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Determination of vancomycin pharmacokinetic/pharmacodynamic target and individualized dosing regimen recommendation in ICU neonates

By ZHE TANG, Jing Guan, Jingjing Li, Yanxia Yu, Miao Qian, Jing Cao, Weiwei Shuai, Zheng Jiao

Posted 01 Apr 2020
medRxiv DOI: 10.1101/2020.03.30.20045971

Few studies incorporating population pharmacokinetic/pharmacodynamic (Pop-PK/PD) modelling have been conducted to quantify the exposure target of vancomycin in neonates. To determine this target and dosing recommendations, a retrospective observational cohort study was established in neonates (chictr.org.cn, ChiCTR1900027919). A Pop-PK model was developed to estimate PK parameters. Causalities between acute kidney injury (AKI) occurrence and vancomycin use were verified using Naranjo criteria. Thresholds of vancomycin exposure in predicting AKI or efficacy were identified via classification and regression tree analysis. Associations between exposure thresholds and clinical outcomes including AKI and efficacy, were analysed by logistic regression. Dosing recommendations were designed using Monte Carlo (MC) simulations based on the optimised exposure target. Pop-PK modelling included 182 neonates with 411 observations. In covariate analysis, neonatal physiological maturation, renal function, and concomitant use of vasoactive drugs (VAS) significantly affected vancomycin pharmacokinetics. Seven cases of vancomycin-induced AKI were detected. Area under the concentration-time curve from 0-24 h (AUC0-24) [≥] 485 mg*h/L was an independent risk factor for AKI after adjusting for VAS co-administration. Clinical efficacy of vancomycin was analysed in 42 patients with blood culture-proven staphylococcal sepsis. AUC0-24 to minimum inhibitory concentration (AUC0-24/MIC) [≥] 234 was the only significant predictor of clinical effectiveness. MC simulations indicated that regimens in Neonatal Formulary 7 and Red Book (2018) were not suitable for all neonates. In summary, AUC0-24 of 240-480 assuming MIC = 1 mg/L is a recommended exposure target of vancomycin in neonates. Model-informed dosing regimens are valuable in clinical practice.

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