An innovative population pharmacokinetic/pharmacodynamic strategy for attaining aggressive joint PK/PD target of continuous infusion ceftazidime/avibactam against KPC- and OXA-48- producing Enterobacterales and preventing resistance development in critically ill patients.

IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES
Pier Giorgio Cojutti, Manjunath P Pai, Milo Gatti, Matteo Rinaldi, Simone Ambretti, Pierluigi Viale, Federico Pea
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引用次数: 0

Abstract

Objectives: Ceftazidime/avibactam is a key antibiotic for carbapenemase-producing Enterobacterales (CPE) Gram-negative infections, but current dosing may be suboptimal to grant activity. This study explores the population pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) ceftazidime/avibactam for maximizing treatment efficacy in critically ill patients.

Methods: A retrospective analysis of adult patients receiving CI ceftazidime/avibactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modelling identified the most accurate method for estimating ceftazidime/avibactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive joint PK/PD target attainment of ceftazidime/avibactam.

Results: The European Kidney Function Consortium (EKFC) equation best described kidney function for ceftazidime/avibactam clearance. The findings challenge the current approach of only reducing the ceftazidime/avibactam dose based on kidney function by identifying dose adjustments in patients with augmented kidney function. Our CI ceftazidime/avibactam dosing strategies, adjusted by TDM, showed promise for achieving optimal aggressive joint PK/PD targets and potentially improving clinical/microbiological outcomes against KPC- and OXA-48-producing Enterobacterales. The risk of neurotoxicity associated with these strategies appears acceptable.

Conclusions: This study suggests that adjusting ceftazidime/avibactam dosing regimen based solely on eCLcr might be suboptimal for critically ill patients. Higher daily doses delivered by CI and adjusted based on TDM have the potential to improve aggressive joint PK/PD target attainment and potentially clinical/microbiological outcomes. Further investigations are warranted to confirm these findings and establish optimal TDM-guided dosing strategies for ceftazidime/avibactam in clinical practice.

一种创新的群体药代动力学/药效学策略,用于实现连续输注头孢他啶/阿维菌素对 KPC 和 OXA-48 产肠杆菌的积极联合 PK/PD 目标,并防止重症患者产生耐药性。
目的:头孢他啶/阿维巴坦是治疗产碳青霉烯酶肠杆菌属(CPE)革兰氏阴性菌感染的主要抗生素,但目前的剂量可能不足以发挥其活性。本研究探讨了连续输注(CI)头孢他啶/阿维菌素的群体药代动力学/药效学(PK/PD),以最大限度地提高重症患者的治疗效果:对接受CI头孢他啶/阿维巴坦治疗的成年患者进行了回顾性分析,并对两种化合物进行了治疗药物监测(TDM)。人群 PK/PD 模型确定了根据肾功能估算头孢他啶/阿维巴坦清除率的最准确方法,蒙特卡罗模拟研究了各种 CI 给药方案与头孢他啶/阿维巴坦积极的联合 PK/PD 目标实现之间的关系:结果:欧洲肾功能联盟(EKFC)方程对头孢他啶/阿维菌素清除率的肾功能描述最为准确。研究结果对目前仅根据肾功能减少头孢他啶/阿维巴坦剂量的方法提出了质疑,因为它确定了肾功能增强患者的剂量调整。我们通过TDM调整的CI头孢他啶/阿维巴坦剂量策略有望实现最佳的积极联合PK/PD目标,并有可能改善针对产KPC和产OXA-48肠杆菌的临床/微生物治疗效果。与这些策略相关的神经毒性风险似乎是可以接受的:本研究表明,仅根据 eCLcr 调整头孢他啶/阿维菌素给药方案可能不是重症患者的最佳选择。通过 CI 给药并根据 TDM 调整较高的日剂量,有可能改善侵袭性联合 PK/PD 目标的实现,并有可能改善临床/微生物学结果。为了证实这些发现并在临床实践中确立头孢他啶/阿维菌素在 TDM 指导下的最佳剂量策略,有必要开展进一步的研究。
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
9.20
自引率
5.80%
发文量
423
审稿时长
2-4 weeks
期刊介绍: The Journal publishes articles that further knowledge and advance the science and application of antimicrobial chemotherapy with antibiotics and antifungal, antiviral and antiprotozoal agents. The Journal publishes primarily in human medicine, and articles in veterinary medicine likely to have an impact on global health.
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