Impact of CFTR Modulation on Pseudomonas aeruginosa Infection in People With Cystic Fibrosis

Abstract

Background: Pseudomonas aeruginosa is a multidrug-resistant pathogen causing recalcitrant pulmonary infections in people with cystic fibrosis (pwCF). Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been developed that partially correct the defective chloride channel driving disease. Despite the many clinical benefits, studies in adults have demonstrated that while P. aeruginosa sputum load decreases, chronic infection persists. Here, we investigate how P. aeruginosa in pwCF may change in the altered lung environment after CFTR modulation.

Methods: P. aeruginosa strains (n = 105) were isolated from the sputum of 11 chronically colonized pwCF at baseline and up to 21 months posttreatment with elexacaftor-tezacaftor-ivacaftor or tezacaftor-ivacaftor. Phenotypic characterization and comparative genomics were performed.

Results: Clonal lineages of P. aeruginosa persisted after therapy, with no evidence of displacement by alternative strains. We identified commonly mutated genes among patient isolates that may be positively selected for in the CFTR-modulated lung. However, classic chronic P. aeruginosa phenotypes such as mucoid morphology were sustained, and isolates remained just as resistant to clinically relevant antibiotics.

Conclusions: Despite the clinical benefits of CFTR modulators, clonal lineages of P. aeruginosa persist that may prove just as difficult to manage in the future, especially in pwCF with advanced lung disease.

Keywords: Pseudomonas aeruginosa; CFTR modulators; ETI; cystic fibrosis; elexacaftor-tezacaftor-ivacaftor.

Figure 1.

Workflow of participant recruitment, cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, and Pseudomonas aeruginosa (PA) collection. Thirty-one people with cystic fibrosis (pwCF) were initially recruited. TI/ETI indicates that isolates were collected prior to participants starting tezacaftor-ivacaftor (TI) before switching to elexacaftor-tezacaftor-ivacaftor (ETI).

Figure 2.

Clonal Pseudomonas aeruginosa sequence types persist up to 21 months after CFTR modulator commencement in people with cystic fibrosis. Bacteria were isolated at baseline and various time points after CFTR modulator initiation. Each bacterial strain isolated is represented by a circle, and the color indicates the multilocus sequence type (MLST). Circles with three intersecting lines indicate that the isolate was of mucoid morphology. Shaded background indicates the CFTR modulator therapy characteristics. Cystic fibrosis participants (CFP 9 and 10) who commenced tezacaftor-ivacaftor (TI) and then switched to elexacaftor-tezacaftor-ivacaftor (ETI) are indicated by the line intersecting the x-axis at approximately six and 12 months. Figure created in BioRender. CFTR, cystic fibrosis transmembrane conductance regulator; LI, lumacaftor-ivacaftor.

Figure 3.

Genes mutated after CFTR modulation in >42% of lineages from people with cystic fibrosis. A, Presence-and-absence heat map of 37 commonly mutated genes (≥6/14, 42%) with at least one nonsynonymous modifier indel or frameshift mutation accumulated in lineages after CFTR modulation in people with cystic fibrosis. Heat map is annotated with gene length and whether the gene was previously described as being pathoadaptive or involved in antibiotic resistance. Lineages are shaded by CFTR modulator therapy characteristics. B, PseudoCAP functional class of 37 commonly mutated genes (number and percentage of genes relative to number of genes in class). Figure 3A created in R Studio and BioRender. CFTR, cystic fibrosis transmembrane conductance regulator; ETI, elexacaftor-tezacaftor-ivacaftor; LI, lumacaftor-ivacaftor; LPS, lipopolysaccharide; TI, tezacaftor-ivacaftor.

Figure 4.

Chronic Pseudomonas aeruginosa phenotypes are sustained after CFTR modulation in people with cystic fibrosis. P. aeruginosa (A) mucoid colony morphology, (B) O-antigen expression, and (C) antibiotic resistance at baseline and the latest time point available after CFTR modulator therapy. Resistant, resistant to antibiotics; intermediate, sensitive, although increased antibiotic dosing is advised; sensitive, completely sensitive to antibiotics. No significant differences were found. CFTR, cystic fibrosis transmembrane conductance regulator.