Vol.53 No.S-1 July 2005
Bactericidal activity of doripenem using in vitro pharmacodynamic models
Discovery Research Laboratories, Shionogi & Co., Ltd.,
3-1-1 Futaba-cho, Toyonaka, Osaka, Japan
Abstract
We evaluated the bactericidal activity of doripenem, a novel carbapenem antibiotic, against clinical isolates by exposing strains for 24 h to doripenem concentrations likely to be produced in human plasma by intravenous injection in different dosage regimens. We observed the relationship between bactericidal activity and the percentage of time for which concentration was higher than the MIC for each isolate (T>MIC). Maximum bactericidal activity was observed when T>MIC exceeded 40%, and the number of viable cells at 24 h incubation remained no more than the initial inoculum when T>MIC exceeded 25%.
Doripenem showed strong bactericidal activity against clinical isolates of Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa with a MIC of ≤0.5 μg/mL, under conditions simulating plasma concentrations when 250 mg of doripenem was administered twice a day. Under these conditions, T>MIC exceeded 35% of the total exposure period. Bactericidal activity did not improve significantly when T>MIC duration was prolonged by simulating plasma concentration under the administration of 500 mg twice a day or 250 mg three times a day. Against P. aeruginosa strains with MIC of ≥2 μg/mL, T>MIC was less than 25% under the conditions simulating serum concentration when 250 mg of doripenem was administered twice a day. In these cases, bactericidal activity increased when T>MIC duration was prolonged by simulating serum concentration under the administration of 500 mg twice a day or 250 mg three times a day. The increase in the number of administrations per day caused more potent bactericidal activity than an increasein doses per administration because it prolonged T>MIC duration.
These results show a good relationship between the bactericidal activity of doripenem and the T>MIC duration, useful in determining the optimal dosing regimen.
Key word
doripenem, bactericidal activity, time above MIC
Received
January 24, 2005
Accepted
March 18, 2005
Jpn. J. Chemother. 53 (S-1): 96-103, 2005
