title: In vivo antibacterial activity of RWJ-54428, a new cephalosporin with activity against gram-positive bacteria.
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.
authors.affiliation: Essential Therapeutics Inc., Mountain View, California 94043, USA. dgriffith@etrx.com
authors.forename: David C
authors.initials: DC
authors.lastname: Griffith
authors.forename: Laurie
authors.initials: L
authors.lastname: Harford
authors.forename: Robert
authors.initials: R
authors.lastname: Williams
authors.forename: Ving J
authors.initials: VJ
authors.lastname: Lee
authors.forename: Michael N
authors.initials: MN
authors.lastname: Dudley
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002511:Cephalosporins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006207:Half-Life; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D013203:Staphylococcal Infections / Q000097:blood / Q000188:drug therapy*; D014640:Vancomycin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D002511:Cephalosporins; C420727:RWJ 54428; D014640:Vancomycin