Pharmacodynamic Activity of Fluoroquinolones Against Ciprofloxacin-Resistant Streptococcus pneumoniae
The susceptibility and pharmacodynamic activity of ciprofloxacin and new fluoroquinolones were studied against low-level (MIC 4 mg/L) and high-level (MIC 16 mg/L) ciprofloxacin-resistant Streptococcus pneumoniae. An in vitro pharmacodynamic model simulating free fluoroquinolone (protein unbound) serum concentrations, using Cpmax and AUC0–24 achieved (in healthy volunteers) after standard oral doses that are used for community-acquired respiratory infections, was used to compare bacterial killing by five fluoroquinolones against six ciprofloxacin-resistant S. pneumoniae isolates (four different resistance mutant phenotypes: ParC, efflux, ParC with efflux, and ParC and GyrA) obtained from an ongoing Canadian respiratory organism surveillance study. The potency (MIC only) of fluoroquinolones was gemifloxacin > moxifloxacin > gatifloxacin > levofloxacin > ciprofloxacin. Ciprofloxacin (free AUC0–24/MIC 0.9–3.5) produced no reduction of growth at 6, 24 or 48 h compared with the initial inoculum in all six strains. Levofloxacin (free AUC0–24/MIC 18–35) was bactericidal (≥3 log10 killing) at 6, 24 and 48 h for the ParC as well as the efflux mutants, but only bactericidal at 24 h for the ParC with efflux strain. Levofloxacin (free AUC0–24/MIC 4.4) demonstrated no reduction of growth relative to the initial inoculum against the ParC and GyrA mutants. Gatifloxacin and moxifloxacin (free AUC0–24/MIC 48 and 60, respectively) were bactericidal at 6, 24 and 48 h against the ParC, efflux, and ParC with efflux mutants, but demonstrated little to no growth reduction (free AUC0–24/MIC 6 and 7.5, respectively) in ParC and GyrA mutants. Gemifloxacin (free AUC0–24/MIC 67–133) was bactericidal (≥3 log10 killing) at 6, 24 and 48 h in all low-level ciprofloxacin-resistant S. pneumoniae mutants. Against two of the ParC and GyrA mutants, gemifloxacin (free AUC0–24/MIC 32) was bactericidal at 6, 24 and 48 h but against one ParC and GyrA mutant (free AUC0–24/MIC 16) gemifloxacin demonstrated reduced activity with initial killing at 24 h but with subsequent regrowth. These data indicate that ciprofloxacin produces no inhibition of growth of low- or high-level ciprofloxacin-resistant S. pneumoniae, whereas gatifloxacin, levofloxacin and moxifloxacin (moxifloxacin>gatifloxacin>levofloxacin) were bactericidal for low-level resistant strains but produced little or no inhibition of high-level resistant strains. Gemifloxacin at simulated free AUC0–24/MIC ≥32, was bactericidal against low- and high-level resistant strains. When simulated free AUC0–24/ MIC was <16, gemifloxacin allowed regrowth of high-level ciprofloxacin-resistant strains.
Zhanel G, Roberts D, Walkty A, Laing N, Nichol K, Smith H, Noreddin A, Bellyou T, Hoban D. Pharmacodynamic activity of fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae. J Antimicrob Chemother. 2002;49(5):807-12. doi: 10.1093/jac/dkf022
British Society for Antimicrobial Chemotherapy