Activity of Isavuconazole and Comparator Antifungals Tested against Contemporary (2012) Fungal Clinical Isolates Collected Worldwide

Background: Isavuconazole (ISA) is a new broad-spectrum triazole that is in late-stage clinical development for the treatment of invasive fungal infections (IFIs) caused by Candida spp. (CANS), Aspergillus spp. (ASP) and rare moulds (rMO). We report the activity of ISA and comparators tested against 1,670 fungal organisms collected in 26 countries during 2012. Methods: 1,421 CANS, 130 ASP, 31 non-Candida yeasts, 50 Cryptococcus neoformans (CNEO), and 38 rMO clinical isolates causing IFI were consecutively collected and susceptibility (S) tested by CLSI reference broth microdilution in a central laboratory against ISA and comparators. Yeasts were identified (ID) using CHROMagar, biochemical methods and sequencing of ITS and/or 28S regions (IGS was used for a small subset). Moulds were ID by sequencing of 1 or 2 of the following genes: ITS, 28S, beta-tubulin, TEF. Results: ISA displayed good activity against most prevalent and relevant fungal species/groups (Table). ISA inhibited 93.3 and 97.7% of the CANS at MICs of 0.5 and 1 µg/ml, respectively; and only 15 isolates had MIC values at >2 µg/ml (14 C. glabrata [1 echinocandin-non-S] and 1 C. tropicalis). These isolates also displayed elevated MICs for other azoles (MIC ranges, 32->128, 1->8 and 2-8 µg/ml for fluconazole, posaconazole and voriconazole, respectively). All CNEO from variants grubii (46 isolates) and neoformans (4 isolates) had ISA MIC values ≤0.25 µg/ml. These strains had fluconazole MICs ranging from 1-8 µg/ml. A. niger and A. terreus had ISA MIC values at 2-8 µg/ml, whereas A. fumigatus and A. flavus had lower MICs (1-4 µg/ml). Conclusions: Although unusual, reports of increasing resistance among various fungal species to key antifungals and breakthrough infections highlight the challenges of IFI therapy. ISA has shown good activity against common pathogens associated to IFIs.