title: In vitro activity of cephalosporin RWJ-54428 (MC-02479) against multidrug-resistant gram-positive cocci.
abstract: RWJ-54428 (MC-02479) is a novel cephalosporin that binds to penicillin-binding protein (PBP) PBP 2' (PBP 2a) of methicillin-resistant staphylococci. Its in vitro activity was assessed against 472 gram-positive cocci, largely selected as epidemiologically unrelated isolates with multidrug resistance. The MIC at which 50% of isolates are inhibited (MIC(50)) and MIC(90) of RWJ-54428 for methicillin-resistant Staphylococcus aureus (MRSA) were 1 and 2 microg/ml, respectively, whereas they were 0.5 and 0.5 microg/ml, respectively, for methicillin-susceptible S. aureus. The MIC(50) and MIC(90) were 1 and 4 microg/ml, respectively, for methicillin-resistant coagulase-negative staphylococci (MRCoNS), whereas they were 0.25 and 1 microg/ml, respectively, for methicillin-susceptible isolates. The highest MICs for MRSA and MRCoNS isolates were 2 and 4 microg/ml, respectively. The MIC(50) and MIC(90) of RWJ-54428 for Enterococcus faecalis were 0.5 and 1 microg/ml, respectively, but they were 4 and 8 microg/ml, respectively, for Enterococcus faecium. For penicillin-susceptible, -intermediate, and -resistant pneumococci, the MIC(90)s of RWJ-54428 were 0.03, 0.25, and 0.5 microg/ml, respectively, with the highest MIC for a pneumococcus being 1 microg/ml, recorded for a strain for which penicillin and cefotaxime MICs were 8 and 4 microg/ml. MICs for Lancefield group A, B, C, and G streptococci were < or =0.008 microg/ml; those for viridans group streptococci, including isolates not susceptible to penicillin, were from 0.015 to 0.5 microg/ml. RWJ-54428 did not select resistant mutants of MRSA or enterococci in challenge experiments and has the potential to be useful for the treatment of infections caused by gram-positive cocci.
authors.affiliation: Antibiotic Resistance Monitoring and Reference Laboratory, Central Public Health Laboratory, Colindale, London NW9 5HT, United Kingdom. AJohnson@phls.nhs.uk
authors.forename: Alan P
authors.initials: AP
authors.lastname: Johnson
authors.forename: Marina
authors.initials: M
authors.lastname: Warner
authors.forename: Michael
authors.initials: M
authors.lastname: Carter
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
mesh_terms: D002511:Cephalosporins / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000502:physiology; D018432:Drug Resistance, Multiple / Q000502:physiology*; D013293:Enterococcus faecalis / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects*; D013291:Streptococcus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D002511:Cephalosporins; C420727:RWJ 54428