Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University of Manchester, University Hospital of South Manchester National Health Service Foundation Trust, United Kingdom.
J Infect Dis. 2012 Aug 1;206(3):442-52. doi: 10.1093/infdis/jis372. Epub 2012 May 25.
Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis (IPA). There are increasing reports of Aspergillus fumigatus isolates with reduced susceptibility to voriconazole.
An in vitro dynamic model of IPA was developed that enabled simulation of human-like voriconazole pharmacokinetics. Galactomannan was used as a biomarker. The pharmacodynamics of voriconazole against wild-type and 3 resistant strains of A. fumigatus were defined. The results were bridged to humans to provide decision support for setting breakpoints for voriconazole using Clinical Laboratory Standards Institute (CLSI) and European Committee of Antimicrobial Susceptibility Testing (EUCAST) methodologies.
Isolates with higher minimum inhibitory concentrations (MICs) required higher area under the concentration time curves (AUCs) to achieve suppression of galactomannan. Using CLSI and EUCAST methodologies, the AUC:MIC values that achieved suppression of galactomannan were 55 and 32.1, respectively. Using CLSI and EUCAST methodologies, the trough concentration:MIC values that achieved suppression of galactomannan were 1.68 and 1, respectively. Potential CLSI breakpoints for voriconazole are ≤ 0.5 mg/L for susceptible and >1 mg/L for resistant. Potential EUCAST breakpoints for voriconazole are ≤1 mg/L for susceptible and >2 mg/L for resistant.
This dynamic model of IPA is a useful tool to address many remaining questions related to antifungal treatment of Aspergillus spp.
伏立康唑是治疗侵袭性肺曲霉病（IPA）的一线药物。越来越多的报告显示，烟曲霉分离株对伏立康唑的敏感性降低。
开发了一种 IPA 的体外动态模型，该模型能够模拟人类样的伏立康唑药代动力学。半乳甘露聚糖被用作生物标志物。定义了伏立康唑对野生型和 3 种耐药烟曲霉菌株的药效学。将结果与人类联系起来，为使用临床实验室标准化协会（CLSI）和欧洲抗菌药物敏感性测试委员会（EUCAST）方法为伏立康唑设定折点提供决策支持。
MIC 值较高的分离株需要更高的 AUC 来达到抑制半乳甘露聚糖的效果。使用 CLSI 和 EUCAST 方法，抑制半乳甘露聚糖所需的 AUC:MIC 值分别为 55 和 32.1。使用 CLSI 和 EUCAST 方法，抑制半乳甘露聚糖所需的谷浓度:MIC 值分别为 1.68 和 1。潜在的 CLSI 伏立康唑折点为敏感株≤0.5mg/L，耐药株＞1mg/L。潜在的 EUCAST 伏立康唑折点为敏感株≤1mg/L，耐药株＞2mg/L。
IPA 的这种动态模型是解决与抗真菌治疗曲霉菌属相关的许多剩余问题的有用工具。
