Use of voriconazole to predict susceptibility and resistance to isavuconazole for Aspergillus fumigatus using CLSI methods and interpretive criteria.

Aspergillus fumigatus is a common cause of pulmonary and invasive mold infections among immunocompromised hosts. Mortality in immunocompromised hosts with invasive Aspergillus infections (IAI) has been reported to be as high as 80%. Therefore, appropriate therapy is essential in treating IAI. Both isavuconazole and voriconazole are first-line agents in treatment guidelines for IAI, but isavuconazole has favorable properties, often leading it to be preferred over voriconazole, given the lengthy duration of treatment. It is difficult to perform mold antifungal susceptibility testing, which often requires a reference lab and several weeks to determine results. Therefore, use of surrogate markers can be helpful to infer susceptibility when testing is not possible or delayed. We performed isavuconazole and voriconazole broth microdilution susceptibility testing by the Clinical and Laboratory Standards Institute (CLSI) method on a collection of 976 non-duplicate A. fumigatus isolates from a global surveillance program between 2017 and 2022. We found that voriconazole and isavuconazole have a very high essential agreement within two doubling dilutions at 99.9% and a categorical agreement of 92.7% with no very major errors, one major error (0.11%), and <10% minor errors. Many of the minor errors were in the setting of voriconazole testing at a MIC of 0.5 mg/L (susceptible) but isavuconazole at 2 mg/L (intermediate). Genetic analysis of cyp51 genes confirmed that isavuconazole and voriconazole susceptibility testing identified isolates with cyp51A and cyp51B mutations. Voriconazole can be used to predict the isavuconazole susceptibility testing result when A. fumigatus is tested by CLSI broth microdilution methodology.