CEPHALOSPORIN-INDUCED HYPOPROTHROMBINAEMIA: RELATION TO CEPHALOSPORIN SIDE CHAIN, VITAMIN K METABOLISM AND VITAMIN K STATUS

An increased incidence of bleeding episodes due to hypopro-thrombinaemia has been associated with several cephalosporins especially those which contain an N-methyl-thio-tetrazole (NMTT) side chain. To study the etiology of cephalosporin-induced hypo-prothrombinaemia in the clinical situation we have investigated the ability of different cephalosporins to alter the metabolism of vitamin K and the relationship between hypoprothrombinaemia and vitamin K status as assessed from plasma levels of vitamin K. Cephalosporins containing an NMTT side chain (latamoxef, cefmenoxime, cefoperazone, cefotetan, cefamandole) or related structure (cefozolin) all caused the transient plasma appearance of vitamink₁ 2,3-epoxide in response to a 10 mg intravenous dose of vitamin ; those without NMTT (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 phenprccoumon. In 36 patients eating normally, the median endogenous plasma vitamin k₁ (370 pg/ml) was not significantly different from that in healthy, fasting subjects (372 pg/ml) and clotting tests remained consistently normal for all antibiotics tested. In 22 patients on total parenteral nutrition the median plasma vitamin k₁. (223 pg/ml) was significantly lower than normal (p < 0.01) with 61patients having levels below the normal range (< 150 pg/ml) but normal clotting before starting antibiotic therapy. All 7 parenterally-fed patients treated with latamoxef developed hypoprothrombinaemia (as shown by prothrombin time, PIVKA-II and protein C measurements) within 4 days whereas 12 patients treated with cefotaxime or cefoxitin did not. Latamoxef-associated hypoprothrombinaemia was readily reversible by 1 mg of vitamin k₁ given intravenously but hypoprothrombinaemia and sub-normal plasma vitamin k₁ could recur within 2-3 days. The data suggest that NMTT-cephalosporins are inhibitors of hepatic vitamin K epoxide reductase and that a lowered vitamin K status predisposes to hypoprothrombinaemia.