Quinolone resistance has increased with the widespread use of fluoroquinolones, with resistance rates varying by organism and geographic region. Resistance arises from target enzyme alterations (DNA gyrase and topoisomerase IV), changes in drug entry/efflux, and plasmid-mediated resistance via the Qnr protein. Qnr plasmids, found globally, protect targets from inhibition, facilitating higher resistance mutations. Resistance to quinolones has been a problem since nalidixic acid was introduced over 40 years ago. Increased fluoroquinolone use in the 1990s led to higher resistance rates, especially in gram-negative bacteria. Resistance is associated with other resistance mechanisms like oxacillin resistance in S. aureus and ESBL production in K. pneumoniae. Resistance is also seen in respiratory pathogens and in treating gonorrhea and enteric infections. Resistance mechanisms include target enzyme mutations, reduced drug accumulation, and plasmid-mediated resistance. DNA gyrase and topoisomerase IV are key targets. Mutations in the quinolone-resistance-determining region (QRDR) reduce drug affinity, increasing resistance. Efflux pumps, such as AcrAB-TolC in E. coli, also contribute to resistance by expelling quinolones. Resistance is often a combination of target alterations and efflux activation. The mutant selection window and mutant prevention concentration (MPC) determine resistance development. A higher MPC allows more resistance mutations to occur. Plasmid-mediated resistance, such as the Qnr gene, increases resistance by protecting targets from inhibition. Qnr is found globally and often linked with ESBLs. Qnr provides low-level resistance but facilitates higher resistance mutations. Other resistance mechanisms include plasmid-encoded mutator genes and efflux systems. Bacteria continue to develop resistance due to selective pressure, showing remarkable versatility in acquiring resistance to therapeutic agents.Quinolone resistance has increased with the widespread use of fluoroquinolones, with resistance rates varying by organism and geographic region. Resistance arises from target enzyme alterations (DNA gyrase and topoisomerase IV), changes in drug entry/efflux, and plasmid-mediated resistance via the Qnr protein. Qnr plasmids, found globally, protect targets from inhibition, facilitating higher resistance mutations. Resistance to quinolones has been a problem since nalidixic acid was introduced over 40 years ago. Increased fluoroquinolone use in the 1990s led to higher resistance rates, especially in gram-negative bacteria. Resistance is associated with other resistance mechanisms like oxacillin resistance in S. aureus and ESBL production in K. pneumoniae. Resistance is also seen in respiratory pathogens and in treating gonorrhea and enteric infections. Resistance mechanisms include target enzyme mutations, reduced drug accumulation, and plasmid-mediated resistance. DNA gyrase and topoisomerase IV are key targets. Mutations in the quinolone-resistance-determining region (QRDR) reduce drug affinity, increasing resistance. Efflux pumps, such as AcrAB-TolC in E. coli, also contribute to resistance by expelling quinolones. Resistance is often a combination of target alterations and efflux activation. The mutant selection window and mutant prevention concentration (MPC) determine resistance development. A higher MPC allows more resistance mutations to occur. Plasmid-mediated resistance, such as the Qnr gene, increases resistance by protecting targets from inhibition. Qnr is found globally and often linked with ESBLs. Qnr provides low-level resistance but facilitates higher resistance mutations. Other resistance mechanisms include plasmid-encoded mutator genes and efflux systems. Bacteria continue to develop resistance due to selective pressure, showing remarkable versatility in acquiring resistance to therapeutic agents.