Carlier Mieke, Noë Michaël, Roberts Jason A, Stove Veronique, Verstraete Alain G, Lipman Jeffrey, De Waele Jan J
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium.
J Antimicrob Chemother. 2014 Oct;69(10):2797-803. doi: 10.1093/jac/dku195. Epub 2014 Jun 10.
To investigate the population pharmacokinetics of cefuroxime in critically ill patients.
In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous cefuroxime. Blood samples were analysed using a validated ultra HPLC tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling.
One hundred and sixty blood samples were collected from 20 patients. CL(CR) ranged between 10 and 304 mL/min. A two-compartment model with between-subject variability on CL, V of the central compartment and V of the peripheral compartment described the data adequately. Twenty-four hour urinary CL(CR) was supported as a descriptor of drug CL. The population model for CL was CL = θ(1) × CL(CR)/100, where θ(1) is the typical cefuroxime CL in the population, which is 9.0 L/h. The mean V was 22.5 L. Dosing simulations showed failure to achieve the pharmacokinetic/pharmacodynamic target of 65% fT(>MIC) for an MIC of 8 mg/L with standard dosing regimens for patients with CL(CR) ≥50 mL/min.
Administration of standard doses by intermittent bolus is likely to result in underdosing for many critically ill patients. Continuous infusion of higher than normal doses after a loading dose is more likely to achieve pharmacokinetic/pharmacodynamic targets. However, even continuous infusion of high doses (up to 9 g per day) does not guarantee adequate levels for all patients with a CL(CR) of ≥300 mL/min if the MIC is 8 mg/L.
研究头孢呋辛在重症患者中的群体药代动力学。
在这项观察性药代动力学研究中，在静脉注射头孢呋辛的一个给药间隔内采集多个血样。使用经过验证的超高效液相色谱串联质谱技术分析血样。使用非线性混合效应模型进行群体药代动力学分析和给药模拟。
从20名患者中采集了160份血样。肌酐清除率（CL(CR)）范围为10至304 mL/分钟。一个具有中央室和外周室的CL、V的个体间变异性的二室模型充分描述了数据。24小时尿CL(CR)被认为是药物CL的一个描述指标。CL的群体模型为CL = θ(1) × CL(CR)/100，其中θ(1)是群体中头孢呋辛的典型CL，为9.0 L/小时。平均V为22.5 L。给药模拟显示，对于CL(CR)≥50 mL/分钟的患者，采用标准给药方案，当MIC为8 mg/L时，未能达到65% fT(>MIC)的药代动力学/药效学目标。
对于许多重症患者，间歇性推注标准剂量可能导致给药不足。在负荷剂量后持续输注高于正常剂量更有可能达到药代动力学/药效学目标。然而，如果MIC为8 mg/L，即使持续输注高剂量（每天高达9 g）也不能保证所有CL(CR)≥300 mL/分钟的患者达到足够的血药浓度。
