title: In vitro efficacy of the combination of voriconazole and anidulafungin against voriconazole-resistant cyp51A mutants of Aspergillus fumigatus.
abstract: We selected voriconazole-resistant (VCZ-R) Aspergillus fumigatus in the laboratory, characterized the cyp51A gene for possible mutations and evaluated the in vitro activities of voriconazole and anidulafungin alone and in combination against VCZ-R isolates of A. fumigatus using a fractional inhibitory concentration index (FICI) methodology. Voriconazole-resistant isolates were selected from wild-type A. fumigatus isolates in the laboratory by a 2-step selection process (plus 1 clinical isolate). The MICs of azoles (VCZ, posaconazole, itraconazole) and echinocandins (anidulafungin, micafungin, and caspofungin) for all A. fumigatus isolates were then determined in RPMI1640 using the broth microdilution technique recommended by the Clinical Laboratory and Standards Institute M38-A2 methodology and the FICI calculated. The combination of VCZ and anidulafungin was synergistic (FICI <0.5) not only against VCZ-susceptible isolates, but also against 8 of 10 VCZ-R, G448S mutants of A. fumigatus. The combination demonstrated synergy against the VCZ-R clinical isolate as well.
authors.affiliation: Wayne State University, Detroit, MI, USA. skrishn@med.wayne.edu
authors.forename: Suganthini
authors.initials: S
authors.lastname: Krishnan-Natesan
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wu
authors.forename: Pranatharthi H
authors.initials: PH
authors.lastname: Chandrasekar
mesh_terms: D000077612:Anidulafungin; D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics*; D006801:Humans; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D011743:Pyrimidines; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System; D000077612:Anidulafungin; C465526:cytochrome P-450 CYP51A, Aspergillus; D065819:Voriconazole