In vitro selection of mutants resistant to ozenoxacin compared with levofloxacin and ciprofloxacin in Gram-positive cocci

Objectives: To determine the frequency of selecting mutants resistant to ozenoxacin, a des-fluoro-(6)-quinolone active against pathogens involved in skin and skin structure infections, compared with levofloxacin and ciprofloxacin in quinolone-susceptible and -resistant Gram-positive cocci.

Methods: Forty-nine quinolone-susceptible and -resistant Gram-positive cocci strains with different profiles of mutations in the Quinolone resistance-determining region (QRDR) were examined to determine the frequency of selecting mutants resistant to ozenoxacin compared with levofloxacin and ciprofloxacin. MICs and mutations in the QRDR were determined by standard broth microdilution and PCR amplification and sequencing, respectively.

Results: The mean resistance rates were 3.8 × 10(-9) (range <9 × 10(-11)-1 × 10(-8)) for ozenoxacin, 9.7 × 10(-9) (range <1.1 × 10(-11)-4.2 × 10(-8)) for levofloxacin and 1.2 × 10(-8) (range <1.6 × 10(-10)-2.6 × 10(-7)) for ciprofloxacin. Spontaneous mutants resistant to ozenoxacin showed lower MICs (≤ 16 mg/L) than mutants resistant to levofloxacin and ciprofloxacin (≤ 512 mg/L). Additional mutations were observed only in ParC at Ser-80 in Staphylococcus spp., Ser-79 in Streptococcus agalactiae and Asp-83 and Ser-89 in Streptococcus pyogenes.

Conclusions: The probability of ozenoxacin selecting spontaneous resistant mutants in quinolone-susceptible and -resistant strains with pre-existing mutations in the QRDR is low, supporting the potential utility of ozenoxacin as a therapeutic alternative in the treatment of skin infections caused by strains highly resistant to quinolones.