METHODS: Four C. auris isolates with Clinical and Laboratory Standards Institute (CLSI) AMB MICs = 0.5-2 mg/L were tested in an in vitro PK/PD model simulating L-AMB pharmacokinetics. The in vitro model was validated using a Candida albicans isolate tested in animals. The peak concentration (Cmax)/MIC versus log10 colony-forming units (CFU)/mL reduction from the initial inoculum was analyzed with the sigmoidal model with variable slope (Emax model). Monte Carlo analysis was performed for the standard (3 mg/kg) and higher (5 mg/kg) L-AMB doses.
RESULTS: The in vitro PK/PD relationship Cmax/MIC versus log10 CFU/mL reduction followed a sigmoidal pattern (R2 = 0.91 for C. albicans, R2 = 0.86 for C. auris). The Cmax/MIC associated with stasis was 2.1 for C. albicans and 9 for C. auris. The probability of target attainment was >95% with 3 mg/kg for wild-type C. albicans isolates with MIC ≤2 mg/L and C. auris isolates with MIC ≤1 mg/L whereas 5 mg/kg L-AMB is needed for C. auris isolates with MIC 2 mg/L.
CONCLUSIONS: L-AMB was 4-fold less active against C. auris than C. albicans. Candida auris isolates with CLSI MIC 2 mg/L would require a higher L-AMB dose.
方法:在模拟L-AMB药代动力学的体外PK/PD模型中测试了四种耳弧菌分离株(AMBMIC0.5-2mg/L)。使用在动物中测试的白色念珠菌分离物验证体外模型。用Emax模型分析从初始接种物的Cmax/MIC相对于log10CFU/mL的减少。对标准(3mg/kg)和更高(5mg/kg)的L-AMB剂量进行蒙特卡罗分析。
结果:体外PK/PD关系Cmax/MIC与log10CFU/mL降低遵循S形模式(白色念珠菌的R2≥0.91,C.auris的R2≥0.86)。与淤滞相关的Cmax/MIC对于白色念珠菌为2.1,对于金黄色念珠菌为9。对于MIC≤2mg/L的野生型白色念珠菌分离株和MIC≤1mg/L的金黄色念珠菌分离株,3mg/kg的达到目标概率>95%,而MIC为2mg/L的金黄色念珠菌分离株需要5mg/kgL-AMB。
结论:L-AMB对金黄色葡萄球菌的活性比白色念珠菌低4倍。具有CLSIMIC2mg/L的C.auris分离物将需要较高的L-AMB剂量。