Clinical Microbiology Laboratory, Attikon University General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Laboratory of Molecular Biology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, Athens, Greece.
Clin Microbiol Rev. 2024 Sep 12;37(3):e0004424. doi: 10.1128/cmr.00044-24. Epub 2024 Jul 29.
SUMMARYDespite the early recognition of their therapeutic potential and the current escalation of multidrug-resistant (MDR) pathogens, the adoption of bacteriophages into mainstream clinical practice is hindered by unfamiliarity with their basic pharmacokinetic (PK) and pharmacodynamic (PD) properties, among others. Given the self-replicative nature of bacteriophages in the presence of host bacteria, the adsorption rate, and the clearance by the host's immunity, their PK/PD characteristics cannot be estimated by conventional approaches, and thus, the introduction of new considerations is required. Furthermore, the multitude of different bacteriophage types, preparations, and treatment schedules impedes drawing general conclusions on their PK/PD features. Additionally, the drawback of acquired bacteriophage resistance of MDR pathogens with clinical and environmental implications should be taken into consideration. Here, we provide an overview of the current state of the field of PK and PD of bacteriophage therapy with a focus on its application against MDR Gram-negative infections, highlighting the potential knowledge gaps and the challenges in translation from the bench to the bedside. After reviewing the PKs and PDs of bacteriophages against the four major MDR Gram-negative pathogens, , complex, , and , specific data on PKs (tissue distribution, route of administration, and basic PK parameters in animals and humans) and PDs (survival and reduction of bacterial burden in relation to the route of administration, timing of therapy, dosing regimens, and resistance) are summarized. Currently available data merit close scrutiny, and optimization of bacteriophage therapy in the context of a better understanding of the underlying PK/PD principles is urgent to improve its therapeutic effect and to minimize the occurrence of bacteriophage resistance.
摘要
尽管人们很早就认识到噬菌体具有治疗潜力，而且目前多药耐药（MDR）病原体的耐药性不断升级，但由于对其基本药代动力学（PK）和药效动力学（PD）特性等方面不熟悉，噬菌体仍难以在主流临床实践中得到应用。鉴于噬菌体在宿主细菌存在的情况下具有自我复制的特性，以及噬菌体的吸附率和宿主免疫清除率，不能用传统方法来估计其 PK/PD 特征，因此需要引入新的考虑因素。此外，由于噬菌体类型、制剂和治疗方案繁多，难以对其 PK/PD 特征得出一般性结论。此外，还应考虑到 MDR 病原体获得噬菌体耐药性的影响，这既有临床方面的，也有环境方面的。在这里，我们概述了噬菌体治疗 PK 和 PD 领域的现状，重点介绍了其在治疗 MDR 革兰氏阴性感染方面的应用，强调了潜在的知识空白和从实验室到临床转化的挑战。在回顾了噬菌体针对四大主要 MDR 革兰氏阴性病原体（ 、 、 复杂菌和 ）的 PK 和 PD 之后，针对 PK（组织分布、给药途径和动物及人体的基本 PK 参数）和 PD（与给药途径、治疗时机、剂量方案和耐药性相关的存活和细菌负荷减少），总结了特定的 PK 和 PD 数据。目前可用的数据值得仔细审查，迫切需要优化噬菌体治疗，在更好地理解潜在 PK/PD 原则的背景下，以提高其治疗效果并最大限度地减少噬菌体耐药性的发生。
