Pulmonary Outcomes Associated with Long-Term Azithromycin Therapy in Cystic Fibrosis

Abstract

Rationale: Chronic azithromycin is commonly used in cystic fibrosis based on short controlled clinical trials showing reductions in pulmonary exacerbations and improved FEV₁. Long-term effects are unknown.Objectives: Examine pulmonary outcomes among chronic azithromycin users compared with matched controls over years of use and consider combined azithromycin use in cohorts using chronic inhaled tobramycin or aztreonam.Methods: This retrospective cohort study used the U.S. cystic fibrosis Foundation Patient Registry. Incident chronic azithromycin users were compared with matched controls by FEV₁% predicted rate of decline and rates of intravenous antibiotic use to treat pulmonary exacerbations. Propensity score methods were utilized to address confounding by indication. Predefined sensitivity analyses based on lung function, Pseudomonas aeruginosa (PA) status, and follow-up time intervals were conducted.Measurements and Main Results: Across 3 years, FEV₁% predicted per-year decline was nearly 40% less in those with PA using azithromycin compared with matched controls (slopes, -1.53 versus -2.41% predicted per yr; difference: 0.88; 95% confidence interval [CI], 0.30-1.47). This rate of decline did not differ based on azithromycin use in those without PA. Among all cohorts, use of intravenous antibiotics was no different between azithromycin users and controls. Users of inhaled tobramycin and azithromycin had FEV₁% predicted per-year decline of -0.16 versus nonusers (95% CI, -0.44 to 0.13), whereas users of inhaled aztreonam lysine and azithromycin experienced a mean 0.49% predicted per year slower decline than matched controls (95% CI, -0.11 to 1.10).Conclusions: Results from this study provide additional rationale for chronic azithromycin use in PA-positive patients to reduce lung function decline.

Keywords: Pseudomonas aeruginosa; azithromycin; cystic fibrosis; long-term outcomes; tobramycin.

Figure 1.

(A and B) FEV₁% predicted (FEV₁pp) over 3 years (using all data and, separately, only yearly maximum) after incident chronic azithromycin (AZM) versus control among those without Pseudomonas aeruginosa (A) and those with P. aeruginosa (B). Estimates for all data were derived from the model allowing individual trends per year.

Figure 2.

Relative risk (RR) of pulmonary exacerbations treated with intravenous (IV) antibiotics among those with incident chronic use of azithromycin (AZM) versus controls. Shaded regions show all identified patients (not propensity score matched), and unshaded areas show the propensity score–matched cohorts. (A) Those without Pseudomonas aeruginosa and (B) those with P. aeruginosa. Figure represents high AZM users relative to low AZM users, and RR > 1.0 indicates greater use of IV antibiotics.

Figure 3.

Difference in FEV₁% predicted (FEV₁pp) slopes between high and low azithromycin among concomitant users of chronic inhaled TOB or chronic inhaled AZLI. Data shown for all individuals with ≥1 years of follow-up and, separately, among only those meeting the definition of Pseudomonas aeruginosa positive. Mean estimates and 95% confidence intervals are shown. Positive numbers reflect slower rate of decline in FEV₁pp. AZLI = aztreonam lysine; CI = confidence interval; PA+ = Pseudomonas aeruginosa positive; TOB = tobramycin.