Open AccessFluoroquinolone Resistance in Streptococcus pneumoniae : Area Under the Concentration-Time Curve/MIC Ratio and Resistance Development with Gatifloxacin, Gemifloxacin, Levofloxacin, and Moxifloxacin
Author(s) -
Kerry L. LaPlante,
Michael J. Rybak,
Brian T. Tsuji,
Thomas P. Lodise,
Glenn W. Kaatz
Publication year - 2007
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00646-06
Subject(s) - gatifloxacin , gemifloxacin , moxifloxacin , levofloxacin , streptococcus pneumoniae , ofloxacin , microbiology and biotechnology , antibacterial agent , medicine , ciprofloxacin , antibiotics , biology
The potential for resistance development inStreptococcus pneumoniae secondary to exposure to gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin at various levels was examined at high inoculum (108.5 to 109 log10 CFU/ml) over 96 h in an in vitro pharmacodynamic (PD) model using two fluoroquinolone-susceptible isolates. The pharmacokinetics of each drug was simulated to provide a range of free areas under the concentration-time curves (f AUC) that correlated with various fluoroquinolone doses. Potential first (parC andparE )- and second-step (gyrA andgyrB ) mutations in isolates with raised MICs were identified by sequence analysis. PD models simulatingf AUC/MICs of 51 and ≤60, 34 and 37, ≤82 and ≤86, and ≤24 for gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin, respectively, against each isolate were associated with first-stepparC (S52G, S79Y, and N91D) and second-stepgyrA (S81Y and S114G) mutations. For each fluoroquinolone a delay of first- and second-step mutations was observed with increasingly higherf AUC/MIC ratios and recovery of topoisomerase mutations inS. pneumoniae was related to thef AUC/MIC exposure. Clinical doses of gatifloxacin, gemifloxacin, and moxifloxacin exceeded thef AUC/MIC resistance breakpoint against wild-typeS. pneumoniae , whereas those of levofloxacin (500 and 750 mg) were associated with first- and second-step mutations. The exposure breakpoints for levofloxacin were significantly different (P < 0.001) from those of the newer fluoroquinolones gatifloxacin, gemifloxacin, and moxifloxacin. Additionally, moxifloxacin breakpoints were significantly lower (P < 0.002) than those of gatifloxacin. The order of resistance development determined fromf AUC/MIC breakpoints was levofloxacin > gatifloxacin > moxifloxacin = gemifloxacin, which may be related to structural differences within the class.