Evaluating the effects of ivacaftor exposure on small colony variant development and antibiotic tolerance.

Background: Ivacaftor exhibits anti-staphylococcal properties but does not clear from the lungs of people with cystic fibrosis (pwCF). We assessed whether exposure to therapeutic concentrations of ivacaftor could allow to form small colony variants (SCVs), a phenotype commonly associated with bacterial persistence.

Methods: Humanized G551D-CFTR (hG551D) rats were treated with ivacaftor for 7 days. Concentrations in the plasma, epithelial lining fluid and lung tissue lysate were measured using LC-MS/MS. Survival of during ivacaftor treatment was assessed in an hG551D rat model of lung infection. adaptation to therapeutic concentrations of ivacaftor was investigated by serial passage in the presence of 10 µM ivacaftor. Bacterial survival in the presence of antimicrobials was evaluated using growth curves and density assays.

Results: Ivacaftor plasma concentrations of treated hG551D rats reached 3.488 ± 1.118 µM, with more variable concentrations in the epithelial lining fluid and lung tissue lysate. During infection, ivacaftor-treated hG551D rats returned similar numbers of bacteria from the lung, compared with vehicle-treated controls. Exposure of to ivacaftor led to the formation of ivacaftor-tolerant SCVs with an unstable phenotype and increased antibiotic tolerance.

Conclusions: Treatment with ivacaftor did not alter burden in the cystic fibrosis rat and led to the formation of tolerant SCVs , suggesting that development of an SCV phenotype may allow to persist in the cystic fibrosis lung during ivacaftor therapy.