In vitro and in vivo antibacterial activities of CS-834, a novel oral carbapenem.
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.
Fukuoka
T
T
Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Ohya
S
S
Utsui
Y
Y
Domon
H
H
Takenouchi
T
T
Koga
T
T
Masuda
N
N
Kawada
H
H
Kakuta
M
M
Kubota
M
M
Ishii
C
C
Ishii
C
C
Sakagawa
E
E
Harasaki
T
T
Hirasawa
A
A
Abe
T
T
Yasuda
H
H
Iwata
M
M
Kuwahara
S
S
D000284:Administration, Oral; D000818:Animals; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D001426:Bacterial Proteins; D015780:Carbapenems / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D015281:Cefmenoxime / Q000031:analogs & derivatives / Q000494:pharmacology; D015296:Ceftizoxime / Q000031:analogs & derivatives / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D004355:Drug Stability; D006602:Hexosyltransferases; D015378:Imipenem / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy / Q000382:microbiology; D011355:Prodrugs / Q000494:pharmacology*; D013845:Thienamycins / Q000494:pharmacology; D001618:beta-Lactamases / Q000378:metabolism; D000097623:Cefpodoxime
D001426:Bacterial Proteins; D015780:Carbapenems; D002352:Carrier Proteins; D015281:Cefmenoxime; D015296:Ceftizoxime; D002511:Cephalosporins; D006602:Hexosyltransferases; D015378:Imipenem; D002267:Muramoylpentapeptide Carboxypeptidase; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D011355:Prodrugs; D013845:Thienamycins; D001618:beta-Lactamases; D000097623:Cefpodoxime; C109885:R 95867; C049493:cefteram; C073460:cefditoren; C107030:CS 834