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

  title={Mechanism of Cephalosporin‐induced Hypoprothrombinemia: Relation to Cephalosporin Side Chain, Vitamin K Metabolism, and Vitamin K Status},
  author={Martin J Shearer and Heinrich Bechtold and Konrad Andrassy and Janti Koderisch and Patrick T. McCarthy and Dietmar Trenk and Eberhard J{\"a}hnchen and Eberhard Ritz},
  journal={The Journal of Clinical Pharmacology},
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… 

Studies on oxacephem antibiotics: comparison of the effects of 1-oxa and 1-thia cephalosporins on blood coagulation activities and vitamin K metabolism in rats.

Under the vitamin-deficient states, LMOX, FMOX and their 1-S congeners inhibited the vitamin K epoxide reductase, and they decreased the blood clotting activities in rats fed a vitamin K- deficient diet, suggesting that the 1-oxygen replacement of cephem antibiotics is not responsible for the hypoprothrombinemic effect of the antibiotics.

Lack of Effect of Cefixime on the Metabolism of Vitamin K1

The results indicate that the development of hypoprothrombinemia due to an impairment of the metabolism of vitamin K1 by cefixime seems unlikely because only trace amounts of Vitamin K1‐2,3‐epoxide could be determined in the plasma of the subjects investigated.

Comparison of N-methylthiotetrazole dispositions in healthy volunteers following single intravenous doses of moxalactam, cefoperazone, and cefotetan

A randomized three-way crossover trial was conducted to compare the release of the NMTT side chain from three N MTT-containing antibiotics, demonstrating that the in vivo production of NMTt is dependent on the disposition of the parent cephalosporin.

The Association Between Cephalosporin and Hypoprothrombinemia: A Systematic Review and Meta-Analysis

An Antimicrobial Stewardship Program led by a multidisciplinary team could play a critical role in monitoring cephalosporin-related hypoprothrombinemia or PT prolongation in patients with underlying clinical conditions at risk for bleeding.

Antibiotic-associated hypoprothrombinemia: a review of prospective studies, 1966-1988.

Patients at high risk for coagulopathy should be carefully monitored and serious consideration should be given to the use of prophylactic vitamin K in such cases, according to the hypothesis that the NMTT side chain is primarily responsible for hypoprothrombinemia.

Cephalosporin-Associated Hypoprothrombinemia: Case and Review of the Literature

Cephalosporins containing the NMTT side chain are associated with the development of hypoprothrombinemia and possibly bleeding, especially in high-risk patients.

Comparative effects of cefoxitin and cefotetan on vitamin K metabolism

While hypoprothrombinemia and formation of abnormal prothrombin were not seen in healthy subjects, the effect of cefotetan on the coagulation status of vitamin K-depleted patients may be adverse.

Effects of cephalothin, cefazolin, and cefmetazole on the hemostatic mechanism in normal dogs: implications for the surgical patient.

Cefazolin had no adverse effects on platelet aggregation in response to ADP, bleeding time, platelet count, platelets size, PT, or aPTT, and should be considered as a perioperative antibiotic in dogs with conditions predisposing to hemostatic complications.

Effects of aztreonam on fecal flora and on vitamin K metabolism

The effects of aztreonam on fecal flora and on descarboxy prothrombin (PIVKA-II) in plasma and gamma-carboxyglutamic acid (Gla) in urine as an index of vitamin K metabolism were studied in children with urinary tract infections.

Pharmacokinetics and hemostasis following administration of a new, injectable oxacephem (6315-S, flomoxef) in volunteers and in patients with renal insufficiency

Although the N-methylthiotetrazole group has been replaced by a hydroxyethyl group, an inhibitory effect of flomoxef on vitamin K metabolism persisted, this effect was, however, less pronounced than with latamoxef.



Evidence for impaired hepatic vitamin K1 metabolism in patients treated with N-methyl-thiotetrazole cephalosporins.

In 8 patients on no oral intake and with parenteral alimentation, administration of cephalosporins with N-methyl-thiotetrazole side chain (moxalactam, cefamandole), was associated with prolongation

Metabolism of vitamin K and prothrombin synthesis: anticoagulants and the vitamin K--epoxide cycle.

  • R. Bell
  • Biology, Chemistry
    Federation proceedings
  • 1978
Vitamin K is primarily located in hepatic microsomes, where the vitamin K-dependent carboxylation in prothrombin synthesis occurs and the epoxide-K conversion is impaired in resistant rats, which may explain their high vitamin K requirement.

Hematologic Complications Associated with β-Lactam Antibiotics

The complication of hypoprothrombinemic hemorrhage seen with broad-spectrum antibiotics may result from eradication of vitamin K-producing intestinal microorganisms.

Effect of N-methyl-thiotetrazole on vitamin K epoxide reductase.

Effect of warfarin on the metabolism of phylloquinone (vitamin K1):dose-response relationships in man.

The results are consistent with the hypothesis that the pharmacological action of oral anticoagulants is closely linked to their ability to inhibit the cyclic interconversion of vitamin K and vitamin K epoxide.

The relationship between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin.

The apparent dissociation between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factors activity, produced by warfarin, may reflect the insensitivity of functional clotting factor assays to a small reduction in clottingfactor concentration.

Hypoprothrombinemia in febrile, neutropenic patients with cancer: association with antimicrobial suppression of intestinal microflora.

The hypothesis that menaquinones may play an important physiological role in the maintenance of blood coagulation during episodic dietary deficiency of phylloquinone is supported.