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Antimicrobial Agents and Chemotherapy, August 2005, p. 3239-3250, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3239-3250.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Antibacterial Activities of CS-023 (RO4908463), a Novel Parenteral Carbapenem

Tetsufumi Koga,1* Tomomi Abe,1 Harumi Inoue,1 Takashi Takenouchi,1 Akiko Kitayama,1 Tatsuhiko Yoshida,1 Nobuhisa Masuda,1 Chika Sugihara,1 Masayo Kakuta,1 Miyuki Nakagawa,1 Takahiro Shibayama,2 Yoko Matsushita,2 Takashi Hirota,2 Satoshi Ohya,1 Yukio Utsui,1 Takashi Fukuoka,1 and Syogo Kuwahara3

Biological Research Laboratories, Sankyo Co., Ltd., Shinagawa-ku, Tokyo 140-8710, Japan,1 Drug Metabolism & Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan,2 Toho University School of Medicine, Ohta-ku, Tokyo 143-8540, Japan3

Received 1 February 2005/ Returned for modification 28 March 2005/ Accepted 15 May 2005

CS-023 (RO4908463, formerly R-115685) is a novel 1ß-methylcarbapenem with 5-substituted pyrrolidin-3-ylthio groups, including an amidine moiety at the C-2 position. Its antibacterial activity was tested against 1,214 clinical isolates of 32 species and was compared with those of imipenem, meropenem, ceftazidime, ceftriaxone, ampicillin, amikacin, and levofloxacin. CS-023 exhibited a broad spectrum of activity against gram-positive and -negative aerobes and anaerobes, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae (PRSP), ß-lactamase-negative ampicillin-resistant Haemophilus influenzae, and Pseudomonas aeruginosa. CS-023 showed the most potent activity among the compounds tested against P. aeruginosa and MRSA, with MICs at which 90% of isolates tested were inhibited of 4 µg/ml and 8 µg/ml, respectively. CS-023 was stable against hydrolysis by the ß-lactamases from Enterobacter cloacae and Proteus vulgaris. CS-023 also showed potent activity against extended-spectrum ß-lactamase-producing Escherichia coli. The in vivo efficacy of CS-023 was evaluated with a murine systemic infection model induced by 13 strains of gram-positive and -negative pathogens and a lung infection model induced by 2 strains of PRSP (serotypes 6 and 19). Against the systemic infections with PRSP, MRSA, and P. aeruginosa and the lung infections, the efficacy of CS-023 was comparable to those of imipenem/cilastatin and vancomycin (tested against lung infections only) and superior to those of meropenem, ceftriaxone, and ceftazidime (tested against P. aeruginosa infections only). These results suggest that CS-023 has potential for the treatment of nosocomial bacterial infections by gram-positive and -negative pathogens, including MRSA and P. aeruginosa.

* Corresponding author. Mailing address: Biological Research Laboratories, Sankyo Co., Ltd., 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. Phone: 81-3-3492-3131. Fax: 81-3-5436-8565. E-mail: tekoga{at}sankyo.co.jp.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3239-3250, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3239-3250.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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