Fluoroquinolone resistance without fluoroquinolone use; the genie is truly out of the bottle.

The global dissemination of multidrug-resistant (MDR) bacteria is not merely a clinical byproduct of antibiotic overuse, but an evolutionary transition driven by highly successful, human-adapted clonal lineages. While MDR phenotypes are frequently associated with resistance to various drug classes, FQR-mediated by specific mutations in the Quinolone Resistance-Determining Regions (QRDR) of the chromosomal GyrA and ParC genes-stands out as a primary driver of clonal success. Contrary to the traditional "fitness cost" paradigm of antibiotic resistance, recent evidence suggests long-term commensal colonization of healthy individuals by MDR bacteria even in environments devoid of recent antibiotic use. This review analyzes the literature supporting the role of certain QRDR mutations in the commensal carriage of Escherichia coli, Staphylococcus aureus, and other opportunistic human pathogens. We propose, among other explanations, that the metabolic surplus generated by some QRDR mutations offsets the cost of carrying extensive resistance gene cargoes, allowing MDR clones to outcompete susceptible wild-type strains in the community in the absence of antibiotic pressure. Consequently, public health strategies must evolve beyond antibiotic stewardship alone, toward preventing community transmission of MDR strains and effective decolonization of colonized individuals-the main reservoir of clinically relevant antibiotic resistance.