Changes in Inhaled Antibiotic Associated lung function outcomes in the CFTR-Modulator Era.

Abstract

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

Research question: 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.

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

Results: From 2011 to 2019 the number of pwCF analysed 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. non-prescribed pwCF: HR 1.33 (CI_95% 1.26, 1.41) and was significantly higher in Pa negative compared to Pa chronic pwCF. Similarly, inhaled antibiotics were associated with increased risk of Stenotrophomonas maltophilia and Achromobacter: HR 1.21, (CI_95% 1.14, 1.29) and 1.26 (CI_95% 1.14, 1.39), respectively. Inhaled antibiotics were associated with higher lung function in chronic Pa but lower lung function in Pa negative pwCF. The antibiotic-associated treatment effect on lung function decreased over the three eras of CFTR-modulators.

Interpretation: The risk of treatment emergent infections was highest in Pa negative pwCF 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.