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Condition-dependent effects of Elexacaftor/Tezacaftor/Ivacaftor (Trikafta) on Aspergillus fumigatus growth

Summary

Researchers studied how Trikafta, a new cystic fibrosis medication, affects Aspergillus fungus growth. While Trikafta doesn’t directly kill the fungus, it makes antifungal drugs more effective and improves patients’ lung function to help clear infections naturally. However, high concentrations of the drug may reduce the immune system’s ability to fight the fungus, suggesting careful monitoring of patients is needed.

Background

Cystic fibrosis (CF) patients treated with CFTR modulators (Trikafta) show reduced Aspergillus fumigatus colonization and allergic bronchopulmonary aspergillosis. However, the mechanisms underlying this reduction remain unclear, necessitating investigation into direct antimicrobial effects and immune interactions.

Objective

To investigate whether CFTR modulators (Elexacaftor/Tezacaftor/Ivacaftor) exert direct antimicrobial effects on A. fumigatus or modulate immune responses during fungal infection, using reference strains and clinical isolates from CF patients.

Results

ETI treatment did not directly inhibit initial conidial growth or biofilm formation at clinically relevant concentrations. However, ETI reduced the minimal effective concentration of caspofungin against conidia. During macrophage infection, high ETI concentrations facilitated fungal growth while inhibiting inflammasome activation and reducing IL-1β production despite increased TNF-α release.

Conclusion

CFTR modulators lack direct antimicrobial activity against A. fumigatus conidia but enhance caspofungin efficacy and impair macrophage immune responses at elevated concentrations. The reduced colonization in patients likely results from improved respiratory function and mucus clearance rather than direct fungal inhibition, though long-term effects on antifungal immunity warrant further investigation.
  • Published in:Microbiology Spectrum,
  • Study Type:In vitro experimental study,
  • Source: PMID: 40736245, DOI: 10.1128/spectrum.02275-24
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