Isavuconazole and Micafungin Elicit Synergistic Antifungal and Immunomodulatory Activity Against Azole-Resistant Aspergillus fumigatus

Abstract Azole/echinocandin combinations are often considered in invasive aspergillosis caused by azole-resistant Aspergillus fumigatus (ARAF). Therefore, we studied both direct and immune-mediated activity of isavuconazole and micafungin against 3 ARAF isolates. We observed synergistic activity against all isolates (checkerboard assay). In addition, pre-exposure of all ARAF isolates to subinhibitory concentrations of either drug enhanced hyphal inactivation by human mononuclear cells. While only micafungin-pretreated ARAF hyphae triggered increased NF-κB signaling in reporter macrophages, direct exposure of macrophages to low isavuconazole concentrations (≤1 μg/mL) enhanced Toll-like receptor signaling and stimulated effector pathways. Inversely, high isavuconazole concentrations (≥5 μg/mL) attenuated Toll-like receptor signaling, suggesting immunotoxicity.