In vitro interaction of isavuconazole and anidulafungin against azole-susceptible and azole-resistant Aspergillus fumigatus isolates

Abstract

Abstract Background The voriconazole and echinocandin combination has been found to be synergistic in vitro and in vivo against most Aspergillus fumigatus isolates, both with a WT azole phenotype and an azole-resistant phenotype. The interaction between isavuconazole and echinocandins is less well studied. This is especially true for azole-resistant isolates. Objectives We investigated the in vitro interaction between isavuconazole and anidulafungin for 30 A. fumigatus isolates including 18 azole-resistant isolates with various isavuconazole resistance phenotypes. Methods The isavuconazole/anidulafungin interaction was studied by using an adapted EUCAST-based 2D (12 × 8) chequerboard broth microdilution colorimetric assay using XTT. The interaction was analysed by FIC index (FICi) analysis and Bliss independence (BI) interaction analysis. Results Both the FICi analysis and the BI analysis showed synergistic interaction between isavuconazole and anidulafungin for the majority of WT and azole-resistant isolates. As we did not see significant beneficial effects of combination therapy in TR46/Y121F/T289A isolates at clinically achievable drug concentrations, it is unlikely that TR46/Y121F/T289A infections would benefit from isavuconazole and anidulafungin combination therapy. Conclusions In regions with high azole resistance rates this combination may benefit patients with WT disease, azole-resistant invasive aspergillosis and those with mixed azole-susceptible and azole-resistant infection, but may not be beneficial for aspergillosis due to isolates with high isavuconazole resistance, such as TR46/Y121F/T289A isolates.