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: R Nagano, K Shibata, T Naito, A Fuse, K Asano, T Hashizume, S Nakagawa
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 41 Issue 10 Pg. 2278-81 (Oct 1997) ISSN: 0066-4804 [Print] United States
• PMID: 9333062 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• BO 3482
• Carbapenems
• Vancomycin
• Imipenem
• Dipeptidases
• dipeptidase

Topics

• Animals
• Anti-Bacterial Agents (therapeutic use)
• Area Under Curve
• Carbapenems (pharmacokinetics, pharmacology, therapeutic use)
• Dipeptidases (metabolism)
• Imipenem (therapeutic use)
• Kidney (enzymology)
• Methicillin Resistance (physiology)
• Mice
• Mice, Inbred ICR
• Microbial Sensitivity Tests
• Muscle, Skeletal (microbiology)
• Sepsis (drug therapy, microbiology)
• Staphylococcal Infections (drug therapy, microbiology)
• Staphylococcus aureus (drug effects)
• Vancomycin (therapeutic use)