ABSTRACT
The recent emergence of methicillin-resistant Staphylococcus aureus (MRSA) with decreased susceptibility to vancomycin has intensified the search for alternative therapies for the treatment of infections caused by this organism. One approach has been to identify a beta-lactam with improved affinity for PBP 2a, the target enzyme responsible for methicillin resistance in staphylococci. BMS-247243 is such a candidate, with MICs that inhibit 90% of isolates tested (MIC(90)s) of 4, 2, and 8 microg/ml for methicillin-resistant strains of S. aureus, S. epidermidis, and S. haemolyticus, respectively, as determined on plates with Mueller-Hinton agar and 2% NaCl. The BMS-247243 MICs for MRSA were minimally affected by the susceptibility testing conditions (inoculum size, prolonged incubation, addition of salt to the test medium) or by staphylococcal beta-lactamases. BMS-247243 MIC(90)s for methicillin-susceptible staphylococcal species ranged from < or = 0.25 to 1 microg/ml. The BMS-247243 MIC(90) for beta-lactamase-producing S. aureus strains was fourfold higher than that for beta-lactamase-nonproducing strains. BMS-247243 is hydrolyzed by staphylococcal beta-lactamases at 4.5 to 26.2% of the rates measured for cephaloridine. The affinity of BMS-247243 for PBP 2a was >100-fold better than that of methicillin or cefotaxime. BMS-247243 is bactericidal for MRSA, killing the bacteria twice as fast as vancomycin. These in vitro activities of BMS-247243 correlated with its in vivo efficacy against infections in animals, including the neutropenic murine thigh and rabbit endocarditis models involving MRSA strains. In conclusion, BMS-247243 has in vitro and in vivo activities against methicillin-resistant staphylococci and thus may prove to be useful in the treatment of infections caused by these multidrug-resistant organisms.
Subject(s)
Bacterial Proteins , Carrier Proteins , Methicillin Resistance/physiology , Morpholines/pharmacology , Morpholines/therapeutic use , Muramoylpentapeptide Carboxypeptidase , Pyridines/pharmacology , Pyridines/therapeutic use , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/therapeutic use , Cyclophosphamide/pharmacology , Endocarditis, Bacterial/drug therapy , Endocarditis, Bacterial/microbiology , Hexosyltransferases/genetics , Hexosyltransferases/metabolism , Hydrolysis , Immunosuppression Therapy , Immunosuppressive Agents/pharmacology , Kinetics , Methicillin Resistance/genetics , Mice , Microbial Sensitivity Tests , Morpholines/metabolism , Multienzyme Complexes/genetics , Multienzyme Complexes/metabolism , Muscle, Skeletal/microbiology , Penicillin-Binding Proteins , Peptidyl Transferases/genetics , Peptidyl Transferases/metabolism , Protein Binding , Pyridines/metabolism , Rabbits , Staphylococcal Infections/microbiology , Vancomycin/therapeutic useABSTRACT
BMS-247243, a novel cephalosporin inhibitory for methicillin-resistant staphylococci, primarily has activity against gram-positive bacteria. The activities of BMS-247243, cefotaxime, and ceftriaxone against streptococci and Streptococcus pneumoniae were similar. BMS-247243 inhibits Enterococcus faecalis but not Enterococcus faecium. BMS-247243 also inhibits many inherently vancomycin-resistant species (Leuconstoc, Lactobacillus, Pediococcus) and anaerobic gram-positive bacteria.
