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.

Current Status of Newer Carbapenems

“…New compounds with good PBP2A affinities and low MICs for MRSA have been studied in animal models , demonstrating anti-MRSA activity in murine model of sepsis peritonitis and soft tissue abscesses [28][29][30][31][32].…”

Comparison of In Vivo Pharmacokinetics and Pharmacodynamics of Vancomycin Products Available in Korea

“…Blood was collected from individual mice by cardiac puncture. 17,[20][21][22][23][24] Each animal constituted a single data point. All experiments were repeated 10 times for subgroups of each product.…”

Synthesis of S‐ and N‐Functionalized Dithiocarbamates from Cyclic Sulfates

“…Particularly, S ‐alkyl‐functionalized DTCs have been extensively studied, because they exhibit a broad spectrum of biological effects that have led to their utilization in a number of medicinal fields. They display antibacterial,16 antitumor,17 antihistaminic,18 and anticancer activities,2a,19 besides analgesic and sedative properties,20 and antiproliferative effects 21. Because of these properties, the synthesis of S ‐functionalized DTCs with different substitution patterns at the sulfur chain has received considerable attention.…”