Several small studies evaluating whether macrolides decrease the frequency of acute exacerbations of COPD have reported conflicting results.This RCT tested the hypothesis that azithromycin decreases the frequency of acute exacerbations of COPD when added to the usual care of these patients.

The study involved 1142 subjects at an increased risk of exacerbations but with no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval, who were randomised to azithromycin 250 mg daily (n= 570), or placebo (n= 572) for 1 year in addition to their usual care. The primary outcome was the time to the first acute exacerbation of COPD, with acute exacerbation of defined as “a complex of respiratory symptoms (increased or new onset) of more than one of the following: cough, sputum, wheezing, dyspnoea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids.

The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The following findings were reported:

• The median time to first exacerbation was 266 days (95% CI, 227 to 313) in the azithromycin group vs. 174 days (143 to 215) among those on placebo (p < 0.001).

• The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group vs. 1.83 per patient-year in the placebo group (p = 0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; p<0.001).

• The scores on the St. George’s Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (mean decrease of 2.8 vs. 0.6, p = 0.004); the percentage of participants with more than the minimal clinically important difference of −4 units was 43% in the azithromycin group vs. 36% in the placebo group (p = 0.03).

• Hearing reductions were more common in the azithromycin group than in the placebo group (25% vs. 20%, p = 0.04).

The researchers conclude from these findings that “among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing reduction in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known.”

The author of an accompanying editorial suggests that these findings “tip the scales toward the benefits of azithromycin treatment” but cautions that local antibiotic resistance patterns should be closely monitored if azithromycin is going to be used in patients who are known to have frequent exacerbations of COPD. Furthermore, whether subsequent exacerbations should be treated empirically with a different class of antibiotics, should be considered. On balance, however, the author considers that the “long-term use of azithromycin to prevent acute exacerbations of COPD would not seem to be at odds with the classical advice of Hippocrates- Do good, not harm.”