Vol.53 No.S-1 July 2005
Therapeutic efficacy of doripenem, a novel parenteral carbapenem antibiotic, against experimental infection in mice and rats
Discovery Research Laboratories, Shionogi & Co., Ltd.,
3-1-1 Futaba-cho, Toyonaka, Osaka, Japan
Abstract
The in vivo antibacterial efficacy of doripenem (DRPM), a new parenteral carbapenem antibiotic, was compared to that of meropenem/cilastatin (MEPM/CS), imipenem/cilastatin (IPM/CS), ceftazidime (CAZ), and ampicillin (ABPC) against experimental infection in mice and rats.
Compared to a single administration of DRPM in mice, plasma concentration of DRPM with administration combined with CS (DRPM: CS=1:1) did not improve, but plasma concentration of DRPM in rats was improved by combination with CS. No difference was seen in pharmacokinetic properties of plasma among DRPM, MEPM/CS, and IPM/CS in mice and among DRPM/CS, MEPM/CS, and IPM/CS in rats.
Against murine systemic infection caused by gram-positive bacteria including penicillin-resistant Streptococcus pneumoniae (PRSP), DRPM exhibited good efficacy with ED50 of 0.02-6.26 mg/kg, superior to MEPM/CS, CAZ, and ABPC but inferior to IPM/CS. DRPM also showed potent efficacy (ED50s: 0.04-2.49 mg/kg) against gram-negative bacterial infection including CAZ-resistant Enterobacter cloacae and was more active than IPM/CS, but less active than MEPM/CS. In a mouse lung infection model caused by PRSP, DRPM caused significant reduction of viable cells in the lung at 3 mg/kg or more, though ABPC was not effective at 10 mg/kg. The therapeutic efficacy of DRPM was more active significantly than that of ABPC and CAZ and similar to that of MEPM/CS, but inferior to that of IPM/CS. In rat meningitis caused by PRSP, DRPM/CS caused significant reduction of viable cells in cerebrospinal fluid at 10 mg/kg or more than. DRPM was more active than ABPC, CAZ, and MEPM/CS, but less active than IPM/CS. In a rat endocarditis model caused by Staphylococcus aureus, DRPM showed excellent efficacy with significant reduction of viable cells in the heart at 4 mg/kg or more. Its efficacy was more potent than that of CAZ and MEPM/CS and was comparable to that of IPM/CS.
The in vivo antibacterial efficacy of DRPM against experimental systemic and local infection in mice and rats well reflected its in vitro activity and plasma concentrations in these animals.
Key word
doripenem, pharmacokinetic, animal model, efficacy
Received
January 17, 2005
Accepted
March 29, 2005
Jpn. J. Chemother. 53 (S-1): 71-79, 2005
