Prolonged bleeding times and bleeding diathesis associated with moxalactam administration

Weitekamp, Michael R.

doi:10.1001/jama.249.1.69

Cited by 49 publications

(35 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, some third generation cephalosporins (e.g., moxalactam) caused life-threatening hypoprothrombinemia and hemorrhage (Reddy and Bailey, 1980;Weitkamp and Aber, 1983;Dupuis et al, 1984;Lipsky, 1988). That adverse reaction was shown to be due to inhibition of the ␥-carbox-…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, MTD is present in the tissues of patients treated with cefazolin. These observations also raise the possibility that the TPMT genetic polymorphism may represent a risk factor for cefazolin-induced hypoprothrombinemia since subjects who genetically lack TPMT would be unable to catalyze this MTD biotransformation pathway.Cephalosporin antibiotics such as moxalactam, cefamandole, and cefoperazone can cause life-threatening hypoprothrombinemia and hemorrhage (Reddy and Bailey, 1980;Weitkamp and Aber, 1983;Dupuis et al, 1984;Lipsky, 1988). That adverse reaction is thought to be due to the in vivo release of a heterocyclic leaving group, 1-methyltetrazole-5-thiol (MTT 2 ), which is present in the structures of these drugs (Black et al, 1983;Lipsky, 1983, 1984.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cefazolin Administration and 2-Methyl-1,3,4-Thiadiazole-5-Thiol in Human Tissue: Possible Relationship to Hypoprothrombinemia

Wood

Johnson²,

Naylor

et al. 2002

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Cephalosporin antibiotics with structures that include the heterocyclic leaving group 1-methyltetrazole-5-thiol (MTT) can cause hypoprothrombinemia and hemorrhage as a result of MTT-dependent inhibition of the ␥-carboxylation of glutamate. The structure of cefazolin also includes a heterocyclic thiol, 2-methyl-1,3,4-thiadiazole-5-thiol (MTD), and this compound can also inhibit the ␥-carboxylation of glutamate. However, unlike MTT, which is known to be present in vivo after the administration of drugs that include this structure, there have been no reports that MTD is present in vivo after cefazolin administration. We set out to determine whether MTD might be present in the tissues of patients treated with cefazolin prior to surgery. To do that, we took advantage of the fact that heterocyclic thiols can undergo S-methylation catalyzed by the genetically polymorphic drug-metabolizing enzyme thiopurine S-methyltransferase (TPMT). Initially, we tested recombinant human TPMT as a "reagent" to S-methylate MTD.MTD was a substrate for TPMT-catalyzed S-methylation, with an apparent K m value of 63 M. Recombinant TPMT, with [ 14 C-methyl]S-adenosyl-L-methionine as a cosubstrate, was then used to radioactively label a methyl acceptor substrate present in liver and kidney cytosol preparations from patients who had been treated preoperatively with cefazolin. Pooled renal cytosol from 10 of those patients was used to purify and isolate the methylated product by reverse-phase high-performance liquid chromatography. That methylated compound coeluted with S-methyl MTD. When the methylated product was subjected to tandem mass spectrometry, it was identified as S-methyl MTD. Therefore, MTD is present in the tissues of patients treated with cefazolin. These observations also raise the possibility that the TPMT genetic polymorphism may represent a risk factor for cefazolin-induced hypoprothrombinemia since subjects who genetically lack TPMT would be unable to catalyze this MTD biotransformation pathway.Cephalosporin antibiotics such as moxalactam, cefamandole, and cefoperazone can cause life-threatening hypoprothrombinemia and hemorrhage (Reddy and Bailey, 1980;Weitkamp and Aber, 1983;Dupuis et al., 1984;Lipsky, 1988). That adverse reaction is thought to be due to the in vivo release of a heterocyclic leaving group, 1-methyltetrazole-5-thiol (MTT 2 ), which is present in the structures of these drugs (Black et al., 1983;Lipsky, 1983, 1984. MTT inhibits the ␥-carboxylation of glutamic acid, a vitamin Kdependent reaction required for the formation of active clotting factors (Suttie, 1978). Hypoprothrombinemia has also been reported to occur, but much less frequently, after the administration of another cephalosporin, cefazolin (Lerner and Lubin, 1974;Clark et al., 1983;Dupuis et al., 1984). The structure of cefazolin also includes a heterocyclic sulfhydryl moiety, 2-methyl-1,3,4-thiaziazole-5-thiol (MTD) (Fig. 1A). MTD, like MTT, is a potent in vitro inhibitor of the ␥-carboxylation of glutamic acid (Kerremans et al., 1985;Li...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cefazolin Administration and 2-Methyl-1,3,4-Thiadiazole-5-Thiol in Human Tissue: Possible Relationship to Hypoprothrombinemia

Wood

Johnson²,

Naylor

et al. 2002

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…The hypoprothrombinemia in vitamin K-deficient female rats was caused by beta-lactam antibiotics with N-methyltetrazolethiol, thiadiazolethiol and methyl-thiadiazolethiol as the 3'-position substituent of the cephem nucleus. (1)(2)(3)(4)(5). Subsequent studies demonstrated that the antibiotics-induced hypoprothrombinemia was manifested only in vitamin K-deficient animals and not in rats fed an ordinary diet (6)(7)(8).…”

Section: Abstract-malementioning

confidence: 99%

Vitamin K-reversible hypoprothrombinemia in rats. I. Sex differences in the development of hypoprothrombinemia and the effects of beta-lactam antibiotics.

et al. 1988

View full text Add to dashboard Cite

“…have been reported to cause prolongation of bleeding time in patients with vitamin K deficiency (1) and sometimes bleeding in severe cases (2). In a previous study (3), we examined the effects of latamoxef (LMOX), cefamandole (CMD), carbenicillin (CBPC) and cefotaxime (CTX) on fibrinolytic activity in vitro and reported that these antibiotics showed no fibrinolytic but weak antifibrinolytic activity.…”

Section: Certain 3-lactam Antibioticsmentioning

confidence: 99%

Effects of antibiotics on fibrinolytic activity in vivo.

Okuno

Uchida

1987

Jpn.J.Pharmacol

View full text Add to dashboard Cite

Abstract-The effects of latamoxef, cefamandole, carbenicillin and cefotaxime on fibrinolytic system in rats were examined under feeding of an ordinary diet or a vitamin K-deficient diet for eight days. No obvious change was observed in UK induced plasma clot lysis time, euglobulin lysis time and antiplasmin level in plasma. These findings of the in vitro and ex vivo studies suggest that these antibiotics cause no enhancement of fibrinolytic activity.

show abstract

Prolonged bleeding times and bleeding diathesis associated with moxalactam administration

Cited by 49 publications

References 0 publications

Cefazolin Administration and 2-Methyl-1,3,4-Thiadiazole-5-Thiol in Human Tissue: Possible Relationship to Hypoprothrombinemia

Cefazolin Administration and 2-Methyl-1,3,4-Thiadiazole-5-Thiol in Human Tissue: Possible Relationship to Hypoprothrombinemia

Vitamin K-reversible hypoprothrombinemia in rats. I. Sex differences in the development of hypoprothrombinemia and the effects of beta-lactam antibiotics.

Effects of antibiotics on fibrinolytic activity in vivo.

Contact Info

Product

Resources

About