Background. Pseudomonas aeruginosa is a multi-drug resistant, opportunistic pathogen causing intractable respiratory infections in people with cystic fibrosis (pwCF). In the past decade there has been considerable improvements in CF precision medicine including the development of CF transmembrane conductance regulator (CFTR) modulators that partially correct the underlying defective chloride channel driving disease[1]. Despite the many clinical benefits, multiple studies have revealed that whilst P. aeruginosa sputum load is often reduced, chronic infection persists[2,3]. Here, we investigate how P. aeruginosa in pwCF may change and adapt in the face of the altered lung environment post CFTR modulation.
Methods. One hundred and five P. aeruginosa strains were isolated from the sputum of 11 pwCF at baseline and up to 21 months post treatment with the latest modulator combinations, Elexacaftor-Tezacaftor-Ivacaftor (ETI, n=8) and Tezacaftor-Ivacaftor (TI, n=3). Isolates were sequenced and comparative genomics and phenotypic characterization were performed before and after CFTR treatment.
Results. Considerable improvements in clinical parameters were observed post CFTR modulation, however, not only did participants remain colonised with P. aeruginosa, but the same clonal lineages persisted after modulator therapy with no evidence of displacement by alternative strains. Sustained clonal lineages accumulated between 19 to 3400 modifying mutations after modulator commencement and these mutations were more frequently in previously described pathoadaptive genes but not in antibiotic resistance genes in a large proportion of lineages. Additionally, we identified commonly mutated genes across lineages between participants that may be positively selected for in the CFTR modulated lung environment. Despite the potential impact of these mutations, classic chronic P. aeruginosa phenotypes such as excessive alginate-producing mucoid morphology and lack of O-antigen expression were sustained, and isolates remained just as resistant to clinically relevant antibiotics.
Conclusion. Despite the clinical benefits of CFTR modulators, clonal lineages of P. aeruginosa persist with the same chronic phenotypes that may prove just as difficult to manage in the future especially in individuals with advanced lung disease and irreversible lung damage. Therefore, future research and clinical care should remain focused on P. aeruginosa as well as other lung infections in this post modulator era.