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Antimicrobial Agents and Chemotherapy, December 2004, p. 4754-4761, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4754-4761.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Antistaphylococcal Activity of WCK 771, a Tricyclic Fluoroquinolone, in Animal Infection Models

Mahesh V. Patel,1* Noel J. De Souza,1 Shrikant V. Gupte,1 Mohammad A. Jafri,1 Sachin S. Bhagwat,1 Yati Chugh,1 Habil F. Khorakiwala,1 Michael R. Jacobs,2 and Peter C. Appelbaum3

Wockhardt Research Center, Aurangabad, India,1 Department of Pathology, Case Western Reserve University, Cleveland, Ohio,2 Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania3

Received 18 March 2004/ Returned for modification 25 April 2004/ Accepted 14 August 2004

WCK 771, the arginine salt of S-(–)-nadifloxacin, was evaluated in animal models of staphylococcal infection and in vitro. For 302 methicillin-susceptible strains the MIC at which 50% of isolates are inhibited (MIC50) and the MIC90 of WCK 771 were 0.03 and 0.03 µg/ml, respectively, and for 198 methicillin-resistant strains the MIC50 and the MIC90 were 0.5 and 1.0 µg/ml, respectively. All methicillin-susceptible staphylococci were quinolone susceptible, and almost all methicillin-resistant staphylococci were quinolone resistant. WCK 771 was more potent than moxifloxacin, trovafloxacin, levofloxacin, and ciprofloxacin and had potency comparable to that of clinafloxacin. Only WCK 771 and clinafloxacin demonstrated strong potencies against vancomycin-intermediate Staphylococcus aureus strains (MICs = 1 µg/ml). WCK 771 is not a substrate of the NorA pump, as evident from the lack of an effect of reserpine on the MICs and similar protective doses against infections caused by efflux-positive and -negative staphylococci. WCK 771 was effective by both the oral and the subcutaneous routes in mice infected intraperitoneally with quinolone-susceptible methicillin-susceptible S. aureus (MSSA) strains. For infections caused by quinolone-resistant methicillin-resistant S. aureus (MRSA) strains, the activity of WCK 771 administered subcutaneously was superior to those of trovafloxacin and sparfloxacin, with a 50% effective dose range of 27.8 to 46.8 mg/kg of body weight. The activity of WCK 771 was superior to those of moxifloxacin, vancomycin, and linezolid in a mouse cellulitis model of infection caused by one MSSA and two MRSA strains, with effective doses of 2.5 and 5 mg/kg for the MSSA strain and 10-fold higher effective doses for MRSA strains. WCK 771, like vancomycin and linezolid, eradicated MRSA from mouse liver, spleen, kidney, and lung when it was administered subcutaneously at a dose of 50 mg/kg for four doses. These studies have demonstrated the effectiveness of WCK 771, administered orally and parenterally, for the treatment of diverse staphylococcal infections in mice, including those caused by quinolone-resistant strains.

* Corresponding author. Mailing address: Wockhardt Research Centre, D-4 MIDC Chikalthana, Aurangabad 431210 (MS), India. Phone: 00 91 240 2483854. Fax: 00 91 240 2489219. E-mail: mpatel{at}wockhardtin.com.

Antimicrobial Agents and Chemotherapy, December 2004, p. 4754-4761, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4754-4761.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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