Mutant prevention concentrations for single-step fluoroquinolone-resistant mutants of wild-type, efflux-positive, or ParC or GyrA mutation-containing Streptococcus pneumoniae isolates.

Abstract

Three fluoroquinolone-susceptible and five fluoroquinolone-resistant (two with ParC Ser79Phe mutations, one with a GyrA Ser81Phe mutation, and two that were efflux positive) Streptococcus pneumoniae isolates were exposed to one, two, four, eight, and sixteen times the MICs of ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin. Mutational frequencies were calculated at each multiple of the MIC for which growth was observed. Mutant prevention concentrations (MPCs) and the multiple of the MIC at the MPC (MP(MIC)) were evaluated. All resulting mutants were sequenced for quinolone resistance-determining region changes in GyrA and ParC and were evaluated for reserpine-sensitive efflux. The MPC order was generally ciprofloxacin > levofloxacin > gatifloxacin > moxifloxacin > gemifloxacin. The MP(MIC) order varied depending on the genetic constitution of the original isolates from which the mutants were generated. For those mutants created from fluoroquinolone-susceptible isolates (those that had wild-type ParC and GyrA and were efflux negative), the MP(MIC) order was ciprofloxacin = moxifloxacin > gemifloxacin > levofloxacin > gatifloxacin. The MP(MIC)s of each fluoroquinolone for mutants created from isolates with a ParC mutation (with wild-type GyrA and efflux negative) were similar. A similar occurrence was observed with the mutants created from the efflux-positive isolates (with wild-type ParC and GyrA). The MP(MIC) order for the mutants created from the isolate with a GyrA mutation (with wild-type ParC and efflux negative) was ciprofloxacin = gemifloxacin > levofloxacin = moxifloxacin > gatifloxacin. Gatifloxacin, levofloxacin, and moxifloxacin may be intrinsically more able to prevent the development of resistance by fluoroquinolone-susceptible isolates, isolates that are efflux positive, or isolates that carry a GyrA mutation. However, once a ParC mutation is present, the MPC increases dramatically for all fluoroquinolones.