(528) Linking CFTR modulators to opportunistic bacterial infections in cystic fibrosis

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve clinical outcomes in patients with cystic fibrosis (CF). However, their efficacy varies suggesting a multifactorial response. Since bacterial colonization is a hallmark of CF, changes produced by bacterial persistence and adaptation in addition to antibiotic regimens could influence CFTR modulator efficacy and vice versa and hence clinical outcomes. Thus, we aimed to i) determine the antimicrobial activity of CFTR modulators and their additive or synergistic effects with antibiotics against Pseudomonas aeruginosa and Staphylococcus aureus reference and clonal isolates collected from CF patients at early and advanced stages of lung colonization; and ii) evaluate the concentration of ivacaftor (IVA), as a model CFTR modulator, in plasma and airway samples and its changes during pneumonia in mice.

Methods: We evaluated the effects of IVA, lumacaftor (LUM), tezacaftor, elexacaftor and elexacaftor/tezacaftor/ivacaftor (ETI), alone or combined with antibiotics, on longitudinal clonal S. aureus and P. aeruginosa isolates by minimum inhibitory concentration and checkerboard assays. Next, by exploiting a mouse model of acute P. aeruginosa lung infection, we evaluated the effect of bacterial pneumonia on the pharmacokinetics of IVA in plasma and airways by ultra-performance liquid chromatography-tandem mass spectrometry.

Results: IVA and ETI showed the most potent direct antimicrobial activity against S. aureus, while P. aeruginosa was not affected by any CFTR modulator, independently from the stage of colonization. This indicated that bacterial adaptation to the CF airways does not change either the susceptibility of S. aureus strains to IVA and ETI or the resistance of P. aeruginosa to CFTR modulators. Additive effects or synergies were observed between the CFTR modulators and antibiotics against both S. aureus and P. aeruginosa. IVA and LUM were the most effective in potentiating the antibiotic activity against S. aureus, while IVA and ETI enhanced mainly polymyxins activity against P. aeruginosa. These potentiating effects appeared to be bacterial isolate dependent, but no correlation with the stage of chronic colonization was found. The partitioning to the epithelial lining fluid (ELF), estimated by comparing the area under the curve of the unbound compound in the plasma to that in the ELF, indicated that IVA penetrates ELF well. In addition, the time-concentration curves of IVA and its metabolites in plasma, lung and ELF were influenced by P. aeruginosa infection. The area under the concentration-time curve showed that airway exposure to IVA was greater in infected than non-infected mice.

Conclusions: These results suggest that CFTR modulators can have direct antimicrobial properties and/or enhance antibiotic activity against S. aureus and P. aeruginosa, independently from the stage of colonization. Furthermore, bacterial infection impacts the IVA concentration and airway exposure, potentially affecting its efficacy. Our findings suggest optimizing host- and pathogen-directed drug regimens to improve efficacy for personalized treatment.

Acknowledgements: This work was supported by the Italian CF Research Foundation (FFC#15/2018) and CFF (BRAGON19G0).

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