Efflux pump overexpression in fluoroquinolone multidrug resistance: molecular mechanisms, PK/PD implications, global epidemiology, and translational strategies

Fluoroquinolones are a cornerstone of human antibacterial chemotherapy because they combine broad-spectrum bactericidal activity, high oral bioavailability, and excellent tissue penetration. However, their clinical utility is being eroded by the global spread of multidrug-resistant (MDR) pathogens. While quinolone resistance-determining region (QRDR) mutations in DNA gyrase and topoisomerase IV remain the primary determinants of high-level resistance, mounting evidence implicates active efflux pump overexpression as an important exposure-modifying mechanism. This mechanism can amplify multidrug resistance. This review provides a pharmacology-centered synthesis of fluoroquinolone mechanism of action, pharmacokinetic/pharmacodynamic (PK/PD) indices, and the mutant selection window (MSW) framework, and integrates these concepts with the structural and regulatory biology of efflux systems in major human ESKAPE pathogens. We highlight how resistance-nodulation-division (RND) pumps in Gram-negative bacteria (e.g., AcrAB-TolC, Mex-family systems) and major facilitator superfamily (MFS) pumps in Gram-positive cocci (e.g., NorA/NorB/NorC) lower intracellular drug exposure, widen the MSW, and promote stepwise acquisition of QRDR mutations and plasmid-mediated quinolone resistance. Using recent WHO GLASS data and health-economic analyses, we summarize global resistance trends and discuss the broader healthcare and macroeconomic burden associated with MDR bacterial infections. Finally, we discuss translational strategies to mitigate efflux-mediated resistance, including the preclinical pipeline of efflux pump inhibitors (EPIs), PK/PD-informed high-exposure dosing regimens, and One Health-aligned antimicrobial stewardship interventions. By linking molecular mechanism, PK/PD, epidemiology, and health economics, this review aims to inform rational dosing, drug development, and policy decisions needed to preserve the efficacy of this vital antimicrobial class.