The Impact of CFTR Modulators on the Airway Microbiome and the Need for Antibacterial Therapy in Children with Cystic Fibrosis

Background. One of the main criteria for the severity of the condition of patients with cystic fibrosis is the bacterial composition of bronchial secretions; in this regard, regular monitoring of the microbial landscape and rational use of antibacterial therapy in this category of patients are necessary.

The aim of the study is to assess the impact of CFTR modulators on the respiratory microbiome and the need for antibacterial therapy in children with cystic fibrosis.

Materials and methods. From November 2023 to May 2024, an open prospective study compared 46 children with cystic fibrosis (ages 2–17), including 26 on elexacaftor/tezacaftor/ivacaftor and 20 without CFTR modulators. Microbial composition and antibiotic therapy use were evaluated over 6-month pre- and post-study initiation.

Results. The use of CFTR modulator contributed to a decrease in the duration of ABT courses (p = 0.000), while the absence of therapy, on the contrary, led to an increase in the duration of ABT courses (p = 0.003). No significant differences in the frequency of detection of individual bacterial groups between the groups were found over time. A tendency toward an increase in the amount of bacterial DNA (p = 0.099) was found in patients who didn’t take the CFTR modulator. An increase in the concentration of Enterobacteriales was found in patients without targeted therapy during 6 months of observation (p = 0.005).

Conclusion. CFTR modulator therapy significantly reduced ABT needs in cystic fibrosis children. Although no major differences in microbial detection frequencies were found, PCR identified clinically relevant bacterial colonizations: Staphylococcus aureus, Pseudomonas aeruginosa, Haemophilus influenzae.

1. Palla J, Thapa S, Venkatachalam A, Runge JK, Laguna TA, Luna RA. The upper airway microbiome in Hispanic children with cystic fibrosis. Pediatric Pulmonology. 2023;58(8):2298–2307. DOI: https://doi.org/10.1002/ppul.26484.

2. Kirst ME, Baker D, Li E, Abu-Hasan M, Wang GP. Upper versus lower airway microbiome and metagenome in children with cystic fibrosis and their correlation with lung inflammation. PLоS One. 2019;14(9): e0222323. DOI: https://doi.org/10.1371/journal.pone.0222323.

3. Zemanick ET, Wagner BD, Robertson CE, Stevens MJ, Szefler SJ, Accurso FJ, et al. Assessment of airway microbiota and inflammation in cystic fibrosis using multiple sampling methods. Annals of the American Thoracic Society. 2015;12(2):221–229. DOI: https://doi.org/10.1513/AnnalsATS.201407-310OC.

4. Hoppe JE, Towler E, Wagner BD, Accurso FJ, Sagel SD, Zemanick ET. Sputum induction improves detection of pathogens in children with cystic fibrosis. Pediatric Pulmonology. 2015;50(7):638–646. DOI: https://doi.org/10.1002/ppul.23150.

5. Yi B, Dalpke AH, Boutin S. Changes in the cystic fibrosis airway microbiome in response to CFTR modulator therapy. Frontiers in Cellular and Infection Microbiology. 2021;11:548613. DOI: https://doi.org/10.3389/fcimb.2021.548613.

6. Cox MJ, Allgaier M, Taylor B, Baek MS, Huang YJ, Daly RA, et al. Airway microbiota and pathogen abundance in age-stratified cystic fibrosis patients. PLоS One. 2010;5(6):e11044. DOI: https://doi.org/10.1371/journal.pone.0011044.

7. Zhao J, Schloss PD, Kalikin LM, Carmody LA, Foster BK, Petrosino JF, et al. Decade-long bacterial community dynamics in cystic fibrosis airways. PNAS. 2012;109(15):5809–5814. DOI: https://doi.org/10.1073/pnas.1120577109.

8. Сoburn B, Wang PW, Diaz Caballero J, Clark ST, Brahma V, Donaldson S, et al. Lung microbiota across age and disease stage incystic fibrosis. Scientific Reports. 2015;5:10241. DOI: https://doi.org/10.1038/srep10241.

