1-n-methyl-5-thiotetrazole and Hemorrhage

Several new beta-lactam antibiotics impair normal hemostasis. Hypoprothrombinemia has occurred frequently with cephalosporins that possess a methylthiotetrazole substitution (cefamandole, moxalactam, and cefoperazone). The incidence ranges from 4% to 68%, and the risk is greatest in debilitated patients with cancer, intra-abdominal infection, or renal failure. Impaired platelet function caused by perturbation of agonist receptors on the platelet surface has occurred primarily with beta-lactam antibiotics having an alpha-carboxyl substitution (moxalactam, carbenicillin, and ticarcillin). These antibiotics often cause the template bleeding time to be markedly prolonged (greater than 20 minutes). Acylureidopenicillins, which lack the alpha-carboxyl marker, impair platelet function less frequently and only modestly prolong the bleeding time. If serious hemorrhage occurs, hypoprothrombinemia associated with methylthiotetrazole-substituted cephalosporins should be treated with fresh frozen plasma. Likewise, dangerous bleeding due to impaired platelet aggregation requires treatment with platelet concentrates.

Topics: Anti-Bacterial Agents; beta-Lactams; Hemorrhage; Humans; Hypoprothrombinemias; Platelet Aggregation; Risk; Tetrazoles; Vitamin K

A prospective surveillance program was initiated to determine the relative role of antibiotics containing N-methylthiotetrazole (NMTT) versus patient risk factors in producing antibiotic-associated bleeding. Five hundred forty-six critically ill patients with serum albumin 30 g/L or below were evaluated for evidence of a bleeding event as documented by clinical observation, hemoglobin changes, and transfusions. Bleeding events occurred in 16% of patients receiving an aminoglycoside combination, 10% receiving antibiotics with the NMTT side chain, and 14.5% receiving antibiotics not containing NMTT (p greater than 0.05). The bleeding rate was highest in febrile patients with cancer (14.5%) and lowest in those with a suspected or documented abdominal infection (10%) (p = 0.04), but within each patient group there was no difference among the antibiotics. We conclude that the use of NMTT-containing antibiotics is not an independent risk factor for bleeding, but the role of severity of illness may be underappreciated.

Topics: Abdomen; Adolescent; Adult; Aminoglycosides; Anti-Bacterial Agents; Bacterial Infections; Critical Illness; Fever; Hemorrhage; Humans; Neoplasms; Prospective Studies; Risk Factors; Serum Albumin; Tetrazoles

Cephalosporins with an N-methyl-thio-tetrazole (NMTT) side chain interact with warfarin by reducing the production of blood clotting factors. However, cephalosporins without the NMTT side chain also enhance the effects of warfarin. Thus, we aimed to compare the effects of warfarin modified by cephalosporins with and without the NMTT side chain, using a Japanese health insurance claims database. The inclusion criteria were patients who (1) intravenously received second- or third-generation cephalosporins between April 2010 and March 2017 and (2) received warfarin during cephalosporin therapy. Patients were administered either cephalosporins with the NMTT side chain (NMTT group) or those without NMTT (non-NMTT group). After matching patient data by propensity score, the following outcomes were compared between the two groups: (1) proportion of patients administered vitamin K, (2) proportion of bleeding events, and (3) changes in the daily dose of warfarin. Among 203 patients, 100 patients (50 per group) were matched by the propensity score. The proportion of patients administered vitamin K was 6.0% in both groups. These patients intravenously received a single dose of menatetrenone; no bleeding was observed. The proportion of patients subjected to a reduction in the daily dose of warfarin was 6.5% and 4.3% in the NMTT and non-NMTT groups, respectively. As our study had a small sample size, we could not determine whether the risk of over anticoagulation of warfarin is affected by cephalosporins with or without NMTT side chain. However, we showed the bleeding risk was sufficiently low regardless of the presence/absence of the NMTT side chain.

Topics: Anticoagulants; Cephalosporins; Hemorrhage; Humans; Tetrazoles; Vitamin K; Warfarin

Antibiotic therapy, using penicillins or cephalosporins, is frequently required in patients on maintenance hemodialysis. Points to consider are dose adjustment for drugs which are excreted via the kidney, drug dialysability, and cumulation with frequent occurrence of side reactions, neurotoxicity and bleeding being the clinically most important ones. For third-generation cephalosporins with N-methylthiotetrazole side chain, impaired intrahepatic vitamin K metabolism may cause problems of hemostasis which can be avoided by dose adjustment and prophylactic administration of vitamin K1.

Topics: Bacterial Infections; Body Weight; Cephalosporins; Dose-Response Relationship, Drug; Drug Administration Schedule; Hemorrhage; Humans; Kidney Failure, Chronic; Kinetics; Penicillin Resistance; Penicillins; Renal Dialysis; Tetrazoles; Vitamin K 1

1-Methyl-5-thiotetrazole (NMTT), a metabolite of moxalactam (MoxamR), was studied for its potential inhibition of vitamin K-dependent carboxylation. The assay system utilized a detergent solubilized rat liver microsomal preparation. Vitamin K1H2 was artificially produced in situ by the NADH-dependent reduction of exogenous phylloquinone and the resultant carboxylation monitored by 14CO2 incorporation into a soluble peptide substrate. Warfarin, used as a reference inhibitor, gave results expected from the literature - 50% inhibition at a pharmacologically excessive level of 1.0 mM. Carboxylation was unaffected by 1.0 mM NMTT and was marginally (0-14%) diminished by 5.0 mM NMTT. Carboxylation was 25% diminished at 10.0 mM NMTT, a concentration far above that achieved in human testing of moxalactam. When NMTT was pre-incubated with the liver microsomal carboxylase enzyme preparation, 10.0 mM NMTT again caused merely a 25% diminution of carboxylation in the assay. These results do not support a role for NMTT as an inhibition of Vitamin K-dependent carboxylation which would produce pharmacological side effects during moxalactam therapy. During these studies it was found that dramatic consumption of NADH occurs in the presence of liver microsomal preparations (independent of vitamin K and of NMTT) and that NMTT effects on these processes may explain the small carboxylation diminution observed at 10.0 nM NMTT in the carboxylase assay.

Topics: Animals; Azoles; Carbon-Carbon Ligases; Hemorrhage; Humans; In Vitro Techniques; Ligases; Male; Microsomes, Liver; Moxalactam; Rats; Rats, Inbred Strains; Tetrazoles; Warfarin