Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Department of Biology, Emory University, Atlanta, GA, USA.
Nat Microbiol. 2019 Mar;4(3):504-514. doi: 10.1038/s41564-018-0342-0. Epub 2019 Feb 11.
When choosing antibiotics to treat bacterial infections, it is assumed that the susceptibility of the target bacteria to an antibiotic is reflected by laboratory estimates of the minimum inhibitory concentration (MIC) needed to prevent bacterial growth. A caveat of using MIC data for this purpose is heteroresistance, the presence of a resistant subpopulation in a main population of susceptible cells. We investigated the prevalence and mechanisms of heteroresistance in 41 clinical isolates of the pathogens Escherichia coli, Salmonella enterica, Klebsiella pneumoniae and Acinetobacter baumannii against 28 different antibiotics. For the 766 bacteria-antibiotic combinations tested, as much as 27.4% of the total was heteroresistant. Genetic analysis demonstrated that a majority of heteroresistance cases were unstable, with an increased resistance of the subpopulations resulting from spontaneous tandem amplifications, typically including known resistance genes. Using mathematical modelling, we show how heteroresistance in the parameter range estimated in this study can result in the failure of antibiotic treatment of infections with bacteria that are classified as antibiotic susceptible. The high prevalence of heteroresistance with the potential for treatment failure highlights the limitations of MIC as the sole criterion for susceptibility determinations. These results call for the development of facile and rapid protocols to identify heteroresistance in pathogens.
在选择抗生素治疗细菌感染时，通常假设目标细菌对抗生素的敏感性可以通过实验室估计最小抑菌浓度（MIC）来反映，该浓度是阻止细菌生长所需的抗生素浓度。使用 MIC 数据有一个注意事项，即异质性耐药，即在敏感细胞的主要群体中存在耐药亚群。我们调查了 41 株临床分离的病原体大肠杆菌、沙门氏菌、肺炎克雷伯菌和鲍曼不动杆菌对 28 种不同抗生素的异质性耐药的流行情况和机制。在测试的 766 个细菌-抗生素组合中，多达 27.4%的组合存在异质性耐药。遗传分析表明，大多数异质性耐药情况是不稳定的，亚群的耐药性增加是由于自发串联扩增引起的，通常包括已知的耐药基因。通过数学建模，我们展示了在本研究中估计的参数范围内的异质性耐药如何导致被归类为抗生素敏感的细菌感染的抗生素治疗失败。异质性耐药的高流行率和治疗失败的潜在风险突出了 MIC 作为唯一敏感性判断标准的局限性。这些结果呼吁开发简便快速的方案来识别病原体中的异质性耐药。
