Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status

J Clin Pharmacol. 1988 Jan;28(1):88-95. doi: 10.1002/j.1552-4604.1988.tb03106.x.


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.

MeSH terms

  • Adult
  • Aged
  • Cephalosporins / adverse effects*
  • Cephalosporins / pharmacokinetics
  • Female
  • Hemostasis / drug effects
  • Humans
  • Male
  • Middle Aged
  • Prothrombin / metabolism*
  • Prothrombin Time
  • Structure-Activity Relationship
  • Vitamin K / metabolism*
  • Vitamin K 1 / analogs & derivatives
  • Vitamin K 1 / blood


  • Cephalosporins
  • Vitamin K
  • vitamin K1 oxide
  • Vitamin K 1
  • Prothrombin