Universidade do Estado do Rio de Janeiro, Faculdade de Ciências Médicas, Departamento de Microbiologia, Inmunologia e Parasitologia, Boulevard 28 de Setembro, 77 - Vila Isabel, RJ-20551-030, Rio de Janeiro, Brazil; University of Groningen, University Medical Center Groningen, Department of Medical Microbiology and Infection Prevention, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Universidade do Estado do Rio de Janeiro, Faculdade de Ciências Médicas, Departamento de Microbiologia, Inmunologia e Parasitologia, Boulevard 28 de Setembro, 77 - Vila Isabel, RJ-20551-030, Rio de Janeiro, Brazil.
J Glob Antimicrob Resist. 2020 Sep;22:584-593. doi: 10.1016/j.jgar.2020.04.026. Epub 2020 May 7.
Urinary tract infections (UTIs) caused by multidrug-resistant Escherichia coli have become a major medical concern. Old antibiotics such as fosfomycin have become an alternative therapeutic option due to their effectiveness and, as a result, fosfomycin is now used as a first-line drug for the treatment of UTIs in many countries. Despite low resistance rates, fosfomycin heteroresistance, defined as a phenomenon where subpopulations of bacteria are resistant to high antibiotic concentrations whereas most of the bacteria are susceptible, is an underestimated problem.
The frequency of heteroresistance in E. coli isolated from hospitalized patients in Brazil and its effect on susceptibility of E. coli in biofilms was studied and the isolates were molecularly characterized to reveal the mechanisms behind their fosfomycin heteroresistance using whole-genome sequencing.
A higher frequency of fosfomycin heteroresistance compared with other studies was found. In biofilms, most heteroresistant isolates were less sensitive to fosfomycin than control isolates and showed overexpression of metabolic genes thereby increasing their survival rate. Molecular characterization showed that some resistant subpopulations derived from heteroresistant isolates had a defect in their fosfomycin uptake system caused by mutations in transporter and regulatory genes, whereas others overexpressed the murA gene. None to minor effects on bacterial fitness were observed. Oxidative stress protection, virulence and metabolic genes were differentially expressed in resistant subpopulations and heteroresistant isolates.
Frequent detection of heteroresistance in UTIs may play a role in the failure of antibiotic treatments and should therefore be more carefully diagnosed.
由多药耐药大肠杆菌引起的尿路感染（UTI）已成为一个主要的医学关注点。由于其有效性，旧抗生素如磷霉素已成为一种替代治疗选择，因此磷霉素现在在许多国家被用作治疗 UTI 的一线药物。尽管耐药率较低，但磷霉素异质性耐药，定义为细菌的亚群对高抗生素浓度有耐药性，而大多数细菌对其敏感，这是一个被低估的问题。
研究了巴西住院患者分离的大肠杆菌中异质性耐药的频率及其对生物膜中大肠杆菌易感性的影响，并使用全基因组测序对分离株进行分子特征分析，以揭示其磷霉素异质性耐药的机制。
与其他研究相比，发现磷霉素异质性耐药的频率更高。在生物膜中，大多数异质性耐药的分离株对磷霉素的敏感性低于对照分离株，并且表现出代谢基因的过度表达，从而提高了其存活率。分子特征分析表明，一些来源于异质性耐药分离株的耐药亚群由于转运蛋白和调节基因的突变而导致磷霉素摄取系统缺陷，而其他亚群则过度表达 murA 基因。观察到对细菌适应性的影响微乎其微。耐药亚群和异质性耐药分离株中氧化应激保护、毒力和代谢基因的表达存在差异。
UTI 中频繁检测到异质性耐药可能在抗生素治疗失败中起作用，因此应更仔细地诊断。
