Vol.57 No.S-1 March 2009

Antimicrobial activity of tebipenem pivoxil against Streptococcus Pneumoniae and Haemophilus Influenzae, and its pharmacokinetic-pharmacodynamic profile in mice

Toshie Sugano, Takuji Yoshida, Keiko Yamada, Atsuyuki Shimizu, Jun Morita, Koji Kijima, Kazunori Maebashi and Shigeki Shibasaki

Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka, Kohoku-ku, Yokohama, Kanagawa, Japan

Abstract

Tebipenem(TBPM, formerly L-036 or LJC11,036), an active form of the oral carbapenem tebipenem pivoxil(TBPM-PI, formerly ME1211 or L-084), shows potent activity against respiratory pathogens such as Streptococcus pneumoniae and Haemophilus influenzae. We evaluated the in vitro antibacterial property of TBPM and in vivo activity of TBPM-PI against these organisms. TBPM showed strong bactericidal activity against both pathogens, longer post-antibiotic effect against S. pneumoniae and longer post-antibiotic sub-MIC effect against H. influenzae compared to cephem antibiotics. In murine respiratory infection models with penicillin-resistant S. pneumoniae(PRSP) and β-lactamase-nonproducing ampicillin-resistant H. influenzae, TBPM-PI showed higher therapeutic efficacy than cefditoren pivoxil or faropenem. Using the pharmacokinetics(PK) parameter of TBPM after subcutaneous administration and the pharmacodynamics(PD) data of TBPM in a murine thigh infection model with PRSP, we defined PK-PD parameters correlating with TBPM efficacy. Analysis using the sigmoidal E_max model showed that three PK-PD parameters (AUCf/MIC, C_maxf/MIC and time above MIC) all correlated well with TBPM efficacy, AUCf/MIC (R²: 88%) and C_maxf/MIC (R²: 87%) showed a higher correlation compared to time above MIC (R²: 77%).

Key word

tebipenem pivoxil, antimicrobial activity, animal model, PK-PD

Received

October 7, 2008

Accepted

February 17, 2009

Jpn. J. Chemother. 57 (S-1): 38-48, 2009