Pharmacokinetic/Pharmacodynamic Analysis of Extended/Two-Step Infusion Ceftazidime/Avibactam in Children With Gram-Negative Bacterial Infections

IF 3.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical therapeutics Pub Date : 2025-04-21 DOI:10.1016/j.clinthera.2025.03.008

Ruiying Han MPharm, Ying Zhang BPharm, Baosen Yue MPharm, Yuan Zhi BPharm, Weihua Zhang MPharm, Dan Sun MPharm

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引用次数: 0

Abstract

Purpose

To simulate the pharmacokinetic/pharmacodynamic (PK/PD) exposure of ceftazidime/avibactam (CZA) in children with gram-negative bacterial infections, and explore the appropriateness of the CZA standard dosing regimen (STD), further optimize the dosing regimen by extended/two-step infusion.

Methods

Monte Carlo simulations were performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of CZA with varying weight in two age groups (≥6–12 and ≥12–18 years old, respectively), utilizing PK parameters and PD data (from the EUCAST as well as the published data on US children). The simulated dosing regimens included STD and extended/two-step infusion.

Findings

When the PK/PD target for ceftazidime was set at 50% of time that free drug concentrations remain above the minimum inhibitory concentration of the pathogen during the dosing interval (50% fT > MIC), the CZA STD achieved PTAs of ≥90% at susceptibility breakpoint (MIC = 8 mg/L) for children in weighed 15–30 kg (≥6–12years old) and 35–45 kg (≥12–18 years old). However, when the PK/PD target for ceftazidime was set at 100% fT > MIC, none could achieve PTAs of ≥90%. The CFR results showed that the STD couldn't provide CFRs ≥90% in all children, but extended infusion or two-step infusion could achieve the target CFRs in all children based on the MIC distribution of US children, and improve the CFRs based on EUCAST's MIC distribution. Compared with extended infusion, two-step infusion could reduce total infusion time in partial patients.

Implications

The current STD of CZA may not adequately meet the therapeutic requirements in children, thus it is recommended to optimize the dosing regimen by extended/two-step infusion or increasing the daily dose, guided by therapeutic drug monitoring.

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延长/两步输注头孢他啶/阿维巴坦治疗革兰氏阴性细菌感染的药代动力学/药效学分析

目的模拟头孢他啶/阿维巴坦（CZA）在革兰氏阴性细菌感染患儿体内的药代动力学/药效学（PK/PD）暴露，探讨CZA标准给药方案（STD）的适宜性，通过延长/两步输注进一步优化给药方案。方法利用PK参数和PD数据（来自EUCAST和已发表的美国儿童数据），进行蒙特卡罗模拟，计算两个年龄组（分别为≥6-12岁和≥12-18岁）不同权重CZA的目标实现概率（PTA）和累积反应分数（CFR）。模拟给药方案包括性病和延长/两步输注。当头孢他啶的PK/PD靶点设定为50%时，游离药物浓度在给药间隔内保持在病原体的最低抑制浓度以上(50% fT >；对于体重15 - 30kg（≥6 - 12岁）和35 - 45kg（≥12-18岁）的儿童，CZA STD在药敏断点（MIC = 8mg /L）时的PTAs≥90%。然而，当头孢他啶的PK/PD目标设定为100% fT >；MIC，均不能达到≥90%的PTAs。CFR结果显示，STD不能提供所有儿童的CFR≥90%，但根据美国儿童的MIC分布，延长输注或两步输注可以达到所有儿童的目标CFR，并根据EUCAST的MIC分布改善CFR。与延长输注相比，两步输注可减少部分患者的总输注时间。结论CZA患儿目前的性病可能不能充分满足治疗需求，建议在治疗药物监测的指导下，通过延长/两步输注或增加日剂量来优化给药方案。

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

Clinical therapeutics 医学-药学

CiteScore

6.00

自引率

3.10%

发文量

154

审稿时长

9 weeks

期刊介绍： Clinical Therapeutics provides peer-reviewed, rapid publication of recent developments in drug and other therapies as well as in diagnostics, pharmacoeconomics, health policy, treatment outcomes, and innovations in drug and biologics research. In addition Clinical Therapeutics features updates on specific topics collated by expert Topic Editors. Clinical Therapeutics is read by a large international audience of scientists and clinicians in a variety of research, academic, and clinical practice settings. Articles are indexed by all major biomedical abstracting databases.