In vitro and in vivo antibacterial activities of T-2588, a new oral cephalosporin, compared with those of other oral beta-lactam antibiotics

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ME1207 (pivaloyloxymethyl ester of ME1206) is a new oral cephalosporin. ME1206 is (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)- acetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)-ethyl]-cephem-4-carboxy lic acid. The susceptibilities of about 1,600 clinical isolates to ME1206 were determined by the agar dilution method. ME1206 showed a broad spectrum of activity against gram-positive and gram-negative bacteria. ME1206 was more active than cefaclor, T-2525, and cefixime against Staphylococcus aureus and Staphylococcus epidermidis. Against gram-negative bacteria, the activity of ME1206 was comparable with that of T-2525, but ME1206 was less active than cefixime. Against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae, ME1206 had high activity (MIC, less than or equal to 0.05 microgram/ml). ME1206 was stable against various beta-lactamases, except beta-lactamases from Providencia rettgeri, Pseudomonas cepacia, and Escherichia coli W3630 (Rms213). The 50% effective doses of ME1207 after oral administration against systemic infections in mice were comparable with those of T-2588 against gram-negative bacteria and about one-fourth that of T-2588 against Staphylococcus aureus Smith.

mentioning

confidence: 99%

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

Tamura¹,

Okamoto²,

Yoshida³

et al. 1988

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“…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.…”

Section: Methodsmentioning

confidence: 83%

“…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).…”

mentioning

confidence: 99%

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

Sanders

1989

The in vitro activity of four oral cephalosporins was assessed in dilution tests with 50 isolates of the family Enterobacteriaceae possessing well-characterized mechanisms of resistance to Il-lactam antibiotics. The interaction of the drugs with a broad array of 3-lactamases was also determined in spectrophotometric assays and tests for enzyme induction. Overall, the percentages of strains susceptible to each of the study drugs were 82% for cefixime, 62% for cefuroxime, 58% for cephalexin, and 44% for cefaclor. The poor activity of the older cephalosporins was due to a high degree of susceptibility to hydrolysis by both plasmid-mediated and chromosomally mediated P-lactamases. For cefaclor, higher MICs were associated with higher levels of plasmid-mediated 3-lactamases in the strains. Resistance to cefuroxime was seen primarily among strains expressing high levels of class I or IV 1-lactamase. Resistance to cefixime was seen only among strains expressing high levels of class I enzymes. Neither cefixime nor cefuroxime was a strong inducer of class I ,I-lactamases, although enzyme induction did appear to play a role in cefuroxime resistance in a strain of Serratia marcescens. The consistently greater activity of cefixime over cefuroxime was found not to be due to greater drug permeation into the cell. 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). Thus, the purpose of this study was to assess various factors that might influence the activity of oral cephalosporins. To accomplish this, the interactions of four oral cephalosporins with a broad array of 1-lactamases were assessed, as was the activity of the cephalosporins against organisms possessing well-characterized mechanisms of resistance to 3-lactam antibiotics. Cephalexin, cefaclor, cefuroxime, and cefixime were chosen for study, since the two former drugs represent the older compounds and the latter represent two of the most P-lactamase stable of the newer compounds.MATERIALS AND METHODS Strains. Fifty isolates of diverse genera of the family Enterobacteriaceae were examined in this study. They included 23 Escherichia coli, 11 Klebsiella spp., 4 Enterobacter spp., 7 Citrobacter spp., 3 Serratia spp., and one each Providencia stuartii and Morganella morganii isolates. Most were clinical isolates, although three were laboratory-derived mutants from clinical isolates. Most were also resistant to multiple P-lactam antibiotics, and the mechanism(s) resp...

“…Cefaclor is active against gram-positive and some gram-negative bacteria but is hydrolyzed by various f-lactamases (13). Cefixime and cefteram (T-2525) (2,12,14) have good activity against gram-negative bacteria and streptococci and are not hydrolyzed readily by various P-lactamases, but these compounds have relatively low activities against staphylococci (2,6,12,14).…”

mentioning

confidence: 99%

“…BMY-28232 and BMY-28271 (the acetoxyethyl ester of BMY-28232) were synthesized at the Tokyo Research Center of Bristol Myers Research Institute, Ltd., Tokyo, Japan.-The other antimicrobial agents used in this study were obtained from the indicated sources: cefixime, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan; cefteram (T-2525, Ro 19-5247) and cefteram pivoxil (T-2588) (2,12,14), Toyama Chemical Co., Ltd., Tokyo, Japan; cefaclor, Shionogi Pharmaceutical Co., Ltd., Osaka, Japan; benzylpenicillin, Meiji Seika Kaisha, Ltd., Tokyo, Japan; cephaloridine, Nihon Glaxo Co., Ltd., Tokyo, Japan; and methicillin, Banyu Pharmaceutical Co., Ltd., Tokyo, Japan. Organisms. The bacterial strains used in this study were recent clinical isolates from various hospitals in Japan.…”

mentioning

confidence: 99%

Antimicrobial activity and stability to beta-lactamase of BMY-28271, a new oral cephalosporin ester

Matsui¹,

Hiraoka²,

Inoue³

et al. 1990

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BMY-28271, the acetoxyethyl ester of BMY-28232, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3(Z) -propen-1-yl-3- cephem-4-carboxylic acid, is a new oral cephalosporin. BMY-28232 has a widely expanded spectrum with high activity against gram-positive and gram-negative bacteria. BMY-28232 is far more active than cefixime or cefteram against Staphylococcus aureus and Staphylococcus epidermidis. Against gram-negative bacteria, the activity of BMY-28232 was comparable to or somewhat weaker than that of cefixime or cefteram. BMY-28232 was a poor substrate for various beta-lactamases. Orally administered BMY-28271 had a good therapeutic effect on systemic infections with S. aureus and some gram-negative bacteria in mice. Oral BMY-28271 was efficacious against S. aureus Smith infection: the efficacy of BMY-28271 was 80 to 90 times higher than that of cefixime or cefteram.