Isavuconazole susceptibility of clinical Aspergillus fumigatus isolates and feasibility of isavuconazole dose escalation to treat isolates with elevated MICs
Isavuconazole susceptibility of clinical Aspergillus fumigatus isolates and feasibility of isavuconazole dose escalation to treat isolates with elevated MICs
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DOI：
10.1093/jac/dkx425
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发表时间：
2018-01-01
影响因子：
5.2
通讯作者：
Verweij, Paul E.
中科院分区：
文献类型：
--
作者：
Buil, Jochem B.;Bruggemann, Roger J. M.;Verweij, Paul E.
Isavuconazole是一种新的三唑类药物，被批准用于治疗侵袭性曲霉病。研究了异戊康唑的MIC分布、异戊康唑与其他唑的MIC相关性以及异戊康唑在低耐药烟曲霉分离株中的药效学。方法：采用EUCAST肉汤微量稀释法对临床分离的487株烟曲霉进行依沙乌康唑、伏立康唑、伊曲康唑和泊沙康唑的药敏试验。使用体内药效学目标估计和先前发表的药代动力学模型，确定了使用三种给药方案（I， 200 mg每日一次；II， 300 mg每日一次；III， 400 mg每日一次）的一系列异唑康唑MICs的目标达到概率（PTA）。结果：基于伏立康唑、伊曲康唑和泊沙康唑的流行病学截止点，487株分离株中有279株表型为WT。根据1 mg/L的EUCAST断点，279株表型WT菌株中有25株和208株非WT菌株中有196株被分类为异戊康唑耐药。依唑康唑与伏立康唑的mic相关性非常高，与伊曲康唑和泊沙康唑的mic相关性为中、低。三种给药方案中，异唑康唑MIC为1 mg/L的菌株的PTA为92% ~ 99%，EC90为90%有效浓度。对于MIC为2 mg/L的菌株，EC90的PTA降至64%-92%。结论：本研究表明，异戊康唑与伏立康唑的MIC高度相关，对于异戊康唑MIC为2 mg/L的烟曲霉分离菌感染患者，大剂量异戊康唑治疗可能是一种选择。
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 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 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.