Abstract

Antimicrobial therapy is facing a worrisome and underappreciated challenge, the phenomenon of heteroresistance (HR). HR has been gradually documented in clinically relevant pathogens (e.g. Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia spp., Acinetobacter baumannii, Klebsiella pneumoniae, Candida spp.) towards several drugs and is believed to complicate the clinical picture of chronic infections. This type of infections are typically mediated by polymicrobial biofilms, wherein microorganisms inherently display a wide range of physiological states, distinct metabolic pathways, diverging refractory levels of stress responses, and a complex network of chemical signals exchange. This review aims to provide an overview on the relevance, prevalence, and implications of HR in clinical settings. Firstly, related terminologies (e.g. resistance, tolerance, persistence), sometimes misunderstood and overlapped, were clarified. Factors generating misleading HR definitions were also uncovered. Secondly, the recent HR incidences reported in clinically relevant pathogens towards different antimicrobials were annotated. The potential mechanisms underlying such occurrences were further elucidated. Finally, the link between HR and biofilms was discussed. The focus was to recognize the presence of heterogeneous levels of resistance within most biofilms, as well as the relevance of polymicrobial biofilms in chronic infectious diseases and their role in resistance spreading. These topics were subject of a critical appraisal, gaining insights into the ascending clinical implications of HR in antimicrobial resistance spreading, which could ultimately help designing effective therapeutic options.

摘要

抗菌疗法正面临令人担忧且未被充分认识的挑战，即异抗性（HR）现象。HR已在临床相关病原体（例如铜绿假单胞菌，金黄色葡萄球菌，伯克霍尔德氏菌，鲍曼不动杆菌，肺炎克雷伯菌，念珠菌spp。），并被认为会使慢性感染的临床情况复杂化。这种类型的感染通常是由微生物生物膜介导的，其中微生物固有地表现出广泛的生理状态，不同的代谢途径，不同的难治性应激反应水平以及复杂的化学信号交换网络。这篇综述旨在概述HR在临床环境中的相关性，患病率及其影响。首先，阐明了有时会被误解和重叠的相关术语（例如抗性，耐受性，持久性）。还发现了导致误导性HR定义的因素。其次，注释了临床相关病原体中针对不同抗菌药物报道的近期HR发生率。进一步阐明了此类事件的潜在机制。最后，讨论了人力资源与生物膜之间的联系。重点是要认识到大多数生物膜中存在不同水平的抗药性，以及多菌种生物膜在慢性传染病中的相关性及其在抗性传播中的作用。这些主题均经过严格评估，获得了有关HR在抗菌素耐药性传播方面的上升临床意义的见解，这最终可能有助于设计有效的治疗方案。以及微生物生物膜在慢性传染病中的相关性及其在耐药性传播中的作用。这些主题均经过严格评估，获得了有关HR在抗菌素耐药性传播方面的上升临床意义的见解，这最终可能有助于设计有效的治疗方案。以及微生物生物膜在慢性传染病中的相关性及其在耐药性传播中的作用。这些主题均经过严格评估，获得了有关HR在抗菌素耐药性传播方面的上升临床意义的见解，这最终可能有助于设计有效的治疗方案。