9. Allemann A, Kraemer JG, Korten I, Ramsey K, Casaulta C, Wüthrich D, et al. Nasal resistome development in infants with cystic fibrosis in the first year of life. Frontiers in Microbiology. 2019;10:212. DOI: https://doi.org/10.3389/fmicb.2019.00212.

10. Stanojevic S, Davis SD, Retsch-Bogart G, Webster H, Davis M, Johnson RC, et al. Progression of lung disease in preschool patients with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2017;195(9):1216–1225. DOI: https://doi.org/10.1164/rccm.201610-2158OC.

11. Hisert KB, Heltshe SL, Pope C, Jorth P, Wu X, Edwards RM, et al. Restoring cystic fibrosis transmembrane conductance regulator function reduces airway bacteria and inflammation in people with cystic fibrosis and chronic lung infections. American Journal of Respiratory and Critical Care Medicine. 2017;195(12):1617– 1628. DOI: https://doi.org/10.1164/rccm.201609-1954OC.

12. Reznikov LR, Abou Alaiwa MH, Dohrn CL, Gansemer ND, Diekema DJ, Stoltz DA, et al. Antibacterial properties of the CFTR potentiator ivacaftor. Journal of Cystic Fibrosis. 2014;13(5):515–519. DOI: https://doi.org/10.1016/j.jcf.2014.02.004.

13. Miller AC, Harris LM. The rapid reduction of infection-related visits and antibiotic use among people with cystic fibrosis after starting elexacaftor-tezacaftor-ivacaftor. Clinical Infectious Diseases. 2022;75(7):1115– 1122. DOI: https://doi.org/10.1093/cid/ciac117.

14. Migliorisi G, Collura M, Ficili F, Pensabene T, Bongiorno D, Collura A, et al. Elexacaftor-tezacaftor-ivacaftor as a final frontier in the treatment of cystic fibrosis: Definition of the clinical and microbiological implications in a case-control study. Pharmaceuticals. 2022;15(5):606. DOI: https://doi.org/10.3390/ph15050606.

15. Frayman KB, Armstrong DS, Carzino R, Ferkol TW, Grimwood K, Storch GA, et al. The lower airway microbiota in early cystic fibrosis lung disease: A longitudinal analysis. Thorax. 2017;72:1104–1112. DOI: https://doi.org/10.1136/thoraxjnl-2016-209279.

16. Pittman JE, Wylie KM, Akers K, Storch GA, Hatch J, Quante J, et al. Association of antibiotics, airway microbiome, and inflammation in infants with cystic fibrosis. Annals of the American Thoracic Society. 2017; 14(10):1548–1555. DOI: https://doi.org/10.1513/AnnalsATS.201702-121OC.

17. Zemanick ET, Wagner BD, Robertson CE, Ahrens RC, Chmiel JF, Clancy JP, et al. Airway microbiota across age and disease spectrum in cystic fibrosis. European Respiratory Journal. 2017;50(5):1700832. DOI: https://doi.org/10.1183/13993003.00832-2017.

18. Larionova EE, Andrievskaya IY, Andreevskaya SN, Smirnova TG, Chernousova LN. Microbiological diagnosis of coincident mycobacterial infection in cystic fibrosis. Ural Medical Journal. 2018;(8):65–68. (In Russ.). EDN: https://elibrary.ru/SDSJTA.

19. Flight WG, Smith A, Paisey C, Marchesi JR, Bull MJ, Norville PJ, et al. Rapid detection of emerging pathogens and loss of microbial diversity associated with severe lung disease in cystic fibrosis. Journal of Clinical Microbiology. 2015;53(7):2022–2029. DOI: https://doi.org/10.1128/JCM.00432-15.

20. Renwick J, McNally P, John B, DeSantis T, Linnane B, Murphy P. The microbial community of the cystic fibrosis airway is disrupted in early life. PLоS One. 2014;9(12):e109798. DOI: https://doi.org/10.1371/journal.pone.0109798.

