In vitro studies with five quinolones: evidence for changes in relative potency as quinolone resistance rises

Abstract

A panel of 203 staphylococci, Enterobacteriaceae, Pseudomonas aeruginosa, and miscellaneous nonfermentative gram-negative bacilli were chosen for their various susceptibilities to ciprofloxacin. On the basis of agar dilution susceptibilities, each of the four taxonomic groups was divided into ciprofloxacin-susceptible, moderately resistant, and highly resistant subgroups, and each subgroup was then further analyzed for its susceptibility to the fluoroquinolones CI-960, CI-990, sparfloxacin, and ofloxacin. Although the MICs of each quinolone increased as ciprofloxacin resistance increased, the potency of CI-960 appeared to increase relative to the potencies of the other quinolones. Similarly, the MICs of sparfloxacin and ofloxacin appeared to be less affected by ciprofloxacin resistance than were the MICs of ciprofloxacin or CI-990. Single-step mutants of representative clinical isolates with different levels of ciprofloxacin resistance were selected to determine whether the study quinolones differed in their propensity to select resistant mutants and whether the presence of preexisting ciprofloxacin resistance influenced the subsequent development of resistance. Each of the five fluoroquinolones and nalidixic acid selected mutants that exhibited generally modest decreases in quinolone susceptibility (4- to 16-fold). However, CI-960 inhibited significantly more mutants (80%) than did the other quinolones (39 to 59%) at a concentration of 1 microgram/ml. The presence of preexisting ciprofloxacin resistance appeared to be associated with higher mutational frequencies in coagulase-negative staphylococci exposed to each of the fluoroquinolones and in Serratia marcescens exposed to nalidixic acid. Preexisting ciprofloxacin resistance did not influence the development of resistance in the strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Pseudomonas aeruginosa that were studied. The results of this study suggest that quinolones are not affected equally by all resistance mechanisms, and although each one can select mutants, some quinolones may be active against these mutants at clinically achievable concentrations.