In vitro activity and beta-lactamase stability of two oral cephalosporins, ceftetrame (Ro 19-5247) and cefetamet (Ro 15-8074)

Abstract

Ceftetrame and cefetamet (Ro 15-8074), two new orally administered aminothiazolyl imimomethoxy cephalosporins, inhibited hemolytic streptococci and Streptococcus pneumoniae at .0.5 ,ug/ml but were less active against staphylococci than were cephalexin and cefaclor. They did not inhibit S. faecalis, S. faecium, Listeria monocytogenes, Corynebacterium JK species, or Pseudomonas aeruginosa. Haemophilus influenzae, Branhamella catarrhalis, and Neisseria gonorrhoeae, including ampicillin-resistant isolates, were inhibited at <0.25 ,ug/ml. Both agents inhibited Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Salmonella species, Shigella species, Citrobacter diversus, and Aeromonas hydrophila resistant to ampicillin, cephalexin, and cefaclor at .2 ,ug/ml, although many isolates of Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens resistant to cefotaxime were not inhibited by these agents. A marked inoculum effect was noted for Enterobacteriaceae carrying the Richmond-Sykes type 1A chromosomally mediated beta-lactamases, but plasmid-mediated beta-lactamases did not hydrolyze the compounds. Both drugs inhibited the chromosomally mediated beta-lactamase of E. cloacae, P99. Although there has been great progress in the development of parenteral cephalosporins stable to attack by betalactamases and active against a wide spectrum of grampositive and -negative bacteria, this goal has not been achieved for oral cephalosporins (2). The early oral cephalosporins, cephalexin and cephradine, although moderately stable to attack by beta-lactamases, have had relatively poor activity against important respiratory pathogens such as Haemophilus influenzae and Br-anhacmellai catarrhalis (1, 7). Furthermore, their activity against Streptococcus pneiumoniae is significantly lower than that of the parenteral cephalosporins, and these compounds do not inhibit many beta-

In vitro and in vivo antibacterial activities of ME1207, a new oral cephalosporin

“…T-2525 (cefterame) is the biologically active product of the orally administered prodrug (T-2588). T-2525 is active against gram-negative bacteria and Streptococculs pneumoniae, but is less active than cefaclor against staphylococci (2,11,13). R-3746 is the biologically active product of CS-807.…”

beta-Lactamase stability and in vitro activity of oral cephalosporins against strains possessing well-characterized mechanisms of resistance

“…In contrast, cefixime did not elevate enzyme levels in this strain and was thus very active against it (MIC, <0.06 ,ug/ml). The variable to strong inducer activities of cefixime and cefuroxime for M. morganii may explain the diminished activities seen by other investigators in tests with a large number of strains of this species (17). Overall, the greater in vitro potency of cefixime over cefuroxime seen in this and other studies could be only partly explained by differences in stability to and/or induction of P-lactamases.…”

“…Thus, in this study, only 7 of 50 members of the Enterobacteriaceae were resistant to cefaclor but susceptible to cephalexin. A number of other investigators have also observed this difference in ,-lactamase stability between cefaclor and cephalexin (1,2,8,11,16,17,20,26). However, the difference is most apparent when a cephalosporin rather than a penicillin is used as the standard for comparison.…”

“…It should also be noted that cefaclor was hydrolyzed by ,-lactamases produced by Haemophilus influenzae and Branhamella catarrhalis. The susceptibility of cefaclor to hydrolysis by these enzymes has been demonstrated in various laboratories previously (15,17,28). It is probably responsible for the inoculum effect and diminished activity of this drug seen with many strains producing these enzymes (7, 10-12; R. N. Jones, Antimicrob.…”

“…Rather, it appeared to result from the high affinity of the drug for target enzymes. There has recently been intense activity in the development of new orally absorbable cephalosporins. Some of these compounds are directly absorbable in their active forms (2,6,7,10,11,13,16,28,30), while others are esters which must be enzymatically cleaved to their active forms after absoi-ption (3,5,9,17,18,20,27,29). Many of these newer compounds possess expanded antimicrobial spectra compared with spectra of older oral cephalosporins, which is thought to be due in large part to a diminished susceptibility to hydrolysis by 1-lactamases (1-6, 8, 9, 15-17, 19-21, 26, 27, 29).…”