21. Cribbs SK, Beck JM. Microbiome in the pathogenesis of cystic fibrosis and lung transplant-related disease. Translational Research. 2017;179:84–96. DOI: https://doi.org/10.1016/j.trsl.2016.07.022.

22. Whelan FJ, Surette MG. Clinical insights into pulmonary exacerbations in cystic fibrosis from the microbiome. What are we missing? Annals of the American Thoracic Society. 2015;12(Suppl 2):207–211. DOI: https://doi.org/10.1513/AnnalsATS.201506-353AW.

23. Rogers GB, Bruce KD, Hoffman LR. How can the cystic fibrosis respiratory microbiome influence our clinical decision-making? Current Opinion in Pulmonary Medicine. 2017;23(6):536–543. DOI: https://doi.org/10.1097/MCP.0000000000000419.

24. Feigelman R, Kahlert CR, Baty F, Rassouli F, Kleiner RL, Kohler P, et al. Sputum DNA sequencing in cystic fibrosis: Non-invasive access to the lung microbiome and to pathogen details. Microbiome. 2017;5(1):20. DOI: https://doi.org/10.1186/s40168-017-0234-1.

25. Granchelli AM, Adler FR, Keogh RH, Kartsonaki C, Cox DR, Liou TG. Microbial interactions in the cystic fibrosis airway. Journal of Clinical Microbiology. 2018;56(8):e00354–18. DOI: https://doi.org/10.1128/JCM.00354-18.

26. Vasenyova YO, Vakhlova IV, Averyanov OY. Evaluation of the effectiveness of using the CFTR modulator ivacaftor/lumacaftor in children with cystic fibrosis in the Sverdlovsk Region (prospective cohort study). Pediatric Pharmacology. 2024;21(4):309–319. (In Russ). DOI: https://doi.org/10.15690/pf.v21i4.2772.

27. Vasenyova YO, Vakhlova IV, Averyanov OY. Results of comparative effectiveness of pathogenetic therapy with CFTR modulators in children with cystic fibrosis. Ural Medical Journal. 2025;24(2):95–108. (In Russ.). DOI: https://doi.org/10.52420/umj.24.2.95.

28. Whelan FJ, Heirali AA, Rossi L, Rabin HR, Parkins MD, Surette MG. Longitudinal sampling of the lung microbiota in individuals with cystic fibrosis. PLоS One. 2017;12(3):e0172811. DOI: https://doi.org/10.1371/journal.pone.0172811.

29. Bhagirath AY, Li Y, Somayajula D, Dadashi M, Badr S, Duan K. Cystic fibrosis lung environment and Pseudomonas aeruginosa infection. BMC Pulmonary Medicine. 2016;16(1):174. DOI: https://doi.org/10.1186/s12890-016-0339-5.

30. Cuthbertson L, Rogers GB, Walker AW, Oliver A, Green LE, Daniels TW, et al. Respiratory microbiota resistance and resilience to pulmonary exacerbation and subsequent antimicrobial intervention. The ISME Journal. 2016;10(5):1081–1091. DOI: https://doi.org/10.1038/ismej.2015.198.

31. Zemanick ET, Harris JK, Wagner BD, Robertson CE, Sagel SD, Stevens MJ, et al. Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations. PLоS One. 2013;8(4):e62917. DOI: https://doi.org/10.1371/journal.pone.0062917.

32. Fodor AA, Klem ER, Gilpin DF, Elborn JS, Boucher RC, Tunney MM, et al. The adult cystic fibrosis airway microbiota is stable over time and infection type, and highly resilient to antibiotic treatment of exacerbations. PLоS One. 2012;7(9):e45001. DOI: https://doi.org/10.1371/journal.pone.0045001.

33. Price KE, Hampton TH, Gifford AH, Doben EL, Hogan DA, Morrison HG, et al. Unique microbial communities persist in individual cystic fibrosis patients throughout clinical exacerbation. Microbiome. 2013; 1(1):11. DOI: https://doi.org/10.1186/2049-2618-1-27.