The increased use of fluoroquinolones has led to a rise in resistance, with rates varying by organism and geographic region. Resistance typically arises from alterations in target enzymes (DNA gyrase and topoisomerase IV) and changes in drug entry and efflux. Mutations first occur in the more susceptible target, followed by additional mutations in the next most susceptible target, leading to the selection of highly resistant isolates. Plasmids producing the Qnr protein can also mediate resistance, protecting quinolone targets from inhibition. Qnr plasmids have been found in various regions, contributing to the alarming increase in resistance. Resistance to quinolones has been a concern since their introduction over 40 years ago, with the greater potency of fluoroquinolones initially leading to complacency. However, increased use has driven an escalating rate of resistance, particularly in gram-negative bacteria. Resistance mechanisms include mutations in the target enzymes, reduced drug accumulation, and plasmid-mediated protection. The presence of Qnr plasmids, while producing only low-level resistance, facilitates the selection of higher-level resistance mutations. The rate of mutation and the mutant protective concentration (MPC) are critical factors in the emergence of resistance, with higher mutation rates and MPC values increasing the likelihood of resistance. Plasmid-mediated resistance, such as that mediated by the qnr gene, further complicates the situation, widening the mutant selection window and increasing the MPC. Despite ongoing efforts to develop new quinolones, the persistent selective pressure for resistance suggests that bacteria will continue to demonstrate their versatility in acquiring resistance.The increased use of fluoroquinolones has led to a rise in resistance, with rates varying by organism and geographic region. Resistance typically arises from alterations in target enzymes (DNA gyrase and topoisomerase IV) and changes in drug entry and efflux. Mutations first occur in the more susceptible target, followed by additional mutations in the next most susceptible target, leading to the selection of highly resistant isolates. Plasmids producing the Qnr protein can also mediate resistance, protecting quinolone targets from inhibition. Qnr plasmids have been found in various regions, contributing to the alarming increase in resistance. Resistance to quinolones has been a concern since their introduction over 40 years ago, with the greater potency of fluoroquinolones initially leading to complacency. However, increased use has driven an escalating rate of resistance, particularly in gram-negative bacteria. Resistance mechanisms include mutations in the target enzymes, reduced drug accumulation, and plasmid-mediated protection. The presence of Qnr plasmids, while producing only low-level resistance, facilitates the selection of higher-level resistance mutations. The rate of mutation and the mutant protective concentration (MPC) are critical factors in the emergence of resistance, with higher mutation rates and MPC values increasing the likelihood of resistance. Plasmid-mediated resistance, such as that mediated by the qnr gene, further complicates the situation, widening the mutant selection window and increasing the MPC. Despite ongoing efforts to develop new quinolones, the persistent selective pressure for resistance suggests that bacteria will continue to demonstrate their versatility in acquiring resistance.