Mohamed Ami F, Cars Otto, Friberg Lena E
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
J Antimicrob Chemother. 2014 May;69(5):1350-61. doi: 10.1093/jac/dkt520. Epub 2014 Jan 27.
An optimized dosing regimen of the prodrug of colistin, colistin methanesulphonate (CMS), against resistant Pseudomonas aeruginosa is needed to ensure effective bacterial killing. The objectives of this study were to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model that characterizes the time course of the antibacterial activity of colistin against P. aeruginosa in a static in vitro system and to perform simulations of different dosing regimens and dosing algorithms to evaluate the effect of interindividual variability and interoccasion variability in PK on bacterial killing.
Static in vitro time-kill curve experiments were conducted on two different strains of P. aeruginosa (MIC 1 and 1.5 mg/L). Mechanism-based PK/PD models were fitted in NONMEM7 and the final model was combined with a previously developed population PK model of CMS and colistin to perform simulations of variability based on different dosing algorithms.
A model with compartments for growing and resting bacteria, with a function allowing the maximal bacterial killing of colistin to reduce upon increasing colistin exposure, characterized both the fast bactericidal effect and the adaptive resistance. The variability in PK was shown to translate into pronounced interoccasion variability in bacterial killing. A flat fixed loading dose was demonstrated to result in less variability than an algorithm based on weight.
The developed PK/PD model described the growth, death and resistance development of P. aeruginosa in response to colistin for two different strains. Based on simulations, a flat fixed loading dose followed by an 8 or 12 hourly maintenance dose with an infusion duration of up to 2 h appeared adequate.
需要一种针对耐药铜绿假单胞菌的多粘菌素前体药物多粘菌素甲磺酸盐（CMS）的优化给药方案，以确保有效杀灭细菌。本研究的目的是建立一个药代动力学（PK）/药效动力学（PD）模型，该模型可描述在静态体外系统中多粘菌素对铜绿假单胞菌抗菌活性的时间进程，并对不同给药方案和给药算法进行模拟，以评估PK中的个体间变异性和个体间变异性对细菌杀灭的影响。
对两种不同的铜绿假单胞菌菌株（MIC为1和1.5mg/L）进行静态体外时间杀灭曲线实验。基于机制的PK/PD模型在NONMEM7中进行拟合，最终模型与先前开发的CMS和多粘菌素群体PK模型相结合，以基于不同给药算法进行变异性模拟。
一个具有生长和静止细菌区室的模型，其功能是随着多粘菌素暴露增加，允许多粘菌素的最大细菌杀灭作用降低，该模型既表征了快速杀菌作用，又表征了适应性耐药。PK的变异性被证明会转化为细菌杀灭的明显个体间变异性。结果表明，固定负荷剂量比基于体重的算法导致的变异性更小。
所建立的PK/PD模型描述了两种不同菌株的铜绿假单胞菌对多粘菌素的生长、死亡和耐药性发展情况。基于模拟，先给予固定负荷剂量，然后每8或12小时给予维持剂量，输注持续时间长达2小时似乎是合适的。
