De Cock Pieter A J G, Mulla Hussain, Desmet Sarah, De Somer Filip, McWhinney Brett C, Ungerer Jacobus P J, Moerman Annelies, Commeyne Sabrina, Vande Walle Johan, Francois Katrien, Van Hasselt Johan G C, De Paepe Peter
Department of Pharmacy, Ghent University Hospital, Ghent, Belgium.
Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
J Antimicrob Chemother. 2017 Mar 1;72(3):791-800. doi: 10.1093/jac/dkw496.
The objective of this study was to characterize cefazolin serum pharmacokinetics in children before, during and after cardiopulmonary bypass (CPB), in order to derive an evidence-based dosing regimen.
This study included children who received cefazolin before surgical incision, before cessation of CPB and after surgery. Blood samples of total and unbound cefazolin concentrations were collected before, during and after CPB. The cefazolin concentration-time profiles were analysed using population pharmacokinetic modelling and predictors for interindividual variability in pharmacokinetic parameters were investigated. Subsequently, optimized dosing regimens were developed using stochastic simulations. Clinicaltrials.gov: NCT02749981.
A total of 494 total and unbound cefazolin concentrations obtained from 56 children (aged 6 days to 15 years) were included. A two-compartment model with first-order elimination plus an additional compartment for the effect of CPB best described the data. Clearance (1.56 L/h), central volume (1.93 L) and peripheral volume (2.39 L) were allometrically scaled by body weight. The estimated glomerular filtration rate (eGFR) was identified as a covariate on clearance and the serum albumin concentration was associated with maximum protein binding capacity. Our simulations showed that an additional bolus dose at the start of CPB improves the PTA in typical patients from 59% to >94%. Prolonged surgery and preserved renal function (i.e. drop in eGFR <25%) had a negative impact on PTA.
We propose an optimized dosing regimen for cefazolin during cardiac surgery in paediatric patients to avoid treatment failure due to inadequate antibiotic prophylaxis.
本研究的目的是描述儿童在体外循环（CPB）前、期间和之后头孢唑林的血清药代动力学，以便得出基于证据的给药方案。
本研究纳入了在手术切口前、CPB停止前和手术后接受头孢唑林治疗的儿童。在CPB前、期间和之后采集头孢唑林总浓度和游离浓度的血样。使用群体药代动力学模型分析头孢唑林浓度-时间曲线，并研究药代动力学参数个体间变异的预测因素。随后，通过随机模拟制定优化的给药方案。Clinicaltrials.gov：NCT02749981。
共纳入了56名儿童（年龄6天至15岁）的494个头孢唑林总浓度和游离浓度数据。一个具有一级消除的二室模型加上一个用于CPB影响的额外隔室最能描述这些数据。清除率（1.56 L/h）、中央室容积（1.93 L）和外周室容积（2.39 L）均按体重进行了异速缩放。估计肾小球滤过率（eGFR）被确定为清除率的协变量，血清白蛋白浓度与最大蛋白结合能力相关。我们的模拟表明，在CPB开始时额外给予一次推注剂量可将典型患者的目标达成概率（PTA）从59%提高至>94%。手术时间延长和肾功能保留（即eGFR下降<25%）对PTA有负面影响。
我们提出了一种针对小儿心脏手术期间头孢唑林的优化给药方案，以避免因抗生素预防不足导致的治疗失败。
