Therapeutic efficacy of BO-3482, a novel dithiocarbamate carbapenem, in mice infected with methicillin-resistant Staphylococcus aureus
| Autor: | Tomoyo Naito, Kaneyoshi Shibata, Terutaka Hashizume, Kayo Asano, Aisaku Fuse, Nakagawa Susumu, Rie Nagano |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Dipeptidases
Staphylococcus aureus Carbapenem Imipenem medicine.drug_class Antibiotics Microbial Sensitivity Tests Biology Kidney medicine.disease_cause Staphylococcal infections Microbiology Mice Vancomycin Sepsis polycyclic compounds medicine Animals Pharmacology (medical) Muscle Skeletal Pharmacology Mice Inbred ICR Cilastatin Staphylococcal Infections biochemical phenomena metabolism and nutrition bacterial infections and mycoses medicine.disease Methicillin-resistant Staphylococcus aureus Anti-Bacterial Agents Infectious Diseases Carbapenems Area Under Curve Methicillin Resistance Research Article medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 41:2278-2281 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.41.10.2278 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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