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Abstract：
BACKGROUND: Candida auris isolates exhibit elevated amphotericin B (AMB) minimum inhibitory concentrations (MICs). As liposomal AMB (L-AMB) can be safely administered at high doses, we explored L-AMB pharmacodynamics against C. auris isolates in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) dilution model.
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.
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.
摘要：
背景：C.耳分离株表现出升高的两性霉素BMIC。由于脂质体AMB（L-AMB）可以安全地以高剂量给药，我们在体外PK/PD稀释模型中探索了L-AMB对C.auris分离株的药效学。
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。
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。
