Centre for Medicine Use and Safety, Monash University, Parkville Campus, Melbourne, VIC, Australia.
Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
Adv Exp Med Biol. 2019;1145:251-288. doi: 10.1007/978-3-030-16373-0_16.
Combinations of antimicrobial agents are often used in the management of infectious diseases. Antimicrobial agents used as part of combination therapy are often selected empirically. As regrowth and the emergence of polymyxin (either colistin or polymyxin B) resistance has been observed with polymyxin monotherapy, polymyxin combination therapy has been suggested as a possible means by which to increase antimicrobial activity and reduce the development of resistance. This chapter provides an overview of preclinical and clinical investigations of CMS/colistin and polymyxin B combination therapy. In vitro data and animal model data suggests a potential clinical benefit with many drug combinations containing clinically achievable concentrations of polymyxins, even when resistance to one or more of the drugs in combination is present and including antibiotics normally inactive against Gram-negative organisms. The growing body of data on the emergence of polymyxin resistance with monotherapy lends theoretical support to a benefit with combination therapy. Benefits include enhanced bacterial killing and a suppression of polymyxin resistant subpopulations. However, the complexity of the critically ill patient population, and high rates of treatment failure and death irrespective of infection-related outcome make demonstrating a potential benefit for polymyxin combinations extremely challenging. Polymyxin combination therapy in the clinic remains a heavily debated and controversial topic. When combinations are selected, optimizing the dosage regimens for the polymyxin and the combinatorial agent is critical to ensure that the benefits outweigh the risk of the development of toxicity. Importantly, patient characteristics, pharmacokinetics, the site of infection, pathogen and resistance mechanism must be taken into account to define optimal and rational polymyxin combination regimens in the clinic.
抗菌药物联合应用常用于感染性疾病的治疗。联合治疗中使用的抗菌药物通常是经验性选择的。由于多粘菌素单药治疗已观察到多粘菌素（多粘菌素 E 或多粘菌素 B）耐药的再生和出现，因此多粘菌素联合治疗被认为是增加抗菌活性和减少耐药发展的一种可能手段。本章概述了 CMS/多粘菌素 E 和多粘菌素 B 联合治疗的临床前和临床研究。体外数据和动物模型数据表明，许多含有临床可达到多粘菌素浓度的药物组合具有潜在的临床益处，即使存在对联合用药中一种或多种药物的耐药性，包括对抗革兰氏阴性菌通常无效的抗生素。越来越多的关于单药治疗中多粘菌素耐药性出现的数据从理论上支持联合治疗的益处。益处包括增强细菌杀伤和抑制多粘菌素耐药亚群。然而，重症患者人群的复杂性以及无论感染相关结局如何，治疗失败和死亡的高发生率使得证明多粘菌素联合治疗的潜在益处极具挑战性。多粘菌素联合治疗在临床上仍然是一个备受争议的话题。在选择组合时，优化多粘菌素和组合药物的剂量方案对于确保益处超过毒性发展的风险至关重要。重要的是，患者特征、药代动力学、感染部位、病原体和耐药机制必须考虑在内，以在临床上确定最佳和合理的多粘菌素联合治疗方案。
