Changes in Inhaled Antibiotic-Associated Lung Function Outcomes in the CFTR Modulator Era

Chronic inhaled antibiotics are recommended for people with cystic fibrosis (pwCF) chronically infected with Pseudomonas aeruginosa (Pa). However, chronic antibiotics may increase the risk for other infections, and benefits may have changed as outcomes of pwCF improved.

Does the risk of infections associated with inhaled antibiotic prescriptions and the treatment benefit on lung function differ by Pa infection status, and has the antibiotic-associated treatment effect changed since introduction of CFTR modulators?

US CF Foundation Patient Registry data were analyzed for the years 2011 to 2019. Pa infection status was defined per the Leeds criteria. Analyses included inverse probability treatment weighting. Survival modeling compared differences in incidence of Aspergillus species and gram-negative bacteria between pwCF prescribed antibiotics vs not prescribed antibiotics within each Pa infection cohort. Differences in lung function associated with inhaled antibiotics were modeled using generalized estimating equations, with testing of whether the mean effect of antibiotics differed across CFTR modulator eras (ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor).

From 2011 to 2019, the number of pwCF analyzed increased from 12,000 to 16,041, with decreasing prevalence in chronic Pa, increasing age, and better lung function. Risk of Aspergillus infections was higher in antibiotic prescribed vs nonprescribed pwCF: the hazard ratio (HR) was 1.33 (95% CI, 1.26-1.41) and was significantly higher in pwCF who were Pa negative compared with pwCF who had chronic Pa. Similarly, inhaled antibiotics were associated with increased risk of Stenotrophomonas maltophilia and Achromobacter species (HR, 1.21; 95% CI, 1.14-1.29; and HR, 1.26; 95% CI, 1.14-1.39, respectively). Inhaled antibiotics were associated with higher lung function in pwCF with chronic Pa but lower lung function in pwCF who were Pa negative. The antibiotic-associated treatment effect on lung function decreased over the 3 eras of CFTR modulators.

Our results show that the risk of treatment-emergent infections was highest in pwCF who were Pa negative who conversely did not have antibiotic-associated benefit on lung function. For pwCF with chronic Pa, the antibiotic-associated benefit decreased as CFTR modulator use increased.