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Antimicrobial Agents and Chemotherapy, June 2006, p. 1931-1936, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.01586-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Activity of Gatifloxacin in an In Vitro Pharmacokinetic-Pharmacodynamic Model against Staphylococcus aureus Strains either Susceptible to Ciprofloxacin or Exhibiting Various Levels and Mechanisms of Ciprofloxacin Resistance

Laboratoire de Pharmacocinétique et de Pharmacie Clinique,¹ Laboratoire de Microbiologie, EA525,² Laboratoire de Pharmacochimie, EA2962, Faculté de Pharmacie, Université Victor Segalen Bordeaux 2, France³

Received 14 December 2005/ Returned for modification 12 February 2006/ Accepted 21 March 2006

Gatifloxacin (GAT) is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. Its activity was studied in an in vitro pharmacokinetic-pharmacodynamic model against five Staphylococcus aureus strains, either susceptible to ciprofloxacin or exhibiting various levels and mechanisms of ciprofloxacin (CIP) resistance: the ATCC 25923 reference strain (MICs of CIP and GAT: 0.5 and 0.1 µg/ml, respectively), its efflux mutant SA-1 (16 and 0.5 µg/ml; mutation in the norA promoter region), and three clinical strains, Sa2102 (2 and 0.2 µg/ml), Sa2667 (4 and 0.5 µg/ml), and Sa2669 (16 and 1 µg/ml), carrying mutations in the grlA (Ser80Tyr or Phe) and gyrA (Ser84Ala) quinolone resistance-determining regions (QRDRs) for Sa2669. Plasmatic pharmacokinetic profiles after daily 1-h perfusion of 400 mg for 48 h were accurately simulated. Thus, mean maximum concentration of drug in serum values for the two administration intervals were 5.36 and 5.80 µg/ml, respectively, and the corresponding half-life at ß-phase values were 8.68 and 7.80 h (goodness of fit coefficient, >0.98). Therapeutic concentrations of GAT allowed the complete eradication of the susceptible strain within 12 h (difference between the bacterial counts at the beginning of the treatment and at a defined time: –2.18 at the 1-h time point [t₁] and –6.80 at t₂₄ and t₄₈; the bacterial killing and regrowth curve from 0 to 48 h was 30.2 h x log CFU/milliliter). However, mutants (M) with GAT MICs increased by 4- to 40-fold were selected from the other strains. They acquired mutations either supplementary (MSa2102 and MSa2667) or different (Ala84Val for MSa2669) in gyrA or in both gyrA and grlA QRDRs (MSA-1). MSa2667 additionally overproduced efflux system(s) without norA promoter modification. Thus, GAT properties should allow the total elimination of ciprofloxacin-susceptible S. aureus, but resistant mutants might emerge from strains showing reduced susceptibility to older fluoroquinolones independently of the first-step mutation(s).

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