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 on a collection of nonduplicate A. fumigatus isolates from a global surveillance program between 2017 and 2022. Analysis of two known targets of voriconazole and isavuconazole activity, Cyp51A and Cyp51B, and associated regulatory regions were examined for alterations potentially influencing the activity of these antifungal agents when nonsusceptible MIC values were observed.