Cephalosporin Induced Bleeding Disorder

Cephalosporins are important antibiotics that are commonly used in the treatment of various infections and in the prophylaxis of surgical patients. Some cephalosporins (mox-alactam, cefamandole, and cefoperazone) have been reported to cause life-threatening hypoprothrombinemia and hemorrhage (152,153). The cause of cephalosporin-induced bleeding lies within the chemical structure of these drugs. Cephalosporins contain an 1-methyltetrazole-5-thiol (MTT) leaving group that undergoes S-methylation, which is catalyzed by thiopurine S-methyltranferase (TPMT). MTT has been shown to be the cause of hypoprothrombinemia and hemorrhage. MTT inhibits the gamma-carboxylation of glutamic acid, a vitamin K-dependent reaction required for the formation of active clotting factors (153-155). A recent study showed that 2-methyl-1,3,4-thiadiazole-5-thiol (MTD), a thiol found in the structure of cefazolin, is found in tissues of patients who were treated with cefazolin (156). MTD is also a substrate for S-methylation catalyzed by TPMT, and it is also an inhibitor of gamma carboxylation of glutamate in vitro (152).

TPMT is a genetically polymorphic drug-metabolizing enzyme specifically catalyzing the conjugation of aromatic and heterocyclic sulfhydryl compounds. Individual variation in S-methylation catalyzed by TPMT may be responsible for differences in susceptibility to cephalosporin-induced hypoprothrombinemia (153). Those individuals who have genetically low or absent TPMT and can therefore not effectively catalyze S-methylation may be more prone to develop adverse events. A trimodal distribution of TPMT activity has been shown in a large randomly selected population, with 89% of the subjects having the homozygous trait with high TPMT activity, 11% heterozygous with intermediate activity, and approximately 1 in 300 subjects homozygous for the trait of low or absent TPMT activity (157). Similar TPMT polymorphic patterns have been observed in Caucasians and Black subjects, with 17% lower TPMT activity in Blacks (158). The functional gene of TPMT has now been cloned and was localized on chromosome 6. At least eight variant alleles that are associated with low levels of TPMT enzyme activity have been characterized (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C, TPMT*3D, TPMT*4, TMPT*5, and TPMT*6). TPMT*2 is a relatively rare allele (159,160), and TPMT*3A is the most common variant allele in Caucasians, accounting for 55-57% of all variant forms of TPMT. The mechanism responsible for low TPMT activity in variant alleles *2, *3A, *3B, and *3C has been shown to be the reduced levels of TPMT immunoreactive protein due to enhanced protein degradation (161), and for TPMT*4 it is due to very low mRNA levels (162). Differences in the level of TPMT activity have also been found to depend on ethnicity, gender, and age; however, the mechanisms underlying these findings are not clear (163). Patients with genetically low or absent TPMT who are treated with cephalosporin antibiotics may be at risk of developing hypoprothrombi-nemia and hemorrhage as a result of the inability to S-methylate MTT and MTD.

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