Shah Reya V, Kipper Karin, Baker Emma H, Barker Charlotte I S, Oldfield Isobel, Philips Barbara J, Johnston Atholl, Lipman Jeffrey, Rhodes Andrew, Basarab Marina, Sharland Mike, Almahdi Sarraa, Wake Rachel M, Standing Joseph F, Lonsdale Dagan O
Institute for Infection and Immunity, St George's, University of London, London SW17 0RE, UK.
Department of Clinical Pharmacology & Therapeutics, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
Antibiotics (Basel). 2023 Mar 24;12(4):643. doi: 10.3390/antibiotics12040643.
Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell patients receiving benzylpenicillin, using data from the ABDose study. Population pharmacokinetic modelling was undertaken using NONMEM version 7.5, and simulations using the final model were undertaken to optimize the pharmacokinetic profile. We included 77 samples from 12 participants. A two-compartment structural model provided the best fit, with allometric weight scaling for all parameters and a creatinine covariate effect on clearance. Simulations (n = 10,000) demonstrated that 25% of simulated patients receiving 2.4 g 4-hourly failed to achieve a conservative target of 50% of the dosing interval with free drug above the clinical breakpoint MIC (2 mg/L). Simulations demonstrated that target attainment was improved with continuous or extended dosing. To our knowledge, this study represents the first full population PK analysis of benzylpenicillin in critically ill adults.
在危重症中，药代动力学具有高度变异性，抗生素暴露不足与治疗失败相关。苄青霉素是一种常用的β-内酰胺类抗生素，但缺乏其在危重症成年患者中使用的药代动力学数据。我们利用ABDose研究的数据，对接受苄青霉素治疗的危重症患者进行了一项药代动力学研究。使用NONMEM 7.5版进行群体药代动力学建模，并使用最终模型进行模拟以优化药代动力学特征。我们纳入了12名参与者的77个样本。一个二室结构模型拟合最佳，所有参数采用异速生长体重标度，肌酐协变量对清除率有影响。模拟（n = 10,000）表明，25%每4小时接受2.4 g剂量的模拟患者未能达到一个保守目标，即在给药间隔的50%时间内游离药物浓度高于临床断点MIC（2 mg/L）。模拟表明持续给药或延长给药可提高目标达成率。据我们所知，本研究是对苄青霉素在危重症成年患者中进行的首次全面群体药代动力学分析。
