ABSTRACT
With a view to understanding the interaction between Salmonella and the drugs used to treat it, our aim was to compare the different capacities of various antibiotics to generate mutants resistant to fluoroquinolones following repeated exposure of the microorganisms to subinhibitory concentrations of these drugs. Mutants were generated by repeated exposure to fluoroquinolones and beta-lactams. In order to compare the different capacity to generate resistant mutants, we studied the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of the wild-type strains and of the mutants generated. These data were compared with pharmacokinetic parameters. Mutants generated following repeated exposure to fluoroquinolones exhibit an increased MPC as compared to the wild-type strains, both in strains that are nalidixic acid susceptible and in those that are nalidixic acid resistant, with repeated exposure to ciprofloxacin leading to the smallest increases. This increase in MPC is gradual and depends on the number of exposures the bacteria are subjected to. It results in a decrease in the AUC/MPC ratio, although the absolute values vary. Ciprofloxacin is the most active drug, both against nalidixic acid-susceptible and nalidixic acid-resistant strains, although in late mutants of originally nalidixic acid-resistant strains, the AUC/MPC values are low. Repeated exposure to amoxicillin and cefotaxime also produces an increase in the MPC of fluoroquinolones, with ciprofloxacin being the least affected. Exposure to amoxicillin leads to the greatest increase in the MPC of fluoroquinolones. When the AUC/MPC ratios of these mutants are compared, the values are still seen to be high (between 25 and 75). When we compare the MPC data with the antibiotic levels in humans following administration of the usual doses, it can be seen that ciprofloxacin exhibits the highest AUC/MPC and therefore the lowest risk of therapeutic failures. In addition, administration of subinhibitory concentrations of beta-lactams produces a decrease in fluoroquinolone susceptibility, which may lead to an increase in the risk of therapeutic failure if these compounds are subsequently used.
