title: In vitro and in vivo antibacterial activities of CS-023 (RO4908463), a novel parenteral carbapenem.
abstract: CS-023 (RO4908463, formerly R-115685) is a novel 1beta-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), beta-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 microg/ml and 8 microg/ml, respectively. CS-023 was stable against hydrolysis by the beta-lactamases from Enterobacter cloacae and Proteus vulgaris. CS-023 also showed potent activity against extended-spectrum beta-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.
authors.affiliation: Biological Research Laboratories, Sankyo Co., Ltd., 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. tekoga@sankyo.co.jp
authors.forename: Tetsufumi
authors.initials: T
authors.lastname: Koga
authors.forename: Tomomi
authors.initials: T
authors.lastname: Abe
authors.forename: Harumi
authors.initials: H
authors.lastname: Inoue
authors.forename: Takashi
authors.initials: T
authors.lastname: Takenouchi
authors.forename: Akiko
authors.initials: A
authors.lastname: Kitayama
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Masuda
authors.forename: Chika
authors.initials: C
authors.lastname: Sugihara
authors.forename: Masayo
authors.initials: M
authors.lastname: Kakuta
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shibayama
authors.forename: Yoko
authors.initials: Y
authors.lastname: Matsushita
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirota
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohya
authors.forename: Yukio
authors.initials: Y
authors.lastname: Utsui
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukuoka
authors.forename: Syogo
authors.initials: S
authors.lastname: Kuwahara
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D015780:Carbapenems / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; C492232:tomopenem