The Antibiotic Selective Process: Concentration-Specific Amplification of Low-Level Resistant Populations

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Abstract
The biochemistry and genetics of antibiotic resistance are far better known than the equally important events underlying the selection of resistant populations. The hidden selection of low‐level resistant variants may be a key process in the emergence of high‐level antibiotic resistance. Different low‐level resistant bacterial subpopulations may be specifically selected by different low antibiotic concentrations. The space in the environment (human body) where a given selective concentration exists represents the selective compartment. For pharmacokinetic reasons, low antibiotic concentrations occur in a larger selective compartment and persist longer than high antibiotic concentrations. The specific selection of low‐level variants by low concentrations of antibiotic can be reproduced in experimental in vitro models using mixtures of susceptible and low‐level resistant populations. We demonstrated this in Escherichia coli strains harbouring TEM‐1, TEM‐12 and TEM‐10 β‐lactamases challenged by cefotaxime, and also Streptococcus pneumoniae strains with various levels of penicillin resistance challenged by amoxicillin or cefotaxime. In both cases, four hours of antibiotic challenge produced selective peaks of low‐level resistant variant populations at low‐level antibiotic concentrations. We conclude that variants with small decreases in antibiotic susceptibility may be fully selectable under in vivo circumstances; on the other hand, low‐level antibiotic concentrations may have a considerable selective effect on the emergence of antibiotic resistance.