In vitro and in vivo antibacterial activities of CS-023 (RO4908463), a novel parenteral carbapenem.
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.
Koga
Tetsufumi
T
Biological Research Laboratories, Sankyo Co., Ltd., 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. tekoga@sankyo.co.jp
Abe
Tomomi
T
Inoue
Harumi
H
Takenouchi
Takashi
T
Kitayama
Akiko
A
Yoshida
Tatsuhiko
T
Masuda
Nobuhisa
N
Sugihara
Chika
C
Kakuta
Masayo
M
Nakagawa
Miyuki
M
Shibayama
Takahiro
T
Matsushita
Yoko
Y
Hirota
Takashi
T
Ohya
Satoshi
S
Utsui
Yukio
Y
Fukuoka
Takashi
T
Kuwahara
Syogo
S
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
D000900:Anti-Bacterial Agents; D015780:Carbapenems; C492232:tomopenem