Isavuconazole susceptibility of clinical Aspergillus fumigatus isolates and feasibility of isavuconazole dose escalation to treat isolates with elevated MICs

Introduction: Isavuconazole is a new triazole approved for the treatment of invasive aspergillosis. We investigated isavuconazole MIC distributions, isavuconazole MIC correlations with those of other azoles and pharmacodynamics of isavuconazole in low-level resistant Aspergillus fumigatus isolates.
Methods: Isavuconazole, voriconazole, itraconazole and posaconazole susceptibility of 487 clinical A. fumigatus isolates was determined by EUCAST broth microdilution methodology. Using an in vivo estimation of the pharmacodynamic target and a previously published pharmacokinetic model, the probability of target attainment (PTA) was determined for a range of isavuconazole MICs using three dosing regimens (I, 200mg once daily; II, 300mg once daily; and III, 400mg once daily).
Results: Two hundred and seventy-nine of 487 isolates were phenotypically WT based on epidemiological cutoffs of voriconazole, itraconazole and posaconazole. Twenty-five of 279 phenotypically WT isolates and 196 of 208 non-WT isolates were classified as isavuconazole resistant based on the EUCAST breakpoint of 1mg/L. Isavuconazole MICs showed very high correlation with voriconazole MICs, butmoderate and low correlation with itraconazole and posaconazole MICs. The PTA for isolates with an isavuconazole MIC of 1mg/L was 92%-99% for 90% effective concentration (EC90) for the three dosing regimens. For isolates with an MIC of 2mg/L the PTA decreased to 64%-92%for EC90.
Conclusions: Our study indicated that isavuconazole and voriconazole MICs are highly correlated and that highdose isavuconazole treatment might be an option in patients infected with an A. fumigatus isolate with an isavuconazole MIC of 2 mg/L.