Transiently silent acquired antimicrobial resistance: an emerging challenge in susceptibility testing

Abstract

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.

Antibiotic Resistance/Susceptibility Profiles of <em>Staphylococcus equorum </em>Strains from Cheese, and Genome Analysis for Antibiotic Resistance Genes

“…It also allowed for acquired but silent genes to be detected. In the absence of antibiotic pressure, the acquisition of tightly regulated genes (silent genes) that do not lead to the phenotypic expression of resistance have been abundantly described [47], of these some might easily activate under certain conditions [72]. The transfer of silent genes to clinically important pathogens could lead to therapy failure [73].…”

Non-Canonical Aspects of Antibiotics and Antibiotic Resistance

“…It can easily be confused with hetero-resistance and adaptive resistance, discussed above, but it has distinctive features. However, they do have in common an added difficulty for assessment in routine susceptibility assays [ 53 ]. Another recently described phenotype called “perseverance”, very similar to hetero-resistance but detectable only in cell-to-cell comparison assays, affects the in vitro activity of at least nitrofurantoin and rifampicin [ 54 ].…”

Antibiotic Resistance/Susceptibility Profiles of Staphylococcus equorum Strains from Cheese, and Genome Analysis for Antibiotic Resistance Genes

“…It also allowed for acquired but silent genes to be detected. In the absence of antibiotic pressure, the acquisition of tightly regulated genes (silent genes) that do not lead to the phenotypic expression of resistance have been abundantly described [10,53]; of these, some might easily activate under certain conditions [54]. Then, the transfer of silent genes to clinically important pathogens could still lead to therapy failure [55].…”