Azithromycin for COPD

Motivation: During the first couple of months of internship, I have often taken care of patients with COPD, and in the morning presentations, the conversation inevitably turns towards the benefits of adding an antibiotic to the steroid regimen.  Macrolide antibiotics are thought to have additional anti-inflammatory benefits beyond the standard anti-microbial effects.  Recently, this hypothesis was extended further to test for beneficial effects of azithromycin in COPD patients as a standing drug in-between flares.

Paper: "Azithromycin for Prevention of Exacerbations of COPD", Albert, R.K. et. al. NEJM (2011) 365: 689-698.

Methods: A multi-centered, randomized controlled trial.  The trial included patients over 40 with a history of COPD (>10 pack year of smoking, FEV1/FVC<70%, and FEV1<80% of predicted value).  To the included in the study, the patients had to have either used systemic steroids or required ED/hospital care in the past 12 months.  Patients could also be included if using home oxygen.  The exclusion criteria were tachycardia, prolonged QTc, and hearing impairment.  The intervention was daily dose of 250 mg of azithromycin.  The primary outcome was the time to first acute exacerbation of COPD.  The follow-up period was one year.

Results: 
Patient Recruitment: Overall, 558 patients were in the treatment arm, and 559 patients were in the placebo group.  The completion rate was 89% in the treatment arm and 90% in the placebo group.  The treatment and placebo group did not differ significantly in terms of age, gender, race, disease severity, or home treatment regimens.

COPD Exacerbation: The median time to acute exacerbation was 266 days in the azithromycin group vs. 174 days in the placebo group (p<0.001).  A total of 741 exacerbations among 558 patients occurred in the azithromycin group while 900 exacerbations occurred in the placebo group (p=0.01).  The number needed to treat to prevent one acute exacerbation of COPD was 2.86.

Secondary Outcomes: There was not a statistically significant difference between the azithromycin and placebo groups in hospitalizations related to COPD (156 vs. 200, p =0.15), exacerbations requiring intubations (11 vs. 16, p=0.56), or hospitalization for any cause (323 vs. 329, p=0.52).  There was a trend towards decreased ED or urgent care visit (199 vs 257, p=0.09).

Adverse Effects: The rate of death was 3% in the azithromycin group and 4% in the placebo group (difference not significant).  The only adverse effect that occurred more frequently in the azithromycin group was audiogram confirmed hearing decrease (25% vs 20%, p=0.04).  At the end of the one year study, patients receiving azithromycin were also more likely to be colonized in the nasopharynx with azithromycin resistant organisms.

Discussion: The trial demonstrates that a daily standing regimen of azithromycin results in decreased number of total exacerbations.  While there is evidence that increased number of exacerbations results in increased morbidity and mortality, the trial was not sufficiently powered and did not have a long-enough follow-up time to demonstrate mortality benefits or decreased hospitalizations.  I think that showing a mortality benefit or showing decreased hospital stays would have made this trial much more significant.  There was an interesting side effect of increased hearing loss in a sizable minority of patients.  The data presented in the paper though is unclear about the magnitude of hearing loss.  A little bit might be tolerable while total deafness is likely not.

In summary, if a patient keeps coming back with repeated exacerbations of COPD, a standing regimen of azithromycin might be the next medicine for them!