In Vivo Antibacterial Activity of RWJ-54428, a New Cephalosporin with Activity against Gram-Positive Bacteria

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Abstract
RWJ-54428 (MC-02,479) is a new cephalosporin with activity against resistant gram-positive organisms, including methicillin-resistant Staphylococcus aureus , vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae . The in vivo efficacy of RWJ-54428 was evaluated against gram-positive bacteria in four mouse models of infection. RWJ-54428 was effective in vivo against methicillin-susceptible and -resistant S. aureus in a mouse model of sepsis, with 50% effective doses being similar to those of vancomycin. In a single-dose neutropenic mouse thigh model of infection, RWJ-54428 at 30 mg/kg of body weight showed activity similar to that of vancomycin at 30 mg/kg against a strain of methicillin-resistant S. aureus . RWJ-54428 also showed a prolonged in vivo postantibiotic effect in this model. In a mouse model of pneumonia due to a penicillin-susceptible strain of Streptococcus pneumoniae , RWJ-54428 displayed efficacy and potency superior to those of penicillin G and cefotaxime. In a mouse model of pyelonephritis due to Enterococcus faecalis , RWJ-54428 had bactericidal effects similar to those of vancomycin and ampicillin, but at two- to threefold lower total daily doses. These studies show that RWJ-54428 is active in experimental mouse models of infection against gram-positive organisms, including strains resistant to earlier cephalosporins and penicillin G.