Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands.
J Antimicrob Chemother. 2018 Jan 1;73(1):134-142. doi: 10.1093/jac/dkx354.
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.
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).
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.
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.
伊曲康唑是一种新型三唑类药物，已被批准用于治疗侵袭性曲霉病。我们研究了伊曲康唑 MIC 分布，伊曲康唑 MIC 与其他唑类药物的相关性，以及低水平耐药烟曲霉分离株中伊曲康唑的药效动力学。
采用 EUCAST 肉汤微量稀释法测定 487 株临床烟曲霉分离株对伊曲康唑、伏立康唑、伊曲康唑和泊沙康唑的敏感性。采用体内药效学靶目标估计和以前发表的药代动力学模型，根据三种给药方案（I 方案：200mg 每日一次；II 方案：300mg 每日一次；III 方案：400mg 每日一次），确定了一系列伊曲康唑 MIC 的目标达标概率（PTA）。
487 株分离株中，根据伏立康唑、伊曲康唑和泊沙康唑的流行病学折点，279 株分离株表型为 WT。25 株表型 WT 分离株和 196 株非 WT 分离株根据 EUCAST 1mg/L 的折点被归类为伊曲康唑耐药。伊曲康唑 MIC 与伏立康唑 MIC 相关性很高，但与伊曲康唑和泊沙康唑 MIC 相关性中等和较低。对于伊曲康唑 MIC 为 1mg/L 的分离株，三种给药方案的 90%有效浓度（EC90）的 PTA 为 92%-99%。对于 MIC 为 2mg/L 的分离株，PTA 降至 64%-92%，EC90。
我们的研究表明，伊曲康唑和伏立康唑 MIC 高度相关，对于感染伊曲康唑 MIC 为 2mg/L 的烟曲霉分离株的患者，高剂量伊曲康唑治疗可能是一种选择。
