THERAPEUTIC EFFICACY OF BO-3482, A NOVEL DITHIOCARBAMATE CARBAPENEM, IN MICE INFECTED WITH METHICILLIN-RESISTANT STAPHYLOCOCCUS-AUREUS

The in vivo activity of BO-3482, which has a dithiocarbamate chain at the C-2 position of 1 beta-methylcarbapenem, was compared with those o f vancomycin and imipenem in murine models of septicemia and thigh inf ection with methicillin-resistant Staphylococcus aureus (MRSA). Becaus e BO-3482 was more susceptible than imipenem to renal dehydropeptidase I in a kinetic study of hydrolysis by this renal enzyme, the therapeu tic efficacy of BO-3482 was determined during coadministration with ci lastatin, In the septicemia models, which involved two homogeneous MRS A strains and one heterogeneous MRSA strain, the 50% effective doses w ere, respectively, 4.80, 6.06, and 0.46 mg/kg of body weight for BO-34 82; 5.56, 2.15, and 1.79 mg/kg for vancomycin; and >200, >200, and 15. 9 mg/kg for imipenem, BO-3482 was also as effective as vancomycin in a n MRSA septicemia model with mice with cyclophosphamide-induced immuno suppression, In the thigh infection model with a homogeneous MRSA stra in, the bacterial counts in tissues treated with BO-3482-cilastatin we re significantly reduced in a dose-dependent manner compared with the counts in those treated with vancomycin and imipenem-cilastatin (P < 0 .001), These results indicate that BO-3482-cilastatin is as effective as vancomycin in murine systemic infections and is more bactericidal t han vancomycin in local-tissue infections, The potent in vivo activity of BO-3482-cilastatin against such MRSA infections can be ascribed to the good in vitro anti-MRSA activity and improved pharmacokinetics in mice when BO-3482 is combined with cilastatin and to the bactericidal nature of the carbapenem.