Azithromycin Exposure and Incident Nontuberculous Mycobacterial Isolation in Bronchiectasis and COPD: A Nationwide Nested Case-Control Study

Azithromycin reduces exacerbations in chronic airway disease, but whether it alters the risk of nontuberculous mycobacterial (NTM) isolation is unresolved.

Is azithromycin exposure in the preceding year associated with incident respiratory NTM isolation in non-cystic fibrosis bronchiectasis and in COPD?

Two nationwide register-based nested case-control analyses in Denmark. Case patients had a first positive respiratory culture for NTM; controls, alive and free of prior NTM isolation on the index date, were matched 1:20 on age, sex, and comorbidity index. The prespecified exposure was at least 3,000 mg of azithromycin with at least two prescriptions redeemed in the preceding 12 months, with a 3-month lag. Conditional logistic regression was adjusted for inhaled and oral corticosteroids. Exploratory analyses examined an active comparator at matched thresholds, recency, and outcome stringency.

The analyses comprised 173 cases and 3,409 controls (bronchiectasis) and 365 and 7,300 (COPD). Under the prespecified definition, azithromycin was not associated with incident NTM isolation (bronchiectasis: OR, 1.31; 95% CI, 0.79-2.18; COPD: 1.29; 0.78-2.13). In COPD, the OR was 1.61 (1.14-2.28) for one or more prescriptions and 1.29 (0.78-2.13) for two or more. The COPD association was concentrated within 90 days of the index date (2.55; 1.73-3.76) and attenuated with microbiological stringency (definite isolates: 0.77; 0.27-2.20). Non-macrolide antibacterials were more strongly associated than azithromycin at every matched threshold in bronchiectasis (one or more prescriptions: 1.90 [1.36-2.65] vs 1.15 [0.75-1.75]), and at the two higher thresholds in COPD (two or more: 1.48 [1.17-1.86] vs 1.24 [0.75-2.05]).

Azithromycin was not associated with NTM isolation under the prespecified definition. Associations under broader definitions were not dose-dependent and clustered close to the index date, more consistent with indication-driven testing than a drug effect, although in COPD an association with any exposure persisted after accounting for other antibacterials.