title: Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status.
abstract: The mechanism of cephalosporin-induced hypoprothrombinemia has been investigated in hospitalized patients, with respect to cephalosporin structure, vitamin K metabolism, and vitamin K status. Cephalosporins containing side chains of N-methylthiotetrazole (latamoxef, cefmenoxime, cefoperazone, cefotetan, cefamandole) or methyl-thiadiazole (cefazolin) all caused the transient plasma appearance of vitamin K1 2,3-epoxide in response to a 10-mg intravenous dose of vitamin K1, whereas two cephalosporins without a heterocyclic side chain (cefotaxime and cefoxitin) did not. The plasma accumulation of vitamin K1 2,3-epoxide was qualitatively similar to, but quantitatively less than, that produced by the oral anticoagulant phenprocoumon. Patients eating normally had plasma vitamin K1 concentrations (176 to 1184 pg/mL) that were within the normal range (150 to 1550 pg/mL) and their clotting tests remained consistently normal for all antibiotics tested. Patients on total parenteral nutrition had lower plasma vitamin K1 concentrations (50 to 790 pg/mL) but normal clotting before starting antibiotic therapy. Of 19 parenterally fed patients, all seven treated with latamoxef developed hypoprothrombinemia, PIVKA-II and a decrease of protein C within four days whereas 12 patients treated with cefotaxime or cefoxitin showed no clotting changes. Latamoxef-associated hypoprothrombinemia was readily reversible by 1 mg of vitamin K1 given intravenously, but hypoprothrombinemia and sub-normal plasma vitamin K1 could recur within two to three days. The data suggest that NMTT-cephalosporins are inhibitors of hepatic vitamin K epoxide reductase and that a lower nutritional-vitamin K status predisposes to hypoprothrombinemia.
authors.affiliation: Department of Haematology, Guy's Hospital, London, United Kingdom.
authors.forename: M J
authors.initials: MJ
authors.lastname: Shearer
authors.forename: H
authors.initials: H
authors.lastname: Bechtold
authors.forename: K
authors.initials: K
authors.lastname: Andrassy
authors.forename: J
authors.initials: J
authors.lastname: Koderisch
authors.forename: P T
authors.initials: PT
authors.lastname: McCarthy
authors.forename: D
authors.initials: D
authors.lastname: Trenk
authors.forename: E
authors.initials: E
authors.lastname: Jähnchen
authors.forename: E
authors.initials: E
authors.lastname: Ritz
mesh_terms: D000328:Adult; D000368:Aged; D002511:Cephalosporins / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011516:Prothrombin / Q000378:metabolism*; D011517:Prothrombin Time; D013329:Structure-Activity Relationship; D014812:Vitamin K / Q000378:metabolism*; D010837:Vitamin K 1 / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D002511:Cephalosporins; D014812:Vitamin K; C016186:vitamin K1 oxide; D010837:Vitamin K 1; D011516:Prothrombin