Recent research explores the long-term impact of triple combination therapy on CF respiratory microbiota remodeling. Specifically, scientists followed a multi-centre cohort for three years to assess how elexacaftor-tezacaftor-ivacaftor (ETI) influences microbial populations. Consequently, they discovered that ETI therapy significantly shifts the lung's ecology toward a healthy-like state. This finding represents a major milestone in understanding how CFTR modulators modify disease outcomes beyond simple lung function metrics.

The Shift Toward Healthy CF Respiratory Microbiota Remodeling

Furthermore, the study indicates that respiratory microbiota characteristics such as diversity and composition align more closely with healthy individuals over time. Canonical CF pathogens, which once dominated the airway, became progressively less ecologically important during the treatment period. However, the microbiota did not reach a fully healthy status. This limitation likely stems from irreversible lung damage and continued antibiotic exposure among patients. Notably, the reduction in pathogen abundance allows for a more diverse microbial community to flourish.

The Paradoxical Role of Azithromycin

Additionally, the research identified an unexpected barrier to complete microbial recovery. Specifically, azithromycin, frequently used for its immunomodulatory benefits, appeared to nullify some positive effects of ETI treatment. Moreover, patients receiving azithromycin alongside ETI showed a persistence of emblematic CF pathogens. Therefore, azithromycin may contribute to maintaining pre-ETI dysbiosis rather than resolving it. Consequently, clinicians may need to re-evaluate the routine use of this antibiotic in the modulator era.

FAQs

Does ETI therapy completely eliminate CF pathogens?

While ETI therapy significantly reduces the abundance and ecological importance of traditional CF pathogens, it does not always eliminate them entirely. Residual lung damage and previous infections may allow certain strains to persist.

Why might azithromycin be detrimental during ETI therapy?

Research suggests that azithromycin might impede the positive remodeling of the lung microbiota. When combined with ETI, it was associated with the persistence of dysbiosis and traditional cystic fibrosis pathogens.

Disclaimer: This content is for informational and educational purposes only. It does not constitute medical advice or a substitute for professional healthcare consultation. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Refer to the latest local and national guidelines for clinical practice.

References

Gavillet H et al. Remodelling of cystic fibrosis respiratory microbiota in response to extended elexacaftor-tezacaftor-ivacaftor therapy. Microbiome. 2026 May 30. doi: 10.1186/s40168-026-02440-7. PMID: 42218569.

Nichols DP, et al. Clinician’s Guide to the Use of Elexacaftor-Tezacaftor-Ivacaftor in Cystic Fibrosis. Thorax. 2022;77(1):1-3.

Shteinberg M, et al. Cystic fibrosis. Lancet. 2021;397(10291):2285-2298.