Mechanism of Cephalosporin‐induced Hypoprothrombinemia: Relation to Cephalosporin Side Chain, Vitamin K Metabolism, and Vitamin K Status

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 K 1 2,3‐epoxide in response to a 10‐mg intravenous dose of vitamin K 1 , whereas two cephalosporins without a heterocyclic side chain (cefotaxime and cefoxitin) did not. The plasma accumulation of vitamin K 1 2,3‐epoxide was qualitatively similar to, but quantitatively less than, that produced by the oral anticoagulant phenprocoumon. Patients eating normally had plasma vitamin K 1 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 K 1 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 K 1 given intravenously, but hypoprothrombinemia and sub‐normal plasma vitamin K 1 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.