Inflammation, Infection and Rheumatology Section, UCL Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, UK.
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
J Antimicrob Chemother. 2019 Apr 1;74(4):1003-1011. doi: 10.1093/jac/dky525.
Vancomycin is commonly used for nosocomial bacterial pathogens causing late-onset septicaemia in preterm infants. We prospectively collected pharmacokinetic data aiming to describe pharmacokinetics and determine covariates contributing to the variability in neonatal vancomycin pharmacokinetics. Further, we aimed to use the model to compare the ratio of AUC24 at steady-state to the MIC (AUC24,ss/MIC) of several intermittent and continuous dosing regimens.
Newborns receiving vancomycin for suspected or confirmed late-onset sepsis were included. Peak and trough concentrations for intermittent vancomycin dosing and steady-state concentrations for continuous vancomycin dosing were measured. NONMEM 7.3 was used for population pharmacokinetic analysis. Monte Carlo simulations were performed to compare dosing schemes.
Data from 54 infants were used for model development and from 34 infants for the model evaluation {corrected gestational age [median (range)] = 29 (23.7-41.9) weeks and 28 (23.4-41.7) weeks, respectively}. The final model was a one-compartment model. Weight and postmenstrual age were included a priori, and then no additional covariate significantly improved the model fit. Final model parameter estimates [mean (SEM)]: CL = 5.7 (0.3) L/h/70 kg and V = 39.3 (3.7) L/70 kg. Visual predictive check of the evaluation dataset confirmed the model can predict external data. Simulations using MIC of 1 mg/L showed that for neonates with gestational age ≤25 weeks and postnatal age ≤2 weeks AUC24,ss/MIC was lower with the intermittent regimen (median 482 versus 663).
A population pharmacokinetic model for continuous and intermittent vancomycin administration in infants was developed. Continuous administration might be favourable for treating infections caused by resistant microorganisms in very young and immature infants.
万古霉素常用于治疗医院获得性细菌病原体引起的早产儿迟发性败血症。我们前瞻性地收集了药代动力学数据，旨在描述药代动力学，并确定导致新生儿万古霉素药代动力学变异性的协变量。此外，我们旨在使用该模型比较几种间歇和连续给药方案的稳态时 AUC24 与 MIC 的比值（AUC24,ss/MIC）。
纳入接受万古霉素治疗疑似或确诊迟发性败血症的新生儿。测量间歇万古霉素给药的峰浓度和谷浓度以及连续万古霉素给药的稳态浓度。使用 NONMEM 7.3 进行群体药代动力学分析。进行蒙特卡罗模拟以比较给药方案。
该模型开发使用了 54 名婴儿的数据，模型评估使用了 34 名婴儿的数据[校正胎龄（中位数（范围））分别为 29（23.7-41.9）周和 28（23.4-41.7）周]。最终模型为单室模型。体重和胎龄是先验纳入的，之后没有其他协变量显著改善模型拟合。最终模型参数估计值[平均值（SEM）]：CL 为 5.7（0.3）L/h/70kg，V 为 39.3（3.7）L/70kg。评估数据集的可视化预测检查证实该模型可以预测外部数据。使用 MIC 为 1mg/L 的模拟结果表明，对于胎龄≤25 周且出生后年龄≤2 周的新生儿，间歇方案的 AUC24,ss/MIC 较低（中位数分别为 482 与 663）。
我们开发了一种用于婴儿连续和间歇万古霉素给药的群体药代动力学模型。连续给药可能对治疗非常年幼和不成熟婴儿的耐药微生物感染有利。
