Vol.53 No.S-1 July 2005

In vitro antibacterial activity of doripenem, a novel parenteral carbapenem

Takaji Fujimura, Yoshiji Kimura, Isamu Yoshida, Isao Higashiyama, Yutaka Jinushi, Tadashi Munekage, Naomi Kuroda, Masayoshi Doi, Toru Nishikawa and Yoshinori Yamano

Discovery Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka, Japan

Abstract

We studied the in vitro antibacterial activity of doripenem (DRPM), a novel parenteral carbapenem. DRPM showed a broad antibacterial spectrum against aerobic gram-positive and negative bacteria and anaerobic bacteria. In a susceptibility test for clinical strains isolated in 2002, MIC₉₀s of DRPM were ≤ 0.016-1 μg/mL for Streptococcus spp. and methicillin-susceptible strains of Staphylococcus spp., and 0.031-1 μg/mL for Enterobacteriaceae, Moraxella catarrhalis, and Haemophilus influenzae, suggesting that DRPM has potent antibacterial activity. Of the 5 carbapenems tested, DRPM was most potent against aerobic gram-positive bacteria, following imipenem (IPM) and panipenem, and is most potent against aerobic gram-negative bacteria, following meropenem (MEPM). MIC₅₀ and MIC₉₀ of DRPM against Pseudomonas aeruginosa were 0.5 and 8 μg/mL, indicating that DRPM has the most potent antipseudomonal activity among antibiotics tested. The antibacterial activity of DRPM was not affected by factors such as medium pH or inoculum size. Results from MBC determination and a time-kill study suggested that DRPM has strong bactericidal activity corresponding to its antibacterial activity. Although DRPM was hydrolyzed by metallo-β-lactamases as well as other carbapenems, it was stable to hydrolysis by class A, C, and D β-lactamases, including extended-spectrum β-lactamase. A study on the affinity of DRPM to penicillin-binding proteins as its mode of action suggested that DRPM probably exhibits antibacterial activity by inhibiting the activity of PBP1 for S. aureus, PBP2 and PBP3 for P. aeruginosa, and PBP2 for E. coli as well as MEPM. When subcultured repeatedly in media containing DRPM, MEPM, or IPM, bacterial strains of S. aureus, P. aeruginosa, and E. coli showed decreased susceptibility to all of these antibiotics, and cross-resistance among tested carbapenems was observed.

Key word

doripenem, antibacterial activity, penicillin-binding protein

Received

February 1, 2005

Accepted

March 16, 2005

Jpn. J. Chemother. 53 (S-1): 57-70, 2005