In vitro and in vivo antibacterial activities of CS-834, a novel oral carbapenem

Abstract

CS-834 is a novel oral carbapenem antibiotic. This compound is an ester-type prodrug of the active metabolite R-95867. The antibacterial activity of R-95867 was tested against 1,323 clinical isolates of 35 species and was compared with those of oral cephems, i.e., cefteram, cefpodoxime, cefdinir, and cefditoren, and that of a parenteral carbapenem, imipenem. R-95867 exhibited a broad spectrum of activity covering both gram-positive and -negative aerobes and anaerobes. Its activity was superior to those of the other compounds tested against most of the bacterial species tested. R-95867 showed potent antibacterial activity against clinically significant pathogens: methicillin-susceptible Staphylococcus aureus including ofloxacin-resistant strains, Streptococcus pneumoniae including penicillin-resistant strains, Clostridium perfringens, Neisseria spp., Moraxella catarrhalis, most members of the family Enterobacteriaceae, and Haemophilus influenzae (MIC at which 90% of strains are inhibited, < or =0.006 to 0.78 microg/ml). R-95867 was quite stable to hydrolysis by most of the beta-lactamases tested except the metallo-beta-lactamases from Stenotrophomonas maltophilia and Bacteroides fragilis. R-95867 showed potent bactericidal activity against S. aureus and Escherichia coli. Penicillin-binding proteins 1 and 4 of S. aureus and 1Bs, 2, 3, and 4 of E. coli had high affinities for R-95867. The in vivo efficacy of CS-834 was evaluated in murine systemic infections caused by 16 strains of gram-positive and -negative pathogens. The efficacy of CS-834 was in many cases superior to those of cefteram pivoxil, cefpodoxime proxetil, cefdinir, and cefditoren pivoxil, especially against infections caused by S. aureus, penicillin-resistant S. pneumoniae, E. coli, Citrobacter freundii, and Proteus vulgaris. Among the drugs tested, CS-834 showed the highest efficacy against experimental pneumonia in mice caused by penicillin-resistant S. pneumoniae.

In Vivo Activities of Peptidic Prodrugs of Novel Aminomethyl Tetrahydrofuranyl-1β-Methylcarbapenems

“…The use of a specific transport system is suggested by the increased efficacies of the CL 191,121 derivatives with the L-form amino acids of alanine and phenylalanine after oral administration but the decreased activities of the D-form amino acids. The novel peptidic prodrugs of this THF carbapenem demonstrated efficacies comparable to those of other investigational oral carbapenems (5,18), ester prodrugs of active carbapenems (16), esters of tribactam antibiotics (15,20), the orally bioavailable oxazolidinones (4) and ketolides (1), and ester-type cephalosporins (6,13,17) against infections caused by both gram-negative and gram-positive isolates. The peptidic prodrugs of these novel aminomethyl THF-1␤-methylcarbapenems are promising new agents for the treatment of infections caused by a variety of gram-positive and gram-negative bacteria.…”

“…The carbapenem class of antibiotics has been shown to be effective against a broad spectrum of gram-positive and gram-negative bacteria and stable to most known resistance mechanisms. Presently, commercial carbapenems are effective only when they are administered by the parenteral route (3), while a few ester-type carbapenems are being developed for use as oral therapy (5,16). In addition, many ester-type prodrugs of cephalosporins and tribactams are in use or are under investigation for use as oral treatments (13,20).…”

Quinolone, Everninomycin, Glycylcycline, Carbapenem, Lipopeptide and Cephem Antibacterials in Clinical Development

“…CS-834 was found to be efficacious in several animal infection models, including systemic infections with grampositive and gram-negative bacteria [127][128][129] and respiratory tract infections with penicillin-sensitive and penicillinresistant S. pneumoniae and H. influenzae [129,130].…”

“…Another advantage of the (R)-isomer is that it was readily obtained in crystalline form. R-95867 is a broad spectrum antibiotic that is slightly less active than imipenem against gram-positive cocci, but more active than imipenem against Enterobacteriaceae [127,128]. The parent carbapenem derivative is stable toward β-lactamases except for the metallo-β-lactamases.…”

Properties of extended-spectrum β-lactamases constructed by site-directed mutagenesis

“…Tazobactam, cefpodoxime, panipenem, and R-95867, the active metabolite of the orally active carbapenem antibiotic CS-834, 13 were synthesized by Sankyo (Tokyo, Japan). Piperacillin, cefoperazone, and cephalothin (Sigma Chemical, St. Louis, MO, USA); cefepime (BristolMyers Squibb, Tokyo, Japan); cefmetazole (Sankyo), cefotaxime, and cefpirome (Chugai Pharmaceutical, Tokyo, Japan), cefozopran (Takeda Chemical Industries, Osaka, Japan); and nitrocefin (Oxoid, Hampshire, UK) were obtained commercially.…”