N-methylthiotetrazole Side Chain Research Articles

Cefoperazone-induced Coagulopathy in Critically Ill Patients Admitted to Intensive Care Unit.

N-methylthiotetrazole side chain (NMTT) of cefoperazone was attributed to inhibit the vitamin K epoxide enzyme. This mechanism is similar to warfarin; thus, vitamin K was suggested to antagonize the hematological effects of cefoperazone. The literature on critically ill patients receiving cefoperazone and its clinical significance on bleeding diathesis is sparse. To assess the incidence of cefoperazone-induced coagulopathy (CIC), its clinical impact on bleeding episodes, and transfusion requirements. Predisposing factors and the role of prophylactic and therapeutic vitamin K were evaluated. Prospective observational study of adult intensive care unit (ICU) patients (>18 years) receiving cefoperazone between December 2017 and December 2018. We excluded those on warfarin, those with preexisting elevated prothrombin time/international normalized ratio (PT/INR), and with bleeding manifestations. Relevant laboratory investigations and specific outcomes were noted for 6 days following therapy. Panel data regression was used to determine predictors of coagulopathy. Among 65 patients, 17 (26%) had probable CIC. Hypoalbuminemia and vancomycin co-administration were risk factors for CIC. Hemoglobin drops and blood transfusions were not different between INR non-elevated and elevated groups (11 vs 8 gm/dL; p = 0.06 and 11 vs 8 units; p = 0.23, respectively). Prophylactic vitamin K did not offer any benefit toward preventing INR elevation. Therapeutic vitamin K significantly reduced INR when elevated [absolute risk reduction (ARR):57.5% and number needed to treat (NNT):1.7]. Results of this study revealed that CIC is not uncommon in ICUs. Based on the findings of the study, we suggest INR monitoring in patients receiving nephrotoxic agents and patients with hypoalbuminemia. We also recommend vitamin K administration in patients with elevated INR. Gudivada KK, Krishna B, Sampath S. Cefoperazone-induced Coagulopathy in Critically Ill Patients Admitted to Intensive Care Unit. Indian J Crit Care Med 2023;27(3):183-189.

Comparison of interactions between warfarin and cephalosporins with and without the N-methyl-thio-tetrazole side chain

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.

Vitamin K deficiency in the patient with short bowel syndrome revealed after administration of Cefmetazole having N-methylthiotetrazole side chain

Vitamin K deficiency in the patient with short bowel syndrome revealed after administration of Cefmetazole having N-methylthiotetrazole side chain

The Association Between Cephalosporin and Hypoprothrombinemia: A Systematic Review and Meta-Analysis.

Cephalosporins that contain the N-methylthiotetrazole side chain (NMTT-cephalosporin) have been reported to be associated with coagulation-related adverse events; however, a comprehensive evaluation regarding the association is lacking. A systematic review and meta-analysis were conducted to assess the safety profile of NMTT-cephalosporins with respect to hypoprothrombinemia and bleeding. The MEDLINE, Embase, Cochrane, and RISS databases were systematically searched for clinical studies up to October 2018. The association between NMTT-cephalosporins and hypoprothrombinemia was estimated using an odds ratio (OR) with a 95% confidence interval (CI). A total of 15 studies on cefamandole, cefoperazone, cefotetan, cefmetazole, and moxalactam were identified and included in the meta-analysis. Hypoprothrombinemia (OR 1.676, 95% CI 1.275–2.203) and prothrombin time (PT) prolongation (OR 2.050, 95% CI 1.398–3.005) were significantly associated with NMTT-cephalosporins, whereas bleeding was not (OR 1.359, 95% CI 0.920–2.009). Subgroup analyses revealed that cefoperazone (OR 2.506, 95% CI 1.293–4.860), cefamandole (OR 3.247, 95% CI 1.083–9.733), and moxalactam (OR 3.367, 95% CI 1.725–6.572) were significantly associated with hypoprothrombinemia. An Antimicrobial Stewardship Program led by a multidisciplinary team could play a critical role in monitoring cephalosporin-related hypoprothrombinemia or PT prolongation in patients with underlying clinical conditions at risk for bleeding. The multidisciplinary team could also assist in communicating the potential safety concerns regarding NMTT-cephalosporin use with healthcare professionals to decrease the risk of adverse events.

