Antistaphylococcal activity of WCK 771, a tricyclic fluoroquinolone, in animal infection models

Abstract

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 microg/ml, respectively, and for 198 methicillin-resistant strains the MIC50 and the MIC90 were 0.5 and 1.0 microg/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 microg/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.

FIG. 1.

Structure of WCK 771.

FIG. 2.

Efficacy of WCK 771 in mouse cellulitis model. The results are shown as histograms of the reductions in viable counts per lesion at the end of therapy compared to the viable counts at the onset of treatment in the controls. Bars indicate standard deviations. MXF, moxifloxacin; VAN, vancomycin; LZD, linezolid. Values above the drug names indicate the dose (in milligrams per kilogram). Results are shown as the organism load reduction at the end of the study period compared with the load in the untreated controls at the start of treatment; results that are significantly different (P < 0.05) from those for the controls are indicated with an asterisk. (A) S. aureus Smith (ATCC 13709; MSSA) infection; treatment schedule, 1, 4, 24, and 27 h postinfection; (B) MRSA 5027 infection; treatment schedule, 1, 3, and 5 h postinfection; (C) MRSA 32 infection; treatment schedule, 1, 3, and 5 h postinfection.

FIG. 3.

Efficacy of eradication of MRSA 32 from multiple organs. The histograms show the reductions of the organism loads per organ 48 h after the end of therapy compared with the organism loads in the untreated controls at the start of treatment. Bars indicate standard deviations. Results that are significantly different (P < 0.05) from those for the controls are indicated with an asterisk. Bars on the left for each organ, vancomycin at 20 mg/kg twice a day for 2 days; bars on the right for each organ, WCK 771 at 50 mg/kg twice a day for 2 days.