title: Therapeutic efficacy of BO-3482, a novel dithiocarbamate carbapenem, in mice infected with methicillin-resistant Staphylococcus aureus.
abstract: The in vivo activity of BO-3482, which has a dithiocarbamate chain at the C-2 position of 1beta-methyl-carbapenem, was compared with those of vancomycin and imipenem in murine models of septicemia and thigh infection with methicillin-resistant Staphylococcus aureus (MRSA). Because BO-3482 was more susceptible than imipenem to renal dehydropeptidase I in a kinetic study of hydrolysis by this renal enzyme, the therapeutic efficacy of BO-3482 was determined during coadministration with cilastatin. In the septicemia models, which involved two homogeneous MRSA strains and one heterogeneous MRSA strain, the 50% effective doses were, respectively, 4.80, 6.06, and 0.46 mg/kg of body weight for BO-3482; 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 an MRSA septicemia model with mice with cyclophosphamide-induced immunosuppression. In the thigh infection model with a homogeneous MRSA strain, the bacterial counts in tissues treated with BO-3482-cilastatin were 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 than 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.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Japan.
authors.forename: R
authors.initials: R
authors.lastname: Nagano
authors.forename: K
authors.initials: K
authors.lastname: Shibata
authors.forename: T
authors.initials: T
authors.lastname: Naito
authors.forename: A
authors.initials: A
authors.lastname: Fuse
authors.forename: K
authors.initials: K
authors.lastname: Asano
authors.forename: T
authors.initials: T
authors.lastname: Hashizume
authors.forename: S
authors.initials: S
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D019540:Area Under Curve; D015780:Carbapenems / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004150:Dipeptidases / Q000378:metabolism; D015378:Imipenem / Q000627:therapeutic use; D007668:Kidney / Q000201:enzymology; D016106:Methicillin Resistance / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D018482:Muscle, Skeletal / Q000382:microbiology; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D014640:Vancomycin / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; C108864:BO 3482; D015780:Carbapenems; D014640:Vancomycin; D015378:Imipenem; D004150:Dipeptidases; C038937:dipeptidase