In vitro and in vivo evaluations of a new broad-spectrum oral cephalosporin, BMY-28232, and its prodrug esters.
The in vitro activity of a new cephalosporin, BMY-28232 (7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[ (Z)-1- propenyl]-3-cephem-4-carboxylic acid), was compared with those of cefuroxime and BMY-28488, the 3-vinyl congener of BMY-28232, against 899 bacteria including strains resistant to newer cephalosporins. BMY-28232 displayed potent, broad-spectrum antibacterial activity with high stability to various types of beta-lactamase. Its acetoxyethyl ester (BMY-28271) and pivaloyloxymethyl ester (BMY-28257) were well absorbed after oral administration to mice and rats. Both esters were metabolized to BMY-28232 and mainly excreted in urine. Oral bioavailability of both prodrug esters (60 to 70%) was better than that of cefuroxime axetil (46%) and gave excellent therapeutic efficacy against gram-positive- and gram-negative-bacterial infections in mice. Oral 50% protective doses (in milligrams per kilogram of body weight) of 0.65 and 0.72 for Staphylococcus aureus Smith, 0.9 and 1.2 for Escherichia coli Juhl, 1.6 and 1.6 for Proteus vulgaris, and 18.9 and 14.3 for Enterobacter cloacae were obtained for BMY-28271 and BMY-28257, respectively.
Tomatsu
K
K
Bristol-Myers Research Institute, Ltd., Tokyo Research Center, Japan.
Masuyoshi
S
S
Hirano
M
M
Kawaguchi
H
H
Oki
T
T
Fung-Tomc
J
J
Desiderio
J V
JV
Kessler
R E
RE
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D011355:Prodrugs; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D001618:beta-Lactamases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D011355:Prodrugs; C058032:BMY 28232; D001618:beta-Lactamases