Research Group for Host-Microbe Interactions, Department of Medical Biology, Faculty of Health Sciences, UiT the Arctic University of Norway, Tromsø, Norway.
Microbiological Diagnostic Unit Public Health Laboratory, The Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
J Antimicrob Chemother. 2023 Mar 2;78(3):586-598. doi: 10.1093/jac/dkad024.
Acquisition and expression of antimicrobial resistance (AMR) mechanisms in bacteria are often associated with a fitness cost. Thus, evolutionary adaptation and fitness cost compensation may support the advance of subpopulations with a silent resistance phenotype when the antibiotic selection pressure is absent. However, reports are emerging on the transient nature of silent acquired AMR, describing genetic alterations that can change the expression of these determinants to a clinically relevant level of resistance, and the association with breakthrough infections causing treatment failures. This phenomenon of transiently silent acquired AMR (tsaAMR) is likely to increase, considering the overall expansion of acquired AMR in bacterial pathogens. Moreover, the augmented use of genotypic methods in combination with conventional phenotypic antimicrobial susceptibility testing (AST) will increasingly enable the detection of genotype and phenotype discrepancy. This review defines tsaAMR as acquired antimicrobial resistance genes with a corresponding phenotype within the wild-type distribution or below the clinical breakpoint for susceptibility for which genetic alterations can mediate expression to a clinically relevant level of resistance. References to in vivo resistance development and therapeutic failures caused by selected resistant subpopulations of tsaAMR in Gram-positive and Gram-negative pathogens are given. We also describe the underlying molecular mechanisms, including alterations in the expression, reading frame or copy number of AMR determinants, and discuss the clinical relevance concerning challenges for conventional AST.
细菌中抗菌药物耐药性（AMR）机制的获得和表达通常与适应性成本相关。因此，当抗生素选择压力不存在时，具有沉默耐药表型的亚群可能会通过进化适应和适应性成本补偿来支持其发展。然而，目前有报道称沉默获得性 AMR 具有短暂性，描述了可以改变这些决定因素表达从而达到临床相关耐药水平的遗传改变，并与导致治疗失败的突破性感染有关。考虑到细菌病原体中获得性 AMR 的总体扩张，这种短暂沉默获得性 AMR（tsaAMR）的现象可能会增加。此外，基因型方法的广泛应用与传统表型抗菌药物敏感性测试（AST）相结合，将越来越多地能够检测到基因型和表型差异。本综述将 tsaAMR 定义为具有野生型分布内或低于临床药敏折点的相应表型的获得性抗菌药物耐药基因，这些表型可通过遗传改变介导表达从而达到临床相关的耐药水平。文中提到了革兰氏阳性和革兰氏阴性病原体中 tsaAMR 选择的耐药亚群导致体内耐药发展和治疗失败的情况。我们还描述了潜在的分子机制，包括 AMR 决定因素表达、读框或拷贝数的改变，并讨论了与传统 AST 相关的临床相关性挑战。
