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Antimicrobial Agents and Chemotherapy, April 2007, p. 1315-1320, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.00646-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Fluoroquinolone Resistance in Streptococcus pneumoniae: Area Under the Concentration-Time Curve/MIC Ratio and Resistance Development with Gatifloxacin, Gemifloxacin, Levofloxacin, and Moxifloxacin

Kerry L. LaPlante,^1,2,4, Michael J. Rybak,^1,2,3,4* Brian Tsuji,^1,2,4, Thomas P. Lodise,⁶ and Glenn W. Kaatz^1,3,5

Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy,¹ Department of Pharmacy Practice,² School of Medicine, Wayne State University,³ Detroit Receiving Hospital and University Health Center,⁴ John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan,⁵ Department of Pharmacy Practice, Albany College of Pharmacy, Albany, New York⁶

Received 26 May 2006/ Returned for modification 31 August 2006/ Accepted 2 February 2007

The potential for resistance development in Streptococcus pneumoniae secondary to exposure to gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin at various levels was examined at high inoculum (10^8.5 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 (fAUC) that correlated with various fluoroquinolone doses. Potential first (parC and parE)- and second-step (gyrA and gyrB) mutations in isolates with raised MICs were identified by sequence analysis. PD models simulating fAUC/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-step parC (S52G, S79Y, and N91D) and second-step gyrA (S81Y and S114G) mutations. For each fluoroquinolone a delay of first- and second-step mutations was observed with increasingly higher fAUC/MIC ratios and recovery of topoisomerase mutations in S. pneumoniae was related to the fAUC/MIC exposure. Clinical doses of gatifloxacin, gemifloxacin, and moxifloxacin exceeded the fAUC/MIC resistance breakpoint against wild-type S. 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 from fAUC/MIC breakpoints was levofloxacin > gatifloxacin > moxifloxacin = gemifloxacin, which may be related to structural differences within the class.

Published ahead of print on 12 February 2007.

Present address: University of Rhode Island, Department of Pharmacy Practice, Fogarty Hall, 41 Lower College Road, Kingston, RI 02881.

Present address: University at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY 14260.