The effects of increasing levels of quinolone resistance on in-vitro activity of four quinolones

A panel of 266 clinically isolated Gram-positive cocci and Gram-negative bacilli with varying levels of resistance to ciprofloxacin were analysed for susceptibility to Du-6859a, ciprofloxacin, ofloxacin, temafloxacin and nalidixic acid. Staphylococci were divided into ciprofloxacin-susceptible, moderately resistant and highly resistant subgroups. Du-6859a was the most potent quinolone against all taxa. As ciprofloxacin resistance increased to high levels, MICs of all quinolones increased but Du-6859a MICs increased least, and ciprofloxacin MICs increased most. Less susceptible single-step mutants were selected from 80% of 15 representative clinical isolates exposed to ciprofloxacin, 71% of isolates exposed to temafloxacin, 67% of isolates exposed to Du-6859a and 53% of isolates exposed to ofloxacin. Du-6859a inhibited more mutants (67%) at a concentration of 1 mg/L than did the other quinolones (26-43%) at their susceptible breakpoints. Du-6859a was the most rapidly bactericidal quinolone in time-kill studies with Enterococcus faecalis and Enterococcus faecium. This study indicated that Du-6859a is more potent than the comparator quinolones, is less affected by the mechanisms responsible for high-level quinolone resistance and may be less likely to select resistant mutants if it has a susceptible breakpoint of 1 mg/L.