title: In vitro evaluation of BRL 42715, a novel beta-lactamase inhibitor.
abstract: The penem BRL 42715, C6-(N1-methyl-1,2,3-triazolylmethylene)penem, is a potent inhibitor of a broad range of bacterial beta-lactamases, including the plasmid-mediated TEM, SHV, OXA, and staphylococcal enzymes, as well as the chromosomally mediated enzymes of Bacteroides, Enterobacter, Citrobacter, Serratia, Morganella, Escherichia, Klebsiella, and Proteus species. The concentration of BRL 42715 needed to reduce the initial rate of hydrolysis of most beta-lactamase enzymes by 50% was less than 0.01 micrograms/ml, which was 10- to 100-fold lower than for other beta-lactamase inhibitors. These potent inhibitory activities were reflected in the low concentrations of BRL 42715 needed to potentiate the antibacterial activity of beta-lactamase-susceptible beta-lactams. Concentrations of 0.25 micrograms/ml or less considerably enhanced the activity of amoxicillin against many beta-lactamase-producing strains. The MIC50 (MIC for 50% of strains tested) of amoxicillin for 412 beta-lactamase-producing members of the family Enterobacteriaceae fell from greater than 128 to 2 micrograms/ml in the presence of 1 microgram of BRL 42715 per ml, whereas 5 micrograms of clavulanic acid per ml brought the MIC50 down to 8 micrograms/ml. Among these 412 strains were 73 Citrobacter and Enterobacter strains, and 1 microgram of BRL 42715 per ml reduced the MIC50 of amoxicillin from greater than 128 to 2 micrograms/ml for the 48 cefotaxime-susceptible strains and from greater than 128 to 8 micrograms/ml for the 25 cefotaxime-resistant strains.
authors.affiliation: Beecham Pharmaceutical Research Division, Chemotherapeutic Research Centre, Betchworth, Surrey, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Coleman
authors.forename: D R
authors.initials: DR
authors.lastname: Griffin
authors.forename: J W
authors.initials: JW
authors.lastname: Page
authors.forename: P A
authors.initials: PA
authors.lastname: Upshon
mesh_terms: D000658:Amoxicillin / Q000378:metabolism / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D002969:Clavulanic Acids / Q000494:pharmacology; D004357:Drug Synergism; D007769:Lactams; D008826:Microbial Sensitivity Tests; D013407:Sulbactam / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D002969:Clavulanic Acids; D007769:Lactams; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C061593:C6-(N1-methyl-1,2,3-trazolylmethylene)penem; D000658:Amoxicillin; D013407:Sulbactam