By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

Dr. Deresinski reports no financial relationships relevant to this field of study.

SYNOPSIS: Azithromycin reduced exacerbations and improved quality of life in patients with chronic persistent asthma.

SOURCE: Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): A randomised, double-blind, placebo-controlled trial. Lancet 2017 Jul 4. pii: S0140-6736(17)31281-3. doi:10.1016/S0140-6736(17)31281-3.

Gibson and colleagues examined the effect of chronic azithromycin administration on the frequency of exacerbations and quality of life in adults with chronic persistent asthma in a multicenter, double-blind, randomized trial. All 420 patients continued to receive inhaled corticosteroids and a long-acting bronchodilator and were randomized to receive in addition either 500 mg azithromycin or placebo three times weekly for 48 weeks. Patients with prolonged QT interval or hearing loss were excluded, as were current smokers.

In the intent-to-treat analysis, azithromycin administration was associated with a significant reduction in exacerbations (1.07 per patient-year [95% confidence interval [CI], 0.85-1.29]) compared to placebo administration (1.86 per patient-year [95% CI, 1.54-2.18]). The incidence rate ratio for the comparison was 0.59 [95% CI, 0.47-0.74]; P < 0.0001). While 127 (61%) placebo recipients had at least one asthma exacerbation, this was true for only 94 (44%) of those assigned to receive azithromycin. Azithromycin recipients had significantly improved asthma-related quality of life, but reported a greater likelihood of developing diarrhea (34% vs. 19%; P = 0.001). The benefit of azithromycin was seen without regard to type of asthma (eosinophilic, non-eosinophilic) and there was no significant effect on the presence of inflammatory cells in sputum.

While there was only a non-significant (P = 0.062) increase in recovery of bacteria resistant to azithromycin in induced sputum at the end of treatment, the study was insufficiently powered to reliably detect such a difference. Examination of the microbiome of the sputum specimens found no evidence of an association of outcomes with bacterial diversity.

COMMENTARY

Macrolide antibiotics have antibacterial, antiviral, and anti-inflammatory effects. While this study demonstrated the benefit of the macrolide (azalide) azithromycin, it was unable to clarify the mechanism responsible for this benefit. There was no effect on the number of sputum inflammatory cells, and the presence or absence of resistant bacteria in sputum at baseline did not appear to affect outcomes. Although there was a reduction in respiratory infections, the viral hypothesis was not addressed by the investigators.

The benefit of azithromycin administration in this evaluation was highly significant. It should be noted that previous studies failed to demonstrate significant benefit from azithromycin administration. These trials, however, were smaller in size than the study reviewed here, were of shorter duration, and used lower doses of the antibiotic.

A critical concern regarding widespread use of chronic azithromycin administration in patients with persistent asthma is the resultant selection of resistance organisms. While this study did not find a statistically significant increase in emergence of resistant bacteria, this likely was the result of a sample size inadequate to fully address this issue resistance selection is inevitable. If the effect of azithromycin is not the result of its antibacterial activity, one can hope that a molecule can be developed that provides benefit in asthma without exerting a selective pressure on the bacterial flora.