Bleeding in Patients With Infections

Hochman, Rodney F.

doi:10.1001/archinte.1982.00340210032005

Cited by 28 publications

(3 citation statements)

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“…The mechanism for the hypoprothrombinemia is in dispute. One hypothesis is that these antibiotics, which are secreted in the bile, destroy intestinal bacteria which produce vitamin K, a necessary cofactor in the synthesis offour of the clotting factors (4). Another theory is that the MTT which is released from the intact antibiotic is able to inhibit gamma carboxylation of glutamic acid (7,11), the vitamin K-dependent step in the synthesis of the clotting factors.…”

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confidence: 99%

Production of hypoprothrombinemia by moxalactam and 1-methyl-5-thiotetrazole in rats

Lipsky¹,

Lewis²,

Novick³

1984

Antimicrob Agents Chemother

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To determine whether the hypoprothrombinemia associated with antibiotics containing a 1-methyl-5-thiotetrazole (MUT) group is a result of the presence of the MUT group, rats were maintained on a vitamin K-deficient diet for 10 days and then received either intravenous moxalactam or cefotaxime or oral MUT for two additional days. MUT and moxalactam, which contains the MUT group, prolonged prothrombin time. Cefotaxime, which lacks the MUT group, had no effect.The use of beta-lactam antibiotics which contain a 1-methyl-5-thiotetrazole (MUT) group has been associated with the development of hypoprothrombinemia in humans. These antibiotics include cefamandole (5), cefoperazone (9), and moxalactam (8). The mechanism for the hypoprothrombinemia is in dispute. One hypothesis is that these antibiotics, which are secreted in the bile, destroy intestinal bacteria which produce vitamin K, a necessary cofactor in the synthesis offour of the clotting factors (4). Another theory is that the MTT which is released from the intact antibiotic is able to inhibit gamma carboxylation of glutamic acid (7,11), the vitamin K-dependent step in the synthesis of the clotting factors. This hypothesis is supported by the observation that MUT inhibits the gamma carboxylation of glutamic acid in an in vitro rat liver microsomal system (6). To test the in vivo relevance of this finding, we examined the effects of moxalactam, cefotaxime, and MTT in rats maintained on a vitamin K-free diet. Moxalactam contains the MTT group; cefotaxime does not (Fig. 1) Both moxalactam and MTT produced hypoprothrombinemia in rats maintained on vitamin K-deficient diets for 10days. There was a three-to fourfold prolongation of prothrombin time within 48 h of the first dose of these drugs (Table 1).* Corresponding author. 380The ability of cefotaxime, a drug which does not contain the MTT group, to produce hypoprothrombinemia was examined and compared with that of moxalactam. Cefotaxime was not able to produce a prolongation of the prothrombin time, but under the same conditions, moxalactam again increased the prothrombin time over fivefold (Table 2). Three animals in the moxalactam group died (two of hemorrhage) before the third prothrombin time determination.The results of these experiments indicate that MTT and moxalactam containing MUT in its structure are capable of producing hypoprothrombinemia in vivo. Cefotaxime, which does, not possess an MUT group, did not produce hypoprothrombinemia. Previous studies by others of rats on normal diets given doses of moxalactam up to 2.7 g/kg did not reveal any evidence of hypoprothrombinemia (12). The vitamin K-deficient diet used in our studies was chosen because a lack of vitamin K intake may be a contributing or necessary factor for humans to become hypoprothrombinemic while on MUT-containing antibiotics. Our use of rats on vitamin K-deficient diets may resemble the clinical situation, in which it appears that lack of oral intake of food, and thus possible decreased intake of vitamin K, may be a predisposing condition ...

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confidence: 99%

Production of hypoprothrombinemia by moxalactam and 1-methyl-5-thiotetrazole in rats

Lipsky¹,

Lewis²,

Novick³

1984

Antimicrob Agents Chemother

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“…Haemorrhagic states can be caused by a number of commonly used antibiotic agents. 5 However, current reports suggest that the newer cephalosporins, including cephamandole and the oxo-beta-lactam, latamoxef, have an increased potential to cause bleeding. T here are numerous reports of coagulopathies associated with the newer cephalosporins, cefoperazone and cephamandole, and the oxo-beta-lactarn, latamoxef, in the overseas literature.…”

Section: Discussionmentioning

confidence: 99%

Antibiotic‐induced hypoprothrombinaemia

Sanburg

Hughes

Nichols

1985

Medical Journal of Australia

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“…Some investigators have speculated that the effect is related to alterations in colonic flora which result in vitamin K deficiency (2). Another hypothesis is that these drugs inhibit the vitamin K-dependent step in clotting factor synthesis, the y-carboxylation of glutamic acid (3,4).…”

Section: Introductionmentioning

confidence: 99%

Cephalosporin-induced alteration in hepatic glutathione redox state. A potential mechanism for inhibition of hepatic reduction of vitamin K1,2,3-epoxide in the rat.

1990

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Hypoprothrombinemia is a serious adverse effect of antimicrobial therapy that occurs after administration of some second-and third-generation cephalosporins which contain the methyltetrazole-thiol (MTT) group. Previous studies have shown that in vitro MTT directly inhibits microsomal y-carboxylation of a synthetic pentapeptide. Since MTT is a thiocarbamide, a type of compound that can increase oxidation of glutathione, the present studies were carried out to determine whether alterations in hepatic glutathione redox state might interfere with vitamin K metabolism.Dose-related increases in biliary efilux and hepatic concentration of oxidized glutathione (GSSG) occurred after intravenous administration of MIT or MUTT-containing antibiotics to rats. This finding suggested that these compounds could alter the hepatic glutathione redox state in vivo. Microsomal reduction of vitamin K epoxide occurred in the presence of 100 MM dithiothreitol (DTI), but was inhibited by preincubation with GSSG at concentrations as low as 10 ;&M. At higher concentrations of DTT (1.0 mM) inhibition by GSSG persisted, but higher concentrations were required, suggesting that the thiol/disulfide ratio, rather than the absolute concentration of GSSG was important. By contrast, GSSG did not effect microsomal "y-carboxylation of a pentapeptide, using either vitamin K1 or its hydroquinone as a cofactor. These findings suggest a novel mechanism for the hypoprothrombinemia occurring after administration of MTT-containing antibiotics. (J. Clin. Invest. 1990Invest. . 86:1589Invest. -1594

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Bleeding in Patients With Infections

Cited by 28 publications

References 10 publications

Production of hypoprothrombinemia by moxalactam and 1-methyl-5-thiotetrazole in rats

Production of hypoprothrombinemia by moxalactam and 1-methyl-5-thiotetrazole in rats

Antibiotic‐induced hypoprothrombinaemia

Cephalosporin-induced alteration in hepatic glutathione redox state. A potential mechanism for inhibition of hepatic reduction of vitamin K1,2,3-epoxide in the rat.

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