Isavuconazole susceptibility of clinical Aspergillus fumigatus isolates and feasibility of isavuconazole dose escalation to treat isolates with elevated MICs. (18th October 2017)

• Record Type: Journal Article
• Authors: Buil, Jochem B; Brüggemann, Roger J M; Wasmann, Roeland E; Zoll, Jan; Meis, Jacques F; Melchers, Willem J G; Mouton, Johan W; Verweij, Paul E
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 73:Number 1(2018)
• Page Start: 134
• Page End: 142
• Publication Date: 2017-10-18
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkx354
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: 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, 200 mg once daily; II, 300 mg once daily; and III, 400 mg once daily). Results: Two hundred and seventy-nine of 487 isolates were phenotypically WT based on epidemiological cut-offs 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 1 mg/L. Isavuconazole MICs showed very high correlation with voriconazole MICs, but moderate and low correlation with itraconazole and posaconazole MICs. The PTA for isolates with an isavuconazole MIC of 1 mg/L was 92%–99% for 90% effective concentration (EC90 ) for the three dosing regimens. For isolates with an MIC of 2 mg/L the PTA decreased to 64%–92% for EC90. Conclusions: Our study indicated that isavuconazole and voriconazole MICs are highly correlated and that high-dose isavuconazole treatment might be an option in patients infected with an A. fumigatus isolate with an isavuconazole MIC of 2 mg/L.