Tyler, Texas – CFTR modulators, a class of medications used to treat cystic fibrosis (CF), were associated with reductions in the airway burden of Pseudomonas aeruginosa and in the number of bacterial clusters over time, but large aggregates persisted, a study suggests.
While CFTR modulator use was linked to a lower overall bacterial burden and fewer bacterial clusters over time, large aggregates continued to make up about one-fifth of all detected P. aeruginosa aggregates. These tightly packed bacterial communities are more tolerant of antibiotics and harder for immune cells to clear, suggesting they may contribute to infections that persist or return despite CFTR modulator therapy. The findings also point to bacterial aggregates as a potential target for future treatments.
“CFTR modulators reduce P. aeruginosa density but not aggregation,” the researchers wrote. “Persistent aggregates may represent structurally resilient communities contributing to chronic infection, highlighting aggregation as a potential adjunctive therapeutic target.”
The study, “Persistence of large P. aeruginosa aggregates despite reduced airway burden in people with cystic fibrosis on CFTR modulator therapy,” was published in the Journal of Cystic Fibrosis.
Why bacterial infections can persist in CF lungs
CF is caused by mutations that impair the production or function of CFTR, a protein that regulates the movement of salt and water across cells. As a result, people with CF produce abnormally thick, sticky mucus that can build up and damage organs, particularly the lungs. In the lungs, this mucus can trap bacteria, making people with CF especially vulnerable to chronic infections, including those caused by P. aeruginosa.
CFTR modulators have dramatically improved the outlook for many people with CF. By improving the function of specific faulty CFTR proteins, these therapies help restore moisture to airway surfaces and make mucus less thick and sticky. These changes can improve lung function and reduce disease flare-ups and have been associated with a lower bacterial burden in the airways.
Yet, chronic lung infections caused by P. aeruginosa “can persist in many individuals,” the researchers wrote. “While CFTR modulator therapy is associated with substantial reductions in overall bacterial load, P. aeruginosa can still be detected by sensitive molecular methods and in many cases recrudesces years later.”
One possible explanation is that the bacteria persist in large aggregates, or dense clusters embedded in a protective matrix. These structures make the bacteria more tolerant of antibiotics and more difficult for immune cells to clear.
To investigate this possibility, researchers conducted a secondary analysis of a three-year prospective observational study carried out from 2022 to 2025 at three Canadian CF centers. The analysis included 42 people with CF and chronic P. aeruginosa infection, including 27 receiving CFTR modulators and 15 who were not. Sputum samples collected over time were analyzed to measure P. aeruginosa biovolume — a microscopy-based measure of bacterial burden — and to assess the size and number of bacterial aggregates.
CFTR modulators lower bacterial burden over time
When researchers compared sputum samples from participants already receiving CFTR modulators with those who were not, they found no significant differences in P. aeruginosa biovolume, aggregate number, maximum aggregate size, or the proportion of large versus smaller aggregates. However, there was a trend toward fewer bacterial aggregates among participants receiving CFTR modulators.
Over time, however, P. aeruginosa biovolume and the number of bacterial aggregates decreased significantly among participants receiving CFTR modulators. Maximum aggregate size and the proportion of large versus smaller aggregates did not change significantly. None of these measures changed significantly among participants who were not receiving CFTR modulators.
As a result, the reductions in bacterial burden and aggregate number over time were significantly greater among participants receiving CFTR modulators than among those who were not.
Among the six participants with sputum samples available before and after starting CFTR modulators, large aggregates made up a similar proportion before and after treatment, accounting for about one-fifth, or approximately 22%, of all detected P. aeruginosa aggregates. Because this paired analysis included only six participants, the researchers did not perform formal statistical comparisons.
According to the researchers, “the persistence of large aggregates despite reductions in overall bacterial burden suggests that these structures may represent a preferentially retained subpopulation within the CF airway.” The findings suggest these resilient bacterial communities may contribute to infections that persist or return.
The findings suggest that future treatments may also need to directly target these bacterial aggregates “to complement CFTR modulators and further improve long-term respiratory outcomes,” the researchers concluded.
Contact
Prof. Amanda J. Morris
University of Texas Health Science Center at Tyler