title: Role of beta-lactamase of methicillin-susceptible Staphylococcus aureus in resistance to first-generation oral cephems both in vitro and in vivo.
abstract: Cefaclor, among the oral cephalosporins tested, showed the largest inoculum effect with respect to MIC values for 61 clinical isolates of methicillin-susceptible Staphylococcus aureus, including 39 beta-lactamase producing strains. These 39 strains were divided into eight type A, 29 type B or C, and two type D producers, by comparisons of specific activities to three substrates. Two producers, one each of types A and C, were further studied to investigate the effect of beta-lactamase on staphylococcal resistance to several beta-lactams. Concentrations of cefaclor and cephalexin in cultures of these strains decreased rapidly, whereas hydrolysis of these drugs by the purified beta-lactamases was moderate to low as detected by spectrophotometric assay. Cefaclor showed high affinities for penicillin-binding proteins 1, 2, and 3 of both beta-lactamase producers and their respective penicillinase-non-producing mutants. In experimental intraperitoneal infections in mice, cefaclor was therapeutically effective against both mutants, showing 50% effective doses of less than 10 mg/kg/dose. In contrast, it was not satisfactory against the parent strains, requiring greater-than-10-fold increases in concentration for the same degree of survival. We concluded that resistance to first-generation oral cephems seen both in vitro and in vivo was due mainly to the beta-lactamase production.
authors.affiliation: Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takenouchi
authors.forename: Y
authors.initials: Y
authors.lastname: Utsui
authors.forename: S
authors.initials: S
authors.lastname: Ohya
authors.forename: T
authors.initials: T
authors.lastname: Nishino
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002433:Cefaclor / Q000494:pharmacology; D002478:Cells, Cultured; D002511:Cephalosporins / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D006868:Hydrolysis; D007274:Injections, Intraperitoneal; D008297:Male; D008712:Methicillin / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D016296:Mutagenesis / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D001618:beta-Lactamases / Q000145:classification / Q000187:drug effects / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D002433:Cefaclor; D001618:beta-Lactamases; D008712:Methicillin