IN-VITRO AND IN-VIVO ANTIBACTERIAL ACTIVITIES OF CS-834, A NOVEL ORALCARBAPENEM

CS-834 is a novel oral carbapenem antibiotic. This compound is an este r-type prodrug of the active metabolite R-95867. The antibacterial act ivity of R-95867 was tested against 1,323 clinical isolates of 35 spec ies and was compared with those of oral cephems, i.e., cefteram, cefpo doxime, cefdinir, and cefditoren, and that of a parenteral carbapenem, imipenem. R-95867 exhibited a broad spectrum of activity covering bot h grampositive and -negative aerobes and anaerobes. Its activity was s uperior to those of the other compounds tested against most of the bac terial species tested. R-95867 showed potent antibacterial activity ag ainst clinically significant pathogens: methicillin-susceptible Staphy lococcus aureus including ofloxacin-resistant strains, Streptococcus p neumoniae including penicillin-resistant strains, Clostridium perfring ens, Neisseria spp., Moraxella catarrhalis, most members of the family Enterobacteriaceae, and Haemophilus influenzae (MIG at which 90% of s trains are inhibited, less than or equal to 0.006 to 0.78 mu g/ml). R- 95867 was quite stable to hydrolysis by most of the beta-lactamases te sted except the metallo-beta-lactamases from Stenotrophomonas maltophi lia and Bacteroides fragilis. R-95867 showed potent bactericidal activ ity against S. aureus and Escherichia coli. Penicillin-binding protein s 1 and 4 of S. aureus and 1Bs, 2, 3, and 4 of E. coli had high affini ties for R-95867. The in vivo efficacy of CS-834 was evaluated in muri ne systemic infections caused by 16 strains of gram-positive and -nega tive pathogens. The efficacy of CS-834 was in many cases superior to t hose of cefteram pivoxil, cefpodoxime proxetil, cefdinir, and cefditor en pivoxil, especially against infections caused by S. aureus, penicil lin-resistant S. pneumoniae, E. call, Citrobacter freundii, and Proteu s vulgaris. Among the drugs tested, CS-834 showed the highest efficacy against experimental pneumonia in mice caused by penicillin-resistant S. pneumoniae.