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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{triangledown}

Kerry L. LaPlante,1,2,4,{dagger} Michael J. Rybak,1,2,3,4* Brian Tsuji,1,2,4,{ddagger} Thomas P. Lodise,6 and Glenn W. Kaatz1,3,5

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 (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 (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.

* Corresponding author. Mailing address: Anti-Infective Research Laboratory, Pharmacy Practice-4148, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201. Phone: (313) 577-4376. Fax: (313) 577-8915. E-mail: m.rybak{at}wayne.edu

{triangledown} Published ahead of print on 12 February 2007.

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

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

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.



This article has been cited by other articles:

  • Singh, R., Ledesma, K. R., Chang, K.-T., Hou, J.-G., Prince, R. A., Tam, V. H. (2009). Pharmacodynamics of moxifloxacin against a high inoculum of Escherichia coli in an in vitro infection model. J Antimicrob Chemother 64: 556-562 [Abstract] [Full Text]  
  • Wargo, K. A., Wright, B. M., Gupta, R. (2008). The Utility of Fluoroquinolones in the Critically Ill. Journal of Pharmacy Practice 21: 346-355 [Abstract]  


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