4.8 Article

Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist

Journal

JOURNAL OF CLINICAL INVESTIGATION
Volume 133, Issue 10, Pages -

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI167957

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In this study, the effect of the newest CFTR modulator, ETI, on CF lung infections was investigated in 236 CF patients. The results showed that ETI treatment led to significant reductions in densities of drug-resistant pathogens in sputum, but most participants still remained infected with the pathogens present before the treatment. Treatment increased bacterial diversity in sputum, but this change was mainly due to the decrease in CF pathogens rather than other bacteria.
BACKGROUND. Lung infections are among the most consequential manifestations of cystic fibrosis (CF) and are associated with reduced lung function and shortened survival. Drugs called CF transmembrane conductance regulator (CFTR) modulators improve activity of dysfunctional CFTR channels, which is the physiological defect causing CF. However, it is unclear how improved CFTR activity affects CF lung infections. METHODS. We performed a prospective, multicenter, observational study to measure the effect of the newest and most effective CFTR modulator, elexacaftor/tezacaftor/ivacaftor (ETI), on CF lung infections. We studied sputum from 236 people with CF during their first 6 months of ETI using bacterial cultures, PCR, and sequencing. RESULTS. Mean sputum densities of Staphylococcus aureus, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp., and Burkholderia spp. decreased by 2-3 log10 CFU/mL after 1 month of ETI. However, most participants remained culture positive for the pathogens cultured from their sputum before starting ETI. In those becoming culture negative after ETI, the pathogens present before treatment were often still detectable by PCR months after sputum converted to culture negative. Sequence-based analyses confirmed large reductions in CF pathogen genera, but other bacteria detected in sputum were largely unchanged. ETI treatment increased average sputum bacterial diversity and produced consistent shifts in sputum bacterial composition. However, these changes were caused by ETI-mediated decreases in CF pathogen abundance rather than changes in other bacteria. CONCLUSIONS. Treatment with the most effective CFTR modulator currently available produced large and rapid reductions in traditional CF pathogens in sputum, but most participants remain infected with the pathogens present before modulator treatment.

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