Cephalosporin-Associated Hypoprothrombinemia: Case and Review of the Literature

Objective:To present a case of cefotetan-associated hypoprothrombinemia and to review the literature concerning cephalosporin-associated hypoprothrombinemia.Data Sources:Information was collected by conducting a MEDLINE search for cases, clinical trials, reviews, and other articles pertaining to cephalosporin use and the development of hypoprothrombinemia.Study Selection:Studies, cases, and letters were selected if they addressed the development of hypoprothrombinemia in cephalosporin-treated patients.Data Synthesis:A case of hypoprothrombinemia is described in an 82-year-old woman who received cefotetan for the treatment of a urinary tract infection. A review of the literature revealed more than 50 reported cases and multiple clinical studies evaluating this adverse effect. The postulated mechanism behind this occurrence is the inhibition of the synthesis of vitamin K-dependent clotting factors by the N-methyl-thiotetrazole (NMTT) moiety found in certain cephalosporin side chains. Risk factors associated with the development of this adverse effect include advanced age, renal and hepatic impairment, recent surgical procedures, malnutrition, and the use of H2-antagonists.Conclusions:Cephalosporins containing the NMTT side chain are associated with the development of hypoprothrombinemia and possibly bleeding, especially in high-risk patients.

Antibiotic-Associated Hypoprothrombinemia: A Review of Prospective Studies, 1966–1988

Many antimicrobial agents have been associated with hypoprothrombinemia. The precise mechanisms are unknown, but alteration in vitamin K status or utilization is involved. The two postulated mechanisms implicate either direct inhibition of biosynthesis of the vitamin K-dependent clotting factors by the N-methylthiotetrazole (NMTT) moiety found in certain antimicrobial agents or eradication of vitamin K-producing intestinal microflora in patients with reduced oral intake of vitamin K. An English-language review of all prospective studies reported between 1966 and 1988 in which serial prothrombin times were monitored in adult patients revealed that the incidence of hypoprothrombinemia varied from 3.7% to 64% with NMTT-containing regimens and from 0% to 24% with non-NMTT-containing regimens. Detailed evaluation of these and other studies suggests that certain risk factors, including malnutrition, hepatic and renal dysfunction, older age, and severity of illness, may be the major determinants of hypoprothrombinemia. The hypothesis that the NMTT side chain is primarily responsible for hypoprothrombinemia may not be justified. We conclude that patients at high risk for coagulopathy should be carefully monitored and that serious consideration should be given to the use of prophylactic vitamin K in such cases.

Effects of cefamandole on spermatogenic development of young CD rats

The testicular toxicity of cefamandole, a β-lactam antibiotic with an N-methylthiotetrazole side chain, was evaluated in neonatal rats. Cefamandole caused delayed maturity of the germinal epithelium of neonatal rats when given on Postpartum Days 6 through 36. In rats given daily subcutaneous injections of 1000 mg/kg during this period, the most mature germinal cells were acrosome phase spermatids, whereas control rats had spermatids in the maturation phase. In studies of specific developmental phases, the effect of 1000 mg/kg daily cefamandole was primarily on the initial waves of spermatogonia during the period of rapid development (Postpartum Days 4 through 13). In animals treated from birth to Postpartum Day 8 and evaluated sequentially on Postpartum Days 5 through 9, there were no morphologically discernible effects on the transformation of gonocytes to immature spermatogonia, but there were slight degenerative changes in the first waves of developing spermatogonia. Cefamandole, 1000 mg/kg daily, given Postpartum Days 14 through 18 during the initial phase of spermatocyte development, also caused a slight degenerative change of the initial waves of pachytene spermatocytes. The significance of the findings in neonatal rats is unknown because differences in spermatogenic development between rat and human preclude direct extrapolation of the effects of cefamandole in neonatal rats to effects in humans.

Spontaneous Reports of Bleeding: Comparison of N-Methylthiotetrazole Side Chain (MTT) and Non-MTT Cephalosporins

Journal Article Spontaneous Reports of Bleeding: Comparison of N-Methylthiotetrazole Side Chain (MTT) and Non-MTT Cephalosporins Get access Richard V. McCloskey Richard V. McCloskey Division of Infectious Diseases, Presbyterian-University of Pennsylvania Medical Center, Philadelphia, Pennsylvania PPlease address requests for reprints to Dr. Richard V. McCloskey, Presbyterian-University of Pennsylvania Medical Center, 51 North 39th Street, Philadelphia, Pennsylvania 19104. Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 158, Issue 6, December 1988, Page 1405, https://doi.org/10.1093/infdis/158.6.1405 Published: 01 December 1988

Cephalosporin-induced hypoprothrombinemia: is the N-methylthiotetrazole side chain the culprit?

The reported high incidence of vitamin-K-reversible hypoprothrombinemia associated with the new beta-lactamase-stable cephalosporins prompted us to evaluate the effect on hemostasis of three cephalosporins (cefamandole, ceftriaxone, and ceftazidime) in 30 patients with serious infections. Cefamandole and ceftriaxone, both containing a sulfhydryl group, induced a significant and similar prolongation of prothrombin time and decrease in factor VII activity. Ceftazidime, in contrast, had no effect on these two parameters.

An evaluation of the safety of cefuroxime axetil during six months oral administration to beagle dogs.

The effects of repeated oral administration of cefuroxime axetil were assessed in Beagles. The test material, an ester, is hydrolysed following absorption from the intestine to yield the therapeutically active moiety, cefuroxime, together with acetic acid and acetaldehyde; in this study cefuroxime and unhydrolyzed cefuroxime axetil were detected in the blood. Cefuroxime axetil was administered twice daily during 27 weeks by gavage of aqueous, suspensions, total daily doses were equivalent to 100, 400 or 1600 mg cefuroxime/kg/day. Apart from three cases of intercurrent illness, unrelated to treatment, the dogs remained in good health. Effects observed in the 1600 mg/kg group included vomiting and slight suppression of body weight gain. Minor variations in haematological measurements included rather low haemoglobin levels, packed cell volumes and erythrocyte counts. Slightly smaller numbers of neutrophils were thought to reflect reduced demand on normal defensive mechanisms due to continued antibiotic treatment. Prolongation of prothrombin time and activated partial thromboplastin time is attributed to disturbance of the intestinal microbial flora and reduced synthesis of vitamin K, on which the dog is highly dependent. Cefuroxime does not have the N-methylthiotetrazole side chain thought to be responsible for inhibition by other cephalosporins of the vitamin K-dependent step in the synthesis of clotting factors. Variations in plasma chemistry included rather low levels of plasma protein. Electrophoresis showed this to be a generalised reduction; only gamma globulins were proportionally decreased and this finding, like the low neutrophil counts, is attributed to the protective action of the antibiotic. Minor metabolic adjustments to the compound are reflected in plasma levels of cholesterol and triglycerides. This spectrum of findings was seen only to a very limited extent in the 400 mg/kg group; the 100 mg/kg group was, with very few exceptions, unaffected by the treatment. Macroscopic post mortem examination and microscopic examination of tissues revealed no treatment-related features indicative of toxicity. Cefuroxime axetil was thus shown to possess very little toxicity when administered repeatedly in large doses to Beagles. The lowest dose level in this study was ten times the proposed daily clinical dose in man.

Antimicrobial therapy in dialysis patients. I. Penicillins and cephalosporins.

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.