Evaluation of the in vitro activity of isavuconazole and comparator voriconazole against 2635 contemporary clinical Candida and Aspergillus isolates.

ABSTRACT

OBJECTIVE: The in vitro activity of isavuconazole was determined for 1677 Candida and 958 Aspergillus isolates from 2012 to 2014 with voriconazole as comparator. METHODS: Aspergillus isolates were screened for resistance using azole-agar. Aspergillus isolates that screened positive and all Candida isolates underwent EUCAST broth microdilution testing. Isolates were categorized as wild-type (wt) or non-wt, adopting EUCAST epidemiological cut-off values (ECOFFs) (where available) or wt upper limits (wtULs; two two-fold dilutions above the MIC50). The CYP51A gene was sequenced for non-wt Aspergillus fumigatus isolates. Itraconazole and posaconazole MICs were determined for selected Aspergillus isolates with isavuconazole MIC ≥2 mg/L. RESULTS: Isavuconazole MIC50 (range) (mg/L) against Candida species were Candida albicans ≤0.03 (≤0.03 to >4), Candida dubliniensis ≤0.03 (≤0.03), Candida glabrata ≤0.03 (≤0.03-4), Candida krusei 0.06 (≤0.03-0.5), Candida parapsilosis ≤0.03 (≤0.03-0.06), Candida tropicalis ≤0.03 (≤0.03 to >4), Saccharomyces cerevisiae (anamorph Candida robusta) ≤0.03 (≤0.03-0.5). Non-wt isavuconazole/voriconazole MICs were found for C. albicans 0.8/1.0%, C. dubliniensis 0/1.8%, C. glabrata 14.9/9.5%, C. krusei 2.7/1.4%, C. parapsilosis 1.7/1.8%, C. tropicalis 14.3/19.1% and S. cerevisiae 10.0/0%. Isavuconazole MIC50 (range) (mg/L) against Aspergillus species were A. fumigatus 1 (≤0.125 to >16), Aspergillus niger 2 (1-8), Aspergillus terreus 1 (0.25-8), Aspergillus flavus 1 (0.5-2), Aspergillus nidulans ≤0.125 (≤0.125-0.25). Non-wt isavuconazole/voriconazole MICs were found for 13.7/15.2% A. fumigatus, 4.9/0% A. niger and 48.2/22.2% A. terreus. CONCLUSION: Isavuconazole displayed broad in vitro activity, similar to that of voriconazole. Up to 15% of C. glabrata, C. tropicalis and A. fumigatus isolates were non-wt, reflecting increased resistance at a reference centre and technical issues. Significant CYP51A alterations were reliably detected applying the isavuconazole breakpoint.