Trikafta shifts CF lung bacteria toward healthier mix, study finds
Long-term treatment leads to more diverse lung bacteria in adults
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For adults with cystic fibrosis (CF), long-term treatment with Trikafta (elexacaftor/tezacaftor/ivacaftor) may significantly improve the composition of bacteria living in the lungs, a study found.
The study showed that with longer periods of Trikafta treatment, the community of lung bacteria (respiratory microbiota) became more diverse. Disease-causing (pathogenic) bacteria that often dominate in the lungs of people with CF, contributing to the risk of respiratory infection, also become less prominent.
However, exposure to the antibiotic azithromycin disrupted these changes.
“The on-[Trikafta] microbiota was impeded from becoming fully ‘healthy’ due to continued antibiotic exposure and irreversible lung damage experienced by [adults with] CF,” the researchers wrote.
The study, “Remodelling of cystic fibrosis respiratory microbiota in response to extended elexacaftor–tezacaftor–ivacaftor therapy,” was published in Microbiome.
Fighting infection
CF is a genetic condition that leads to no or faulty production of the CFTR protein. Healthy CFTR helps regulate the movement of salt and water through cell membranes. This becomes disrupted in CF, and the body produces unusually thick, sticky mucus that provides an ideal environment for bacteria and other pathogens, particularly in the lungs. As a result, lung inflammation and frequent respiratory infections are common CF symptoms.
Trikafta aims to treat CF by boosting the effectiveness of CFTR. It contains three medications that work together to help CFTR function better, reducing abnormal mucus production and easing symptoms, including respiratory symptoms. However, the long-term effects of Trikafta on respiratory microbiota remain unclear.
“Given chronic respiratory infection and concomitant inflammation is the leading cause of morbidity and early mortality for the majority of people living with cystic fibrosis, there is a pressing need to understand the impact of [Trikafta] therapy on the CF airway microbiota,” the researchers wrote.
To address this question, they examined microbiota samples from 276 adults with CF, with a mean age of 33.9. Some of the samples were cough swabs, collected by holding a swab at the back of the throat while the participant coughed. Others were samples of sputum or phlegm, which people with CF may cough up from the lower airways and lungs.
Some participants had samples only from before or during Trikafta, while others had multiple samples. The researchers also included samples from 11 people without CF as healthy controls.
The team used two main metrics to assess the microbiota: diversity and dominance. Microbiota diversity measures the different types of bacteria. Dominance measures the prevalence of bacteria commonly associated with respiratory infections in CF relative to other bacteria.
People with CF had lower diversity and higher pathogen dominance than controls. Diversity was lower and dominance was higher in people with more severe cases of CF.
Conversely, diversity rose and dominance declined during Trikafta treatment. As pathogens became less dominant, other respiratory bacteria took on more prominent roles in the respiratory microbiota. For those who had been receiving Trikafta for two or three years, diversity and dominance differed significantly from pre-treatment samples. However, they didn’t reach the same levels of diversity and dominance as the control participants.
“The on-[Trikafta] microbiota characteristics increasingly remodelled towards those observed in the non-CF healthy cohort, though typically remained significantly different,” the researchers wrote.
A subset of 82 participants had microbiota samples from both before and during treatment. This allowed the researchers to directly track changes in these patients’ microbiota. They found that the bacterial composition changed significantly less over time for participants who received the antibiotic azithromycin, a treatment for some respiratory infections.
“This would suggest that the use of azithromycin when on-[Trikafta] therapy both maintains a pre-[Trikafta] microbiota dysbiosis [imbalance] and enables elevated persistence of key CF pathogens,” the researchers noted.
Since “azithromycin use was associated with adverse effects on the respiratory microbiota nullifying the observed positive effects of ETI treatment,” the scientists wrote, the drug “appears to be an ideal candidate for discontinuation within the polypharmacy of CF treatment with clinical evaluation required for its continued usage.”
Taken together, the results suggest that Trikafta has positive effects on the lung microbiota in CF. However, the team noted that the study had limitations, including fewer sputum samples than cough swab samples, with decreasing CF severity before Trikafta and increasing duration on the triple CFTR modulator therapy. In addition, many participants didn’t have samples from both pre-Trikafta and during treatment, which limited certain analyses.
The researchers suggested that future work could investigate the effects of Trikafta on the respiratory microbiota of children with CF. Other groups of microbes in the lungs may also need close examination, they said.
“While the bacterial respiratory microbiota has been the central focus for all studies to date, we would recommend that the impacts and consequences of [Trikafta] therapy on the poorly understood and understudied fungal microbiota should also be explored,” they wrote.
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