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Antimicrobial Agents and Chemotherapy, January 2002, p. 191-195, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.191-195.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Bactericidal Activities of BMS-284756, a Novel Des-F(6)-Quinolone, against Staphylococcus aureus Strains with Topoisomerase Mutations

Laura E. Lawrence,1* MaryBeth Frosco,1 Brenda Ryan,1 Susan Chaniewski,1 Hyekyung Yang,1 David C. Hooper,2 and John F. Barrett1

BMSPRI, Bristol-Myers Squibb, Wallingford, Connecticut,1 Massachusetts General Hospital, Boston, Massachusetts2

Received 16 February 2001/ Returned for modification 13 August 2001/ Accepted 17 October 2001

The antistaphylococcal activities of BMS-284756 (T-3811ME), levofloxacin, moxifloxacin, and ciprofloxacin were compared against wild-type and grlA and grlA/gyrA mutant strains of Staphylococcus aureus. BMS-284756 was the most active quinolone tested, with MICs and minimal bactericidal concentrations against S. aureus wild-type strain MT5, grlA mutant MT5224c4, and grlA/gyrA mutant EN8 of 0.03 and 0.06, 0.125 and 0.125, and 4 and 4 µg/ml, respectively. In the time-kill studies, BMS-284756 and levofloxacin exhibited rapid killing against all strains. Ciprofloxacin, however, was not bactericidal for the double mutant, EN8. BMS-284756 and levofloxacin were bactericidal (3 log10 decrease in CFU/ml) against the MT5 and MT5224c4 strains at two and four times the MIC within 2 to 4 h. Against EN8, BMS-284756 was bactericidal within 4 h at two and four times the MIC, and levofloxacin achieved similar results within 4 to 6 h. Both the wild-type strain MT5 and grlA mutant MT5224c4 should be considered susceptible to both BMS-284756 and levofloxacin, and both quinolones are predicted to have clinical efficacy. The in vivo efficacy of BMS-284756, levofloxacin, and moxifloxacin against S. aureus strain ISP794 and its single mutant 2C6(1)-1 directly reflected the in vitro activity: increased MICs correlated with decreased in vivo efficacy. The 50% protective doses of BMS-284756 against wild-type and mutant strains were 2.2 and 1.6 mg/kg of body weight/day, respectively, compared to the levofloxacin values of 16 and 71 mg/kg/day and moxifloxacin values of 4.7 and 61.6 mg/kg/day. BMS-284756 was more potent than levofloxacin and equipotent with moxifloxacin against ISP794 both in vitro and in vivo, while BMS-284756 was more potent than levofloxacin and moxifloxacin against 2C6(1)-1.

* Corresponding author. Mailing address: Bristol-Myers Squibb Pharmaceutical Research Institute, Infectious Diseases, Department of Microbiology, 5 Research Pkwy., Wallingford, CT 06492. Phone: (203) 677-6547. Fax: (203) 677-6771. E-mail: lawrencl{at}bms.com.

Antimicrobial Agents and Chemotherapy, January 2002, p. 191-195, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.191-195.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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