Ciprofloxacin selects for RNA polymerase mutations with pleiotropic antibiotic resistance effects.

Objectives: Resistance to the fluoroquinolone drug ciprofloxacin is commonly linked to mutations that alter the drug target or increase drug efflux via the major AcrAB-TolC transporter. Very little is known about other mutations that might also reduce susceptibility to ciprofloxacin. We discovered that an Escherichia coli strain experimentally evolved for resistance to ciprofloxacin had acquired a mutation in rpoB, the gene coding for the β-subunit of RNA polymerase.

Mutant prevention concentrations of pradofloxacin for susceptible and mutant strains of Escherichia coli with reduced fluoroquinolone susceptibility.

Pharmacodynamic and mutant prevention properties of the fluoroquinolone pradofloxacin (PRA) were measured against a set of 17 Escherichia coli strains carrying no, one or two known mutations conferring reduced fluoroquinolone susceptibility. The strains included susceptible wild-types, isogenic constructed mutants, isogenic selected mutants and clinical isolates. The effectiveness of PRA was determined with regard to preventing the selection of resistant mutants, using static and changing concentrations of drug.

Interplay in the selection of fluoroquinolone resistance and bacterial fitness.

Fluoroquinolones are antibacterial drugs that inhibit DNA Gyrase and Topoisomerase IV. These essential enzymes facilitate chromosome replication and RNA transcription by regulating chromosome supercoiling. High-level resistance to fluoroquinolones in E.

Dose-related selection of fluoroquinolone-resistant Escherichia coli.

Objectives: To investigate the effects of clinically used doses of norfloxacin, ciprofloxacin and moxifloxacin on survival and selection in Escherichia coli populations containing fluoroquinolone-resistant subpopulations and to measure the value of the pharmacodynamic index AUC/mutant prevention concentration (MPC) that prevents the growth of pre-existing resistant mutants.

Methods: Mixed cultures of susceptible wild-type and isogenic single (gyrA S83L) or double (gyrA S83L, Delta marR) fluoroquinolone-resistant mutants were exposed to fluoroquinolones for 24 h in an in vitro kinetic model. Antibiotic concentrations modelled pharmacokinetics attained with clinical doses.

Selection of ciprofloxacin resistance in Escherichia coli in an in vitro kinetic model: relation between drug exposure and mutant prevention concentration.

Objectives: To evaluate the mutant prevention concentrations (MPCs) of ciprofloxacin for two susceptible and one first-step gyrA resistant mutant Escherichia coli strains in an in vitro kinetic model and to identify the pharmacodynamic index that best predicts prevention of resistance emergence.

Methods: An in vitro kinetic model was used to measure MPC with static antibiotic concentrations and to test different dosing profiles to study pharmacokinetics/pharmacodynamics indices important to prevent the growth of resistant mutants. In one set of kinetic experiments the starting concentration was equal to the MPC and the T > MPC was varied before antibiotic dilution was begun.

Biological cost of single and multiple norfloxacin resistance mutations in Escherichia coli implicated in urinary tract infections.

Resistance to fluoroquinolones in urinary tract infection (UTIs) caused by Escherichia coli is associated with multiple mutations, typically those that alter DNA gyrase and DNA topoisomerase IV and those that regulate AcrAB-TolC-mediated efflux. We asked whether a fitness cost is associated with the accumulation of these multiple mutations. Mutants of the susceptible E.

Mutant prevention concentrations of ciprofloxacin for urinary tract infection isolates of Escherichia coli.

Objectives: To measure the mutant prevention concentration (MPC) of ciprofloxacin for a set of urinary tract infection (UTI) Escherichia coli isolates with different levels of susceptibility and determine whether MPC can be predicted from MIC.

Methods: MPC was defined as the lowest ciprofloxacin concentration that prevented the growth of resistant colonies when 10(10) bacteria were spread on solid medium and incubated for 96 h at 37 degrees C. MIC was measured by Etest.