RWJ-333441 (MC-04,546), a New Cephalosporin with High Affinity for PBP 2a and Stability to Staphylococcal b-Lactamases
J. BLAIS, M. HOANG, C. PARK, C. DINH, K. DUPREE, F. MALOUIN, S. CHAMBERLAND
Microcide Pharmaceuticals, Inc., Mountain View, CA
Presentation Number: 1072
RWJ-333441 is a new cephalosporin active against gram positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The potency of RWJ-333441 against MRSA is related to its enhanced affinity for PBP 2a, as assessed in a competition assay using biotinylated ampicillin as the reporter molecule. RWJ-333441 had high activity against MRSA COL (MIC of 1 µg/ml) and affinity for PBP 2a (IC50= 0.8 mg/ml). These values were considerably lower than those obtained for imipenem (MRSA COL MIC of 32 mg/ml, PBP 2a IC50= 30 mg/ml). RWJ-333441 was stable to hydrolysis by purified type A b-lactamase isolated from S. aureus PC1 (relative rate of hydrolysis= 7% of cephaloridine) and was active (MIC £ 1mg/ml) against strains of S. aureus bearing the four classes of staphylococcal b-lactamases (including b-lactamase hyperproducers). The effect of inoculum size on the in vitro activity of RWJ-333441 was studied using b-lactamase-positive and -negative strains of MRSA and MSSA, including strains with characterized enzymes. While large inoculum effects were observed for penicillin G (up to 256-fold increase in MIC), no change in RWJ-333441 susceptibility was observed with a 100-fold increased inoculum compared to NCCLS standard. The frequency of isolation of resistant mutants to RWJ-333441 from MRSA COL was very low. Resistant cells were isolated at a frequency of <10-10 on plates containing RWJ-333441 at 2xMIC. In summary, RWJ-333441 has high affinity for MRSA PBP 2a, and is stable to staphylococcal b-lactamases.
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