IN NITRO AND IN-VIVO ANTISTAPHYLOCOCCAL ACTIVITIES OF L-695,256, A CARBAPENEM WITH HIGH-AFFINITY FOR THE PENICILLIN-BINDING PROTEIN PBP 2A

L-695,256 is a synthetic carbapenem beta-lactam antibiotic that binds with a high degree of affinity to penicillin-binding protein (PBP) PBP 2a, the protein that mediates staphylococcal resistance to methicilli n, The concentration of L-695,256 that inhibited binding of radiolabel ed [H-3] penicillin to PBP 2a by 50% was 1.2 mu g/ml, whereas they wer e 14 and 68 mu g/ml for penicillin and imipenem, respectively, Cell wa ll synthesis, determined by incorporation of [C-14]N-acetylglucosamine into whole cells, was inhibited by 50% at concentrations of 1.3, 26, and 132 mu g/ml for L-695,256, penicillin, and imipenem, respectively, for the methicillin-resistant strain COL. Growth of cells of each of two homogeneously resistant strains, COL and 76, was completely inhibi ted by 4 mu g of L-695,256 per ml, whereas growth was inhibited by 100 mu g or more of penicillin or imipenem per ml. The efficacies of L-69 5,256 (10 mg/kg given three times daily [t.i.d.]), imipenem (37.5 mg/k g t.i.d.), penicillin (300,000 units/kg t.i.d.), and vancomycin (25 mg /kg given twice daily) were compared in the rabbit model of aortic val ve endocarditis established with these homogeneous strains, After 4 da ys of treatment, mean bacterial densities in aortic valve vegetations were reduced by 4.0 to 5.8 log(10) CFU/g for L-695,256, 1.0 to 1.8 log (10) CFU/g for imipenem, -1.1 to 3.9 log(10) CFU/g far penicillin, and 1.1 to 3.0 log(10) CFU/g for vancomycin in comparison to the densitie s of controls. Compounds such as L-695,256 that are bound by PBP 2a wi th a high degree of affinity are likely to be extremely effective in t he treatment of infections caused by methicillin-resistant staphylococ ci.