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.