylactic azithromycin in 1,117 adults showed that azithromycin was associated with an increased risk of hearing impairment (p = 0.04, NNH 20). This trial also evaluated antibiotic susceptibility of selected respiratory pathogens in patients who were not colonized at enrollment but became colonized during the study, and found that 84% of patients receiving azithromycin harbored macrolide-resistant organisms compared to 41% of patients receiving placebo (p< 0.001).

Another recent systematic review of 6 randomized trials had consistent findings, showing a 37% relative risk reduction in COPD exacerbations among patients taking macrolides compared to placebo (Respir Med 2013 Sep;107(9):1385). However, the benefit of reduced exacerbations must be balanced against an increased risk of adverse events. Furthermore, the continuous use of prophylactic antibiotics in this population may have a significant impact on antibiotic resistance in the wider community. A large multicenter cohort study in the United States found that the rate of macrolide resistance to Streptococcus pneumoniae isolates increased significantly to 35.3% in 2005-2006 from a stable rate of about 30% in the previous 3 years (Emerg Infect Dis 2009 Aug;15(8):1260 full-text). In some regions resistance rates are much higher, potentially restricting the options available for treating a wide range of infectious diseases commonly managed with these antibiotics.

For more information, see the COPD and Acute exacerbation of COPD topics in DynaMed.