Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA; New York State Center for Excellence in Life Sciences and Bioinformatics, Buffalo, NY, USA; VA Western New York Healthcare System, Buffalo, NY, USA.
Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA; New York State Center for Excellence in Life Sciences and Bioinformatics, Buffalo, NY, USA.
Int J Antimicrob Agents. 2021 Mar;57(3):106269. doi: 10.1016/j.ijantimicag.2020.106269. Epub 2020 Dec 23.
Antimicrobial pharmacokinetics/pharmacodynamics (PK/PD) principles and PK/PD models have been essential in characterizing the mechanism of antibiotic bacterial killing and determining the most optimal dosing regimen that maximizes clinical outcomes. This review summarized the fundamentals of antimicrobial PK/PD and the various types of PK/PD experiments that shaped the utilization and dosing strategies of antibiotics today.
Multiple databases - including PubMed, Scopus, and EMBASE - were searched for published articles that involved PK/PD modelling and precision dosing. Data from in vitro, in vivo and mechanistic PK/PD models were reviewed as a basis for compiling studies that guide dosing regimens used in clinical trials.
Literature regarding the utilization of exposure-response analyses, mathematical modelling and simulations that were summarized are able to provide a better understanding of antibiotic pharmacodynamics that influence translational drug development. Optimal pharmacokinetic sampling of antibiotics from patients can lead to personalized dosing regimens that attain target concentrations while minimizing toxicity. Thus the development of a fully integrated mechanistic model based on systems pharmacology can continually adapt to data generated from clinical responses, which can provide the framework for individualized dosing regimens.
The promise of what PK/PD can provide through precision dosing for antibiotics has not been fully realized in the clinical setting. Antimicrobial resistance, which has emerged as a significant public health threat, has forced clinicians to empirically utilize therapies. Future research focused on implementation and translation of PK/PD-based approaches integrating novel approaches that combine knowledge of combination therapies, systems pharmacology and resistance mechanisms are necessary. To fully realize maximally precise therapeutics, optimal PK/PD strategies are critical to maximize antimicrobial efficacy against extremely-drug-resistant organisms, while minimizing toxicity.
抗菌药药代动力学/药效学（PK/PD）原理和 PK/PD 模型对于阐明抗生素杀菌机制和确定最大化临床疗效的最佳给药方案至关重要。本综述总结了抗菌 PK/PD 的基本原理和各种 PK/PD 实验，这些实验为当今抗生素的应用和给药策略提供了依据。
通过检索 PubMed、Scopus 和 EMBASE 等多个数据库，查找涉及 PK/PD 建模和精准给药的已发表文章。综述了来自体外、体内和机制 PK/PD 模型的数据，为指导临床试验中使用的给药方案的研究提供了依据。
对所综述的暴露-反应分析、数学建模和模拟的文献进行了综合，有助于更好地了解影响转化药物开发的抗生素药效学。从患者中获取抗生素的最佳药代动力学采样可实现目标浓度，同时最小化毒性的个体化给药方案。因此，基于系统药理学的完全集成机制模型的开发可以不断适应来自临床反应的数据，为个体化给药方案提供框架。
PK/PD 通过精准给药为抗生素提供的前景在临床实践中尚未得到充分实现。抗菌药物耐药性已成为一个重大的公共卫生威胁，迫使临床医生凭经验使用治疗方法。未来的研究需要集中在实施和转化基于 PK/PD 的方法上，整合新的方法，将联合治疗、系统药理学和耐药机制的知识结合起来。为了实现最大限度的精准治疗，最佳的 PK/PD 策略对于最大限度地提高对抗极端耐药菌的抗菌疗效，同时最小化毒性至关重要。
