Pediatric Intensive Care Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Gregorio Marañón Health Research Institute (IISGM), Madrid, Spain; Pediatrics Department, Universidad Complutense de Madrid, Spain; Maternal and Child Health and Development Research Network (REDSAMID), Institute of Health Carlos III, Madrid, Spain.
Pharmacometrics & Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
Clin Microbiol Infect. 2022 Sep;28(9):1287.e9-1287.e15. doi: 10.1016/j.cmi.2022.03.031. Epub 2022 Apr 4.
Despite that piperacillin-tazobactam combination is commonly used in critically ill children, increasing evidence suggests that the current dosing schedules are not optimal for these patients. The aim of this work is to develop a population pharmacokinetic model for piperacillin to evaluate the efficacy of standard dosing in children with and without continuous kidney replacement therapy (CKRT) and to propose alternative dosing schemes maximizing target attainment.
Four hundred twenty-nine piperacillin concentrations measured in different matrices, obtained from 32 critically ill children (19 without CKRT, 13 with CKRT) receiving 100 mg/kg of piperacillin/tazobactam every 8 hours (increased to 12 hours after the fourth dose) were modelled simultaneously using the population approach with NONMEM 7.4. The percentage of patients with 90% fT > MIC and target attainment (percentage of dosing interval above MIC) were estimated for different intermittent and continuous infusions in the studied population.
Piperacillin pharmacokinetic was best described with a two-compartment model. Renal, nonrenal, and hemofilter clearances were found to be influenced by the glomerular filtration rate, height (renal clearance), weight (nonrenal clearance), and filter surface (hemofilter clearance). Only seven (37%) children without CKRT and seven (54%) with CKRT achieved 90% fT > MIC with the current dosing schedule. Of the alternative regimens evaluated, a 24-hour continuous infusion of 200 mg/kg (CKRT) and 300 mg/kg (no CKRT) provided 100% fT > MIC (percent of time free drug remains above the minimum inhibitory concentration) (≤16 mg/L) and target attainments ≥90% across all evaluated MICs.
In children with and without CKRT, standard dosing failed to provide an adequate systemic exposure, while prolonged and continuous infusions showed an improved efficacy.
尽管哌拉西林-他唑巴坦合剂在危重症儿童中广泛应用，但越来越多的证据表明，目前的给药方案并不适合这些患者。本研究旨在建立哌拉西林群体药代动力学模型，评估标准剂量在接受和未接受持续肾脏替代治疗（CKRT）的儿童中的疗效，并提出优化目标的替代给药方案。
对 32 名接受 100mg/kg 哌拉西林-他唑巴坦每 8 小时（第 4 次给药后延长至 12 小时）给药的危重症儿童（19 名无 CKRT，13 名有 CKRT）的不同基质中 429 个哌拉西林浓度进行了测量，采用 NONMEM 7.4 进行群体分析。估计了不同间歇性和连续性输注在研究人群中的 90% fT>MIC 和目标达标率（MIC 以上的给药间隔百分比）。
哌拉西林药代动力学最好用两室模型描述。发现肾、非肾和血液滤过清除率受肾小球滤过率、身高（肾清除率）、体重（非肾清除率）和滤器表面积（血液滤过清除率）的影响。无 CKRT 的儿童中仅有 7 名（37%）和有 CKRT 的儿童中 7 名（54%）达到了当前给药方案的 90% fT>MIC。在所评估的替代方案中，24 小时持续输注 200mg/kg（CKRT）和 300mg/kg（无 CKRT）在所有评估的 MIC 下提供了 100% fT>MIC（游离药物浓度保持在最低抑菌浓度以上的时间百分比）（≤16mg/L）和目标达标率≥90%。
在有和没有 CKRT 的儿童中，标准剂量不能提供足够的全身暴露，而延长和连续输注显示出改善的疗效。
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