Role of beta-lactamase of methicillin-susceptible Staphylococcus aureus in resistance to first-generation oral cephems both in vitro and in vivo.
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.
Takenouchi
T
T
Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Utsui
Y
Y
Ohya
S
S
Nishino
T
T
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*
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D002433:Cefaclor; D001618:beta-Lactamases; D008712:Methicillin