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 in vivo 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 in vitro PKs and PDs of bacteriophages against the four major MDR Gram-negative pathogens, Klebsiella pneumoniae, Acinetobacter baumannii complex, Pseudomonas aeruginosa, and Escherichia coli, specific data on in vivo 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.

中文翻译：

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噬菌体治疗的药代动力学和药效学：重点关注多重耐药革兰氏阴性细菌感染的综述。


摘要尽管人们很早就认识到噬菌体的治疗潜力以及当前多重耐药 (MDR) 病原体的增加，但由于对其基本药代动力学 (PK) 和药效学 (PD) 特性不熟悉等因素，噬菌体进入主流临床实践仍受到阻碍。鉴于噬菌体在宿主细菌存在下的自我复制性质、吸附率以及宿主免疫的清除，它们的PK/PD特性无法通过常规方法估计，因此需要引入新的考虑因素。此外，多种不同的噬菌体类型、制剂和治疗方案阻碍了对其体内 PK/PD 特征得出一般性结论。此外，还应考虑耐多药病原体获得性噬菌体耐药性的缺点以及临床和环境影响。在此，我们概述了噬菌体疗法的 PK 和 PD 领域的现状，重点关注其在对抗 MDR 革兰氏阴性感染方面的应用，强调了潜在的知识差距以及从实验室到临床转化的挑战。在回顾了噬菌体针对四种主要MDR革兰氏阴性病原体肺炎克雷伯菌、鲍曼不动杆菌复合体、铜绿假单胞菌和大肠杆菌的体外PK和PD后，获得了体内PK的具体数据（组织分布、给药途径和基本数据）。总结了动物和人类的 PK 参数）和 PD（与给药途径、治疗时间、给药方案和耐药性相关的细菌负荷的存活和减少）。 目前现有的数据值得密切关注，在更好地理解基本的 PK/PD 原理的背景下优化噬菌体疗法迫切需要提高其治疗效果并最大限度地减少噬菌体耐药性的发生。