Objectives: Voriconazole (VCZ) is the preferred treatment for invasive pulmonary aspergillosis but isolates of Aspergillus fumigatus with elevated VCZ MICs are increasingly seen and carry a greater risk of treatment failure. We investigated whether the combination of VCZ with anidulafungin (AFG) may be beneficial for the treatment of A. fumigatus strains with elevated VCZ MICs. Methods: We used an in vitro model of the human alveolus to define the exposure response relationships for wild-type strains and those with defined molecular mechanisms of triazole resistance. A wild-type isolate (VCZ MIC 0.5 mg/L) and two strains with amino acid substitutions in the VCZ target protein Cyp51A (L98H; MIC 4 mg/L, G138C; MIC 16 mg/L) were studied. All strains had AFG minimum effective concentrations (MECs) of 0.0078 mg/L. Twenty-five different combinations of VCZ and AFG were investigated for each strain. Exposure response relationships were estimated using galactomannan (GM) as a biomarker. Drugs were administered to the endothelial compartment 6 hours post inoculation. Concentrations of VCZ and AFG were measured using HPLC. The interaction of VCZ and AFG was described using the Greco model. Results: Fungal growth was progressively inhibited with higher drug exposures of VCZ. Strains with elevated VCZ MICs required proportionally greater VCZ exposures to achieve a comparable antifungal effect, but GM levels could be suppressed for all strains. GM levels were reduced by AFG monotherapy but not fully suppressed, and no additional reduction was achieved by further increases in concentration above the MEC. An additive effect between VCZ and AFG was demonstrated. Conclusion: The combination of VCZ and AFG may be beneficial in the treatment of invasive pulmonary aspergillosis for isolates of A. fumigatus with reduced susceptibility to VCZ.
Full conference title:
22nd European Congress of Clinical Microbiology and Infectious Diseases
- ECCMID 22nd (2012)