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: Tetsufumi Koga, Tomomi Abe, Harumi Inoue, Takashi Takenouchi, Akiko Kitayama, Tatsuhiko Yoshida, Nobuhisa Masuda, Chika Sugihara, Masayo Kakuta, Miyuki Nakagawa, Takahiro Shibayama, Yoko Matsushita, Takashi Hirota, Satoshi Ohya, Yukio Utsui, Takashi Fukuoka, Syogo Kuwahara
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 49 Issue 8 Pg. 3239-50 (Aug 2005) ISSN: 0066-4804 [Print] United States
• PMID: 16048932 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• Carbapenems
• tomopenem

Topics

• Animals
• Anti-Bacterial Agents (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Carbapenems (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Resistance, Bacterial
• Gram-Negative Bacteria (drug effects)
• Gram-Negative Bacterial Infections (drug therapy, microbiology)
• Gram-Positive Bacteria (drug effects)
• Gram-Positive Bacterial Infections (drug therapy, microbiology)
• Humans
• Mice
• Microbial Sensitivity Tests