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.