达托霉素对耐甲氧西林金黄色葡萄球菌和耐甲氧西林表皮葡萄球菌的药代动力学/药效学模型研究及菌血症治疗的蒙特卡罗模拟
PK/PD modeling of daptomycin against MRSA and MRSE and Monte Carlo simulation for bacteremia treatment.
机构信息
Programa de Pós-Graduação Em Biotecnologia, Universidade de Caxias Do Sul, Caxias do Sul, Brazil.
Programa de Pós-Graduação Em Ciências Farmacêuticas, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil.
出版信息
Braz J Microbiol. 2021 Dec;52(4):1967-1979. doi: 10.1007/s42770-021-00582-4. Epub 2021 Aug 2.
OBJECTIVES
The aim of this study was to investigate the effect of daptomycin against methicillin-resistant staphylococci (MRSA and MRSE) bacteremia using computer modeling.
METHODS
A pharmacokinetic/pharmacodynamic (PK/PD) modeling strategy to explain the data from an in vitro dynamic model employing time-kill curves for MRSA and MRSE was proposed. Bacterial killing was followed over time by determining viable counts and the resulting time-kill data was analyzed. Monte Carlo simulations were performed using pharmacokinetic parameters and pharmacodynamic data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (MIC) targets of daptomycin. Simulations were conducted to assess the reduction in the number of colony-forming units (CFU)/mL for 18 days of treatment with daptomycin at doses of 6, 8, and 10 mg/kg/24 h or 48 h with variations in creatinine clearance (CL): 15-29 mL/min/1.73 m, 30-49 mL/min/1.73 m, 50-100 mL/min/1.73 m, as well as for defining the probability of reaching the target fAUC/MIC = 80 in the same dose and clearance range. A PK/PD model with saturation in the number of bacteria in vitro, growth delay, and bacterial death, as well as Hill's factor, was used to describe the data for both MRSA and MRSE.
RESULTS
Monte Carlo simulations showed that for MRSA there was a reduction > 2 log CFU/mL with doses ≥ 6 mg/kg/day in 75th percentile of the simulated population after 18 days of treatment with daptomycin, whereas for MRSE this reduction was observed in 95th percentile of the population.
CONCLUSIONS
The presented in vitro PK/PD model and associated modeling approach were able to characterize the time-kill kinetics of MRSA and MRSE. Our study based on PTAs suggests that doses ≥ 6 mg/kg/day of daptomycin should be used to treat bacteremia caused by MRSA and MRSE in patients with CL of 15-29 mL/min/1.73 m. For patients with CL ≥ 50 mL/min/1.73 m, it would be necessary to employ a dose of 10 mg/kg/day to treat complicated bacteremias.
目的
本研究旨在通过计算机建模来探讨达托霉素对耐甲氧西林金黄色葡萄球菌（MRSA 和 MRSE）菌血症的作用。
方法
提出了一种药代动力学/药效动力学（PK/PD）建模策略，以解释使用时间杀菌曲线对 MRSA 和 MRSE 进行体外动态模型的数据。通过确定活菌数来跟踪随时间的细菌杀灭情况，并对所得的时间杀菌数据进行分析。使用药代动力学参数和药效动力学数据进行蒙特卡罗模拟，以确定达托霉素的浓度曲线/最低抑制浓度（MIC）目标面积与累积反应分数的达标概率。模拟了达托霉素剂量为 6、8 和 10 mg/kg/24 h 或 48 h 时，在 15-29 mL/min/1.73 m、30-49 mL/min/1.73 m、50-100 mL/min/1.73 m 肌酐清除率（CL）下治疗 18 天的情况下，CFU/mL 数量减少的情况，以及为达到相同剂量和清除率范围内的目标 fAUC/MIC=80 的概率。使用体外细菌数量饱和、生长延迟和细菌死亡以及 Hill 因子的 PK/PD 模型来描述 MRSA 和 MRSE 的数据。
结果
蒙特卡罗模拟表明，对于 MRSA，在接受达托霉素治疗 18 天后，在模拟人群的第 75 百分位数中，剂量≥6mg/kg/天时，CFU/mL 的减少量>2 对数；而对于 MRSE，在人群的第 95 百分位数中观察到这种减少。
结论
所提出的体外 PK/PD 模型和相关的建模方法能够描述 MRSA 和 MRSE 的时间杀菌动力学。我们基于 PTA 的研究表明，对于 CL 为 15-29 mL/min/1.73 m 的患者，应使用剂量≥6mg/kg/天的达托霉素来治疗由 MRSA 和 MRSE 引起的菌血症。对于 CL≥50 mL/min/1.73 m 的患者，需要使用 10mg/kg/天的剂量来治疗复杂菌血症。
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