Determination of Isavuconazole Susceptibility of Aspergillus and Candida Species by the EUCAST Method

Abstract

ABSTRACTIsavuconazole is a novel expanded-spectrum triazole, which has recently been approved by the FDA as an orphan drug to treat invasive aspergillosis and is currently being studied in phase III clinical trials for invasive candidiasis. The susceptibility of relatively few clinical isolates has been reported. In this study, the isavuconazole susceptibilities of 1,237Aspergillusand 2,010Candidageographically diverse clinical isolates were determined by EUCAST methodology at four European mycology laboratories, producing the largest multicenter data set thus far for this compound. In addition, a blinded collection of 30cyp51AmutantAspergillus fumigatusclinical isolates and 10 wild-type isolates was tested. From these two data sets, the following preliminary epidemiological cutoff (ECOFF) values were suggested: 2 mg/liter forAspergillus fumigatus,Aspergillus terreus, andAspergillus flavus; 4 mg/liter forAspergillus niger; 0.25 mg/liter forAspergillus nidulans; and 0.03 mg/liter forCandida albicans,Candida parapsilosis, andCandida tropicalis. Unfortunately, ECOFFs could not be determined forCandida glabrataorCandida kruseidue to an unexplained interlaboratory MIC variation. For the blinded collection ofA. fumigatusisolates, all MICs were ≤2 mg/liter for wild-type isolates. Differential isavuconazole MICs were observed for triazole-resistantA. fumigatusisolates with differentcyp51Aalterations: TR34/L98H mutants had elevated isavuconazole MICs, whereas isolates with G54 and M220 alterations had MICs in the wild-type range, suggesting that the efficacy of isavuconazole may not be affected by these alterations. This study will be an aid in interpreting isavuconazole MICs for clinical care and an important step in the future process of setting official clinical breakpoints.