169 Persistent MRSA bacteremia 8 Antibiotic tolerance Antibiotic resistance is the inherited ability of bacteria to grow in the presence of elevated concentrations of antibiotics and is quantified by measuring the minimum inhibitory concentration (MIC). Antibiotic tolerance refers to the ability of a population of bacterial cells to survive in the presence of lethal concentrations of bactericidal antibiotics without a change in the MIC [80]. Resistance generally involves a specific mechanism, such as modification of the target, efflux pumps, or deactivation of the antibiotic, whereas the mechanisms of antibiotic tolerance are more general and are commonly associated with slower growth and decreased metabolic activity. The absence of MIC alteration and the wide variability in the pathways that lead to tolerance means the phenotype is challenging to detect. There is currently no standardized testing protocol allowing for detection of antibiotic tolerance in the clinical microbiology laboratory. Additionally, tolerance is highly dependent on the environment, making it difficult to measure under ex vivo conditions. Studies have shown a proportion of S. aureus can survive phagocytosis by host immune cells and persist in the intracellular space [81]. Due the poor intracellular permeability of antibiotics such as vancomycin and daptomycin, these intracellular bacteria are shielded from the effects of serum antibiotics [82]. Recent work by Rowe et al. discovered that host immune cells can also induce antibiotic tolerance in S. aureus by ROS-mediated inactivation of key tricarboxylic acid cycle (TCA) enzymes [83,84]. Another mechanism of host-induced tolerance was identified by Ledger et al., who report that human serum can induce daptomycin tolerance through LL-37-mediated activation of the GraRS two-component system and membrane lipid remodeling [85]. These studies emphasize the diversity in the mechanisms of antibiotic tolerance and underline the difficulty of detecting these phenotypes once the bacteria is removed from the host environment. The most common method for determining antibiotic tolerance is by performing a time-kill curve, which looks at the rate of antibiotic killing of a pathogen by an antibiotic over time [86], which is laborious and not feasible in a busy clinical microbiology laboratory. The devastating consequences of antibiotic resistance are ubiquitously acknowledged through the scientific community, although the clinical impact of antibiotic tolerance is less well understood. In addition, there is no standardized definition of antibiotic tolerance, although some groups have agreed that a minimum bactericidal concentration (MBC) to MIC ratio of >32 is consistent with tolerant bacteria [87–90]. A key study by Levin-Reisman revealed that antibiotic tolerance acts as a precursor to antibiotic resistance [91]. The mechanism proposes that decreased antibiotic killing in antibiotic-tolerant cells results in an increase in the pool of viable cells available to acquire mutations that confer resistance. Further studies are needed to explore if this phenomenon can be extrapolated beyond ampicillin tolerance and resistance in Escherichia coli. While the clinical relevance of this finding will require further experiments, it provides further
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