Model-informed dose optimization for prophylactic piperacillin-tazobactam in perioperative pediatric critically ill patients.

IF 4.1 2区 医学 Q2 MICROBIOLOGY
Antimicrobial Agents and Chemotherapy Pub Date : 2025-03-05 Epub Date: 2025-02-06 DOI:10.1128/aac.01227-24
Wen Rui Tan, Kei Irie, Carter McIntire, Julie Luna Torres, Rhonda Jones, Abigayle Gibson, Tomoyuki Mizuno, Sonya Tang Girdwood
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Abstract

Piperacillin/tazobactam (PTZ) is frequently prescribed during the perioperative period as prophylaxis in critically ill patients. Current international guidelines recommend that the pediatric intraoperative dosing regimen for PTZ be 90-112.5 mg/kg (80-100 mg/kg as piperacillin [PIP]) administered every 2 hours (Q2H). Concerns have been raised not only about the risk of nephrotoxicity due to elevated PIP exposure but also regarding the practicality of adhering to a 2-h dosing interval in clinical settings. To address these concerns, we employed population pharmacokinetic (PK) modeling and simulation approaches to optimize PTZ dosing regimens in pediatric intraoperative patients. PIP plasma concentration data were obtained from 34 patients using an opportunistic sampling strategy. A two-compartment model was found to adequately describe the PK data. Creatinine clearance was identified as a significant covariate on clearance. The inclusion of inter-occasion variability significantly improved model fit. Simulations across body weights of 10-70 kg and creatinine clearance of 20-130 mL/min/1.73 m2 demonstrated that 6-15 mg/kg Q2H, or a 10 mg/kg loading dose followed by 1.0-2.75 mg/kg/h continuous infusion would achieve free PIP concentrations being above the minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT >1× MIC). For achieving 100% fT >4× MIC, 25-55 mg/kg Q2H or a 20 mg/kg loading dose followed by 3.25-9.25 mg/kg/h continuous infusion was derived. The model-informed simulations indicated that both lower Q2H doses and continuous infusion methods are clinically viable options and potentially resolve current clinical challenges during intraoperative dosing.

基于模型的儿科危重患者围手术期预防性哌拉西林-他唑巴坦剂量优化。
哌拉西林/他唑巴坦(PTZ)常作为危重病人围手术期预防用药。目前的国际指南建议儿科术中给药方案为90-112.5 mg/kg(哌拉西林[PIP]为80-100 mg/kg),每2小时给药一次(Q2H)。人们不仅关注PIP暴露升高引起的肾毒性风险,而且还关注临床环境中坚持2小时给药间隔的实用性。为了解决这些问题,我们采用群体药代动力学(PK)建模和模拟方法来优化儿科术中患者PTZ的给药方案。使用机会抽样策略获得34例患者的PIP血浆浓度数据。发现一个双室模型可以充分描述PK数据。肌酐清除率被确定为清除率的重要协变量。纳入场合间变异性显著改善了模型拟合。体重为10-70 kg,肌酐清除率为20-130 mL/min/1.73 m2的模拟表明,6-15 mg/kg Q2H,或10 mg/kg负荷剂量,然后1.0-2.75 mg/kg/h连续输注,可以使游离PIP浓度在100%的给药间隔(100% fT / bbb10 × MIC)内高于最低抑制浓度(MIC)。为了达到100%的fT >4× MIC,导出了25-55 mg/kg Q2H或20 mg/kg负荷剂量,然后连续注射3.25-9.25 mg/kg/h。基于模型的模拟表明,低Q2H剂量和持续输注方法在临床上都是可行的选择,并有可能解决术中给药过程中当前的临床挑战。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
10.00
自引率
8.20%
发文量
762
审稿时长
3 months
期刊介绍: Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.
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