Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Pediatr Blood Cancer. 2019 Jun;66(6):e27654. doi: 10.1002/pbc.27654. Epub 2019 Feb 10.
Data on piperacillin-tazobactam pharmacokinetics and optimal dosing in children with cancer and fever are limited. Our objective was to investigate piperacillin pharmacokinetics and the probability of target attainment (PTA) with standard intermittent administration (IA), and to simulate PTA in other dosing regimens.
This prospective pharmacokinetic study was conducted from April 2016 to January 2018. Children with cancer receiving empiric piperacillin-tazobactam to treat infections were included. Piperacillin-tazobactam 100 mg/kg was infused over 5 min every 8 hours (IA). An optimized sample schedule provided six blood samples per subject for piperacillin concentration determination. The evaluated targets included: (1) 100% time of free piperacillin concentration above the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4× MIC. MIC and MIC were defined based on an intrainstitutional MIC range.
A total of 482 piperacillin concentrations were obtained from 43 children (aged 1-18 years) during 89 fever episodes. Standard IA resulted in insufficient target attainment, with significant differences in piperacillin pharmacokinetics for different body weights. Median fT > MIC was 61.2%, 53.5%, and 36.3% for MIC (2.0 mg/L), MIC (4.0 mg/L), and breakpoint for Pseudomonas aeruginosa (16.0 mg/L), respectively. Correspondingly, the median fT > 4× MIC was 43%, 36.3%, and 20.1%. Simulations showed that only continuous infusion reached a PTA of 95% for MIC = 16.0 mg/L, while extended infusion lasting half of the dosing interval reached a PTA of 95% for MIC ≤ 8 mg/L.
Our data revealed insufficient PTA with standard IA of piperacillin-tazobactam in children with cancer and fever. Alternative dosing strategies, preferably continuous infusion, are required to ensure adequate PTA.
关于哌拉西林他唑巴坦在癌症伴发热儿童中的药代动力学和最佳剂量的数据有限。我们的目的是研究标准间歇给药（IA）时哌拉西林的药代动力学和目标达到率（PTA），并模拟其他给药方案的 PTA。
这项前瞻性药代动力学研究于 2016 年 4 月至 2018 年 1 月进行。纳入接受经验性哌拉西林他唑巴坦治疗感染的癌症儿童。哌拉西林他唑巴坦 100mg/kg 于 8 小时内每 5 分钟输注一次（IA）。优化的采样方案为每位受试者提供 6 个血样，用于哌拉西林浓度测定。评估的目标包括：（1）游离哌拉西林浓度 100%时间超过最低抑菌浓度（fT> MIC）和（2）50% fT> 4× MIC。MIC 和 MIC 是基于机构内 MIC 范围定义的。
共从 43 名（年龄 1-18 岁）儿童的 89 次发热发作中获得了 482 个哌拉西林浓度。标准 IA 导致目标达成不足，不同体重的哌拉西林药代动力学存在显著差异。MIC（2.0mg/L）、MIC（4.0mg/L）和铜绿假单胞菌的折点（16.0mg/L）的中位 fT> MIC 分别为 61.2%、53.5%和 36.3%。相应地，中位 fT> 4× MIC 分别为 43%、36.3%和 20.1%。模拟结果表明，只有连续输注才能达到 MIC=16.0mg/L 的 95%PTA，而延长输注持续时间达到给药间隔的一半可达到 MIC≤8mg/L 的 95%PTA。
我们的数据显示，癌症伴发热儿童标准 IA 给予哌拉西林他唑巴坦的 PTA 不足。需要替代的给药策略，最好是连续输注，以确保足够的 PTA。
