Taurolidine

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Taurolidine
200px
Identifiers
19388-87-5 YesY
ChemSpider 27486 N
Jmol 3D model Interactive image
PubChem 29566
UNII 8OBZ1M4V3V YesY
  • InChI=1S/C7H16N4O4S2/c12-16(13)3-1-10(5-8-16)7-11-2-4-17(14,15)9-6-11/h8-9H,1-7H2 N
    Key: AJKIRUJIDFJUKJ-UHFFFAOYSA-N N
  • InChI=1/C7H16N4O4S2/c12-16(13)3-1-10(5-8-16)7-11-2-4-17(14,15)9-6-11/h8-9H,1-7H2
    Key: AJKIRUJIDFJUKJ-UHFFFAOYAI
  • C1CS(=O)(=O)NCN1CN2CCS(=O)(=O)NC2
Properties
C7H16N4O4S2
Molar mass 284.35 g·mol−1
Pharmacology
ATC code B05CA05
Vapor pressure {{{value}}}
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Taurolidine ([bis(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)-methane) is an active pharmaceutical ingredient (API) with antimicrobial and anti-lipopolysaccharide properties. Derived from the amino acid taurine, its immuno modulatory action is reported to be mediated with priming and activation of macrophages and polymorphonuclear leukocytes.[1]

Taurolidine has been used to treat patients with peritonitis and as an antiendoxic agent in patients with systemic inflammatory response syndrome. It is a live-saving antimicrobial for severe abdominal sepsis and peritonitis. For severe surgical infections and use in surgical oncology Taurolidine is active against a wide range of micro- organisms that include gram positive bacteria, gram negative bacteria, fungi, mycobateria and also bacteria that are resistant to various antibiotics such as MRSA, VISA, VRSA, ORSA and VRE.[2] Additionally, taurolidine demonstrates some anti-tumor properties, with positive results