BMY 28100, a new oral cephalosporin

Abstract

BMY 28100, a new oral cephalosporin with a (Z)-propenyl side chain at the 3 position and a phydroxyphenylglycyl substituent at the 7 position, was evaluated in comparison with cefaclor and cephalexin and, when appropriate, ampicillin and vancomycin. In vitro, BMY 28100 was more active than the reference cephalosporins against streptococci, Staphylococcus aureus, Staphylococcus epidermidis, Listeria nionocytogenes, Haemophilus influenzae, Propionibacterium acnes, Clostridiunm perfrigens, and Clostridium difficile. BMY 28100 was comfparable to cefaclor and more active than eephalexin against Staphylococcus saprophyticus and ampicillin-susceptible strains of Branhamella cattarhalis; but against ampicillin-resistant strains of B. cattarhalis, BMY 28100 was comparable to cephalexin and more active than cefaclor. Against Neisseria gonorrhoeae, BMY 28100 was comparable to cephalexin, but less active than cefaclor. Members of the family Enterobacteriaceae overall were equally susceptible to BMY 28100 and cefaclor but were less susceptible to cephalexin. In human serum, BMY 28100 was 45% protein bound. After an oral dose to mice, 82% of the drug was recovered in urine. The oral therapeutic efficacy of BMY 28100 in systemically infected mice reflected its activity in vitro.Whereas parenteral cephalosporins have been prepared with an array of side chains at the 3 and 7 positions, structural requirements for good gastrointestinal absorption have limited the choice of side chains for oral cephalosporins. The number of distinct substituents at the 3 position on oral cephalosporins currently in clinical use is small, and all substituents at the 7 position are of a single design: a native or modified phenyglycyl radical. Recent attempts to deviate from this pattern have yielded compounds with a broader spectrum of activity against gram-negative organisms but reduced gastrointestinal absorption and little antistaphylococcal activity (4, 9, 13; T. Suematsu, H. Sakamoto, and K. Takai, Proc. 14th Int. Congr. Chemother., p. 1147-1148 , abstr. no. 595, 1985).BMY 28100 is a new oral cephalosporin of conventional design. It has a (Z)-propenyl side chain at the 3 position and ap-hydroxyphenylglycyl substituent at position 7 (Fig. 1)

Phase I study of single-dose BMY-28100, a new oral cephalosporin

“…The antimicrobial spectrum of BMY-28100 is superior to those of cephalexin and cefadroxil and similar to that of cefaclor (1,3). Animal studies suggest that BMY-28100 may have some pharmacokinetic advantage over cefaclor (6).…”

“…It has a phydroxyphenylglycyl substituent at position 7 and a propenyl side chain at position 3. Its antimicrobial spectrum includes important gram-positive and gram-negative organisms usually associated with infections of the urinary and respiratory tracts (1,3,6,11). The antimicrobial spectrum of BMY-28100 is superior to those of cephalexin and cefadroxil and similar to that of cefaclor (1,3).…”

Penetration of cefprozil into tonsillar and adenoidal tissues

“…Cefprozil consists of the cis and trans isomers in a ratio of 9:1. It has a spectrum of activity similar to that of cefaclor but greater activity against staphylococci and Haemophilus influenzae (1,2,10,12). It is also active against group A streptococci (2) and Branhamella catarrhalis (1).…”

“…Only trace amounts of trans isomer were found in the tonsillar and adenoidal tissue. The estimated time for cefprozil concentrations in the tonsil tissue to remain above the MIC for S. pyogenes, which commonly causes tonsillitis (1,2,10,12), is more than 9 h. In the clinical efficacy trial of treatment of pharyngitis or tonsillitis, clinically significant improvement (86% eradication) was observed (11). This study demonstrated that the excellent penetration of cefprozil into tonsillar and adenoidal tissue corresponds well with the clinical outcome.…”

“…Both isomers are similarly active against staphylococci and streptococci but are 2-to 40-fold less active against a variety of gram-negative bacteria (8). Cefprozil is more stable than cefaclor for the penicillinase-producing Staphylococcus aureus isolates (10). It is anticipated that significant numbers of patients with streptococcal pharyngitis will receive cefprozil.…”