JAC Advance Access originally published online on September 7, 2007
Journal of Antimicrobial Chemotherapy 2007 60(5):1030-1037; doi:10.1093/jac/dkm344
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Effect of GrlA mutation on the development of quinolone resistance in Staphylococcus aureus in an in vitro pharmacokinetic model
1 Research Laboratories, Toyama Chemical Co., Ltd, Toyama, Japan 2 Department of Microbiology, Toho University School of Medicine, Tokyo, Japan
Received 5 March 2007; returned 11 May 2007; revised 20 July 2007; accepted 13 August 2007
* Corresponding author. Tel: +81-76-431-8268; Fax: +81-76-431-8208; E-mail: yoshimi_oonishi{at}toyama-chemical.co.jp
Objectives: To investigate the effect of GrlA mutation on the development of quinolone resistance in Staphylococcus aureus in an in vitro pharmacokinetic (PK) model and to examine the relationship between the emergence of resistance and PK/pharmacodynamic parameters.
Methods: A wild-type and a GrlA mutant of S. aureus were exposed to the Japanese clinical dose of ciprofloxacin in an in vitro PK model, and the development of resistance was measured by population analysis. In addition, several doses of four quinolones (pazufloxacin, ciprofloxacin, levofloxacin and tosufloxacin) were tested against the GrlA mutant. All model simulations were single-dose design and were conducted over 24 h.
Results: Four quinolones were tested against the GrlA mutant, and a resistant population emerged after treatment with 250 mg pazufloxacin intravenous drip infusion, 600 mg ciprofloxacin intravenous drip infusion, 200 mg levofloxacin oral dosing and 150 mg tosufloxacin oral dosing. The emergence of a resistant population was not induced by treatment with 500 mg pazufloxacin intravenous drip infusion, 2400 mg ciprofloxacin intravenous drip infusion, 400 mg levofloxacin oral dosing and 600 mg tosufloxacin oral dosing. Treatment with the clinical dose of ciprofloxacin induced the development of resistance in the GrlA mutant, but not in the wild-type strain.
Conclusions: These data suggest that the frequency of acquisition of additional mutations differs between the wild-type and the GrlA mutant of S. aureus. Also, GrlA mutation predisposes S. aureus to develop high-level quinolone resistance.
Keywords: S. aureus , resistant mutants , mutations