Vol.53 No.S-1 July 2005
Antipseudomonal activity of doripenem, a novel parenteral carbapenem antibiotic
Discovery Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, Japan
Abstract
Doripenem (DRPM), a novel parenteral carbapenem antibiotic synthesized by Shionogi & Co., Ltd., has potent antibacterial activity and a well-balanced spectrum against aerobic Gram-positive and negative bacteria, and anaerobic bacteria. We evaluated its antipseudomonal activity.
DRPM exhibited potent activity with MIC90 of 8 μg/mL against clinical 71 strains of Pseudomonas aeruginosa isolated in 2002, 2-4 times more active than other carbapenems, meropenem (MEPM), imipenem (IPM), biapenem, and panipenem, and 2-8 times more potent than antipseudomonal antibiotics such as ceftazidime (CAZ), amikacin, and sulbactam/cefoperazone. DRPM was most active against CAZ-resistant and IPM-resistant P. aeruginosa compared to other carbapenems and CAZ.
DRPM as well as MEPM reduced antipseudomonal activity against mutant strains deficient in pore-forming protein OprD or overproduced efflux pump system, MexAB-OprM. Activity of DRPM against these strains was only 2-fold less active than their parent strains, whereas that of MEPM was 4-fold less active.
Against 20 clinical isolates of P. aeruginosa, the mean MBC of DRPM was 0.84 μg/mL, which was lower than that of MEPM, IPM, and CAZ. MBC of DRPM against each strain was equal to or only twice larger than its MIC as well as other carbapenems, suggesting DRPM has strong bactericidal activity. In a time-kill study, DRPM exhibited time-dependent bactericidal activity, almost equal to that of MEPM and IPM.
DRPM showed post-antibiotic effect (PAE) against CAZ-susceptible P. aeruginosa in both in vitro and mouse lung infection models, while CAZ had no PAE. PAE of DRPM was similar to that of MEPM and IPM.
DRPM showed excellent therapeutic efficacy with ED50 of 0.17-4.87 mg/kg against systemic infection in both immunocompetent and neutropenic mice infected with P. aeruginosa including CAZ-resistant strains. DRPM was much more active than CAZ, more active than IPM/cilastatin (CS), and similar to MEPM/CS. DRPM also exhibited excellent efficacy against both mouse lung and urinary tract infection due to CAZ-resistant P. aeruginosa, equal to or more potent than IPM/CS and similar to MEPM/CS.
These results suggest that DRPM is clinically effective against P. aeruginosa infection.
Key word
doripenem, Pseudomonas aeruginosa, antibacterial activity, efficacy
Received
January 17, 2005
Accepted
March 29, 2005
Jpn. J. Chemother. 53 (S-1): 80-91, 2005
