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

Abstract

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...

Coagulation disorders during treatment with cefazolin and rifampicin: rare but dangerous

“…In our department, specializing in the treatment of complex osteoarticular infections, we frequently prescribe cefazolin, combined or not with rifampicin, for prolonged durations (several weeks) and at high dose (60-80 mg/kg/24 h). Based on a retrospective series of 100 patients continuously infused with cefazolin for 42 d in our unit, combined with rifampicin for 29 patients, no serious hemorrhagic event was observed (Zeller et al, 2009). Over the last 20 years, this patient's major coagulation disorder was the only one observed in our unit.…”

“…Only a parenteral formulation is available. Its therapeutic utilization is broad and adverse events are rare (Zeller et al, 2009). Its tolerance is better than that observed for oxacillin.…”

“…Cefazolin has a 2-methyl-1,2,3-thiadiazol-5-thiol (MTD) group -not an MTT group (Wood et al, 2002) -which seems to have the same properties as vitamin-K antagonists (Angles et al, 2018). These effects would be enhanced in a context of renal insufficiency and when high doses are administered, leading to the accumulation of this active metabolite.…”

Comparison of the effects of cefazolin and ceftriaxone on canine chondrocyte culture

“…However, subtle differences in the chemical structure and pharmacokinetics of CEFs can influence their potential for cell toxicity and adverse effects (Perez‐Inestrosa et al., ; Thompson & Jacobs, ). Some CEFs contain N‐methyl‐thiotetrazole (N‐MTT) or N‐methyl‐thiadiazole (N‐MTD) in their structures (cef1 contains both MTT and MTD) (Figure ), with similar moiety and which release a heterocyclic living group as a metabolic by‐product that increases the potential for bleeding or hematologic toxicity and can cause hypoprothrombinemia (Kerremans, Lipsky, Van Loon, Gallego, & Weinshilboum, ; Thompson & Jacobs, ; Wood, Johnson, Naylor, & Weinshilboum, ). Moreover, clinical manifestations of neurotoxicity and encephalopathy induced by CEFs have been well documented (Grill & Maganti, ) and are attributed to decreased gamma aminobutyric acid (GABA) release and increased excitatory amino acid release, as well as inducing endotoxin release which generates cytokine (e.g., TNF‐α) release.…”

Peri-renal Hematoma after Intraperitoneal Cefazolin Treatment for Peritonitis

“…Cefazolin has occasionally been reported to cause coagulopathy. Thiopurine S- methyltransferase (TPMT) is the enzyme involved in the metabolism of MTD in humans (11). About 10% of Caucasians have intermediate TPMT activity, and 0.03% have TPMT deficiency, which might explain why adverse effects are relatively rare with cefazolin (12).…”