Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma.

Abstract

Rationale The macrolide antibiotic, azithromycin, reduces exacerbations in adults with persistent symptomatic asthma. However, owing to the pleotropic properties of macrolides, unintended bacteriological consequences such as augmented pathogen colonization or dissemination of antibiotic-resistant organisms can occur, calling into question the long-term safety of azithromycin maintenance therapy. Objectives To assess the effects of azithromycin on the airway microbiota, pathogen abundance, and carriage of antibiotic-resistance genes. Methods 16S rRNA sequencing and quantitative PCR (qPCR) were performed to assess the effect of azithromycin on sputum microbiology from participants of the AMAZES trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500mg oral azithromycin in adults with persistent uncontrolled asthma. Pooled-template shotgun metagenomic sequencing, qPCR, and isolate whole genome sequencing were performed to assess antibiotic resistance. Measurements and Main Results Paired sputum was available from 61 patients (n=34 placebo, n=27 azithromycin). Azithromycin did not affect bacterial load (p=0.37) but did significantly decrease Faith s bacterial diversity (p=0.026) and Haemophilus influenzae load (p<0.001). Azithromycin did not significantly affect levels of Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa or Moraxella catarrhalis. Of the 89 antibiotic resistance genes detected, macrolide resistance genes (erm(B), erm(F), msr(E), mef(A), and mel) and tetracycline resistance genes (tet(M) and tet(W)) were increased significantly. Conclusions In patients with persistent uncontrolled asthma, addition of azithromycin reduced airway H. influenzae load, with no changes to total or pathogenic bacterial loads. Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of non-antibiotic macrolides as long-term therapy for patients with persistent uncontrolled asthma.