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 were performed to assess the effect of
azithromycin on sputum microbiology from participants of the AMAZES (
Asthma and
Macrolides: The
Azithromycin Efficacy and Safety) trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500 mg oral
azithromycin in adults with persistent uncontrolled
asthma. Pooled-template shotgun metagenomic sequencing, quantitative PCR, and isolate whole-genome sequencing were performed to assess antibiotic resistance.Measurements and Main Results: Paired sputum samples were 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 phylogenetic diversity (P = 0.026) and Haemophilus influenzae load (P < 0.0001).
Azithromycin did not significantly affect levels of Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, or Moraxella catarrhalis. Of the 89 antibiotic resistance genes detected, five
macrolide resistance genes and two tetracycline resistance genes were increased significantly.Conclusions: In patients with persistent uncontrolled
asthma,
azithromycin reduced airway H. influenzae load compared with placebo but did not change total bacterial load.
Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of nonantibiotic
macrolides as a long-term
therapy for patients with persistent uncontrolled
asthma.