Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
Departamento de Farmacia y Tecnología de Medicamentos, Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
Antimicrob Agents Chemother. 2017 Nov 22;61(12). doi: 10.1128/AAC.01249-17. Print 2017 Dec.
Pathophysiological changes involved in drug disposition in critically ill patients should be considered in order to optimize the dosing of vancomycin administered by continuous infusion, and certain strategies must be applied to reach therapeutic targets on the first day of treatment. The aim of this study was to develop a population pharmacokinetic model of vancomycin to determine clinical covariates, including mechanical ventilation, that influence the wide variability of this antimicrobial. Plasma vancomycin concentrations from 54 critically ill patients were analyzed simultaneously by a population pharmacokinetic approach. A nomogram for dosing recommendations was developed and was internally evaluated through stochastic simulations. The plasma vancomycin concentration-versus-time data were best described by a one-compartment open model with exponential interindividual variability associated with vancomycin clearance and the volume of distribution. Residual error followed a homoscedastic trend. Creatinine clearance and body weight significantly dropped the objective function value, showing their influence on vancomycin clearance and the volume of distribution, respectively. Characterization based on the presence of mechanical ventilation demonstrated a 20% decrease in vancomycin clearance. External validation ( = 18) was performed to evaluate the predictive ability of the model; median bias and precision values were 0.7 mg/liter (95% confidence interval [CI], -0.4, 1.7) and 5.9 mg/liter (95% CI, 5.4, 6.4), respectively. A population pharmacokinetic model was developed for the administration of vancomycin by continuous infusion to critically ill patients, demonstrating the influence of creatinine clearance and mechanical ventilation on vancomycin clearance, as well as the implications for targeting dosing rates to reach the therapeutic range (20 to 30 mg/liter).
为了优化连续输注万古霉素的给药剂量，应考虑涉及危重症患者药物处置的病理生理变化，并且必须应用某些策略以在治疗的第一天达到治疗目标。本研究旨在建立万古霉素的群体药代动力学模型，以确定影响该抗菌药物广泛变异性的临床协变量，包括机械通气。通过群体药代动力学方法同时分析了 54 例危重症患者的万古霉素血浆浓度。开发了一种用于剂量推荐的列线图，并通过随机模拟进行了内部评估。血浆万古霉素浓度-时间数据最好用一个具有与万古霉素清除率和分布容积相关的个体间指数变异的单室开放式模型来描述。残差误差呈同方差趋势。肌酐清除率和体重显著降低了目标函数值，表明它们分别对万古霉素清除率和分布容积有影响。基于存在机械通气的特征化表明，万古霉素清除率降低了 20%。进行了外部验证（n = 18）以评估模型的预测能力；模型的中位数偏差和精度值分别为 0.7 mg/L（95%置信区间 [CI]，-0.4，1.7）和 5.9 mg/L（95% CI，5.4，6.4）。建立了用于危重症患者连续输注万古霉素给药的群体药代动力学模型，该模型显示了肌酐清除率和机械通气对万古霉素清除率的影响，以及靶向给药率以达到治疗范围（20 至 30 mg/L）的意义。
