title: In vitro interaction of voriconazole and anidulafungin against triazole-resistant Aspergillus fumigatus.
abstract: Voriconazole is the recommended drug of first choice to treat infections caused by Aspergillus fumigatus. The efficacy of voriconazole might be hampered by the emergence of azole resistance. However, the combination of voriconazole with anidulafungin could improve therapeutic outcomes in azole-resistant invasive aspergillosis (IA). The in vitro interaction between voriconazole and anidulafungin was determined against voriconazole-susceptible and voriconazole-resistant (substitutions in the cyp51A gene, including single point [M220I and G54W] and tandem repeat [34-bp tandem repeat in the promoter region of the cyp51A gene in combination with substitutions at codon L98 and 46-bp tandem repeat in the promoter region of the cyp51A gene in combination with mutation at codons Y121 and T289] mutations) clinical A. fumigatus isolates using a checkerboard microdilution method with spectrophotometric analysis and a viability-based XTT {2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide} assay within 2 h of exposure after 24 and 48 h of incubation at 35 °C to 37 °C. Fractional inhibitory concentration (FIC) indexes (FICis) were determined using different MIC endpoints and Bliss independence analysis performed based on the response surface calculation of the no-drug interaction. Significant synergistic interactions obtained based on measuring the FIC index were dependent on the MIC endpoint, in which FICs were inversely related to voriconazole and anidulafungin MICs and were influenced by the CYP51A genotype. A statistically significant difference was observed between FIC indexes of isolates harboring tandem repeat mutations and wild-type controls (P = 0.006 by one-way analysis of variance [ANOVA]), indicating that synergy is decreased in azole-resistant strains. Our results indicated that a combination of voriconazole and anidulafungin might be effective against infections caused by both azole-susceptible and azole-resistant A. fumigatus isolates, but the combination could possibly be less effective in voriconazole-resistant strains with high MICs. Studies in vivo and in vitro-in vivo correlation investigations are required to validate the potential synergy of voriconazole and anidulafungin.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Seyedmojtaba
authors.initials: S
authors.lastname: Seyedmousavi
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
authors.forename: Willem J G
authors.initials: WJ
authors.lastname: Melchers
authors.forename: Antonius J M M
authors.initials: AJ
authors.lastname: Rijs
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
mesh_terms: D000077612:Anidulafungin; D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004347:Drug Interactions; D025141:Drug Resistance, Fungal / Q000235:genetics; D054714:Echinocandins / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics; D008826:Microbial Sensitivity Tests; D017354:Point Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D020080:Tandem Repeat Sequences / Q000235:genetics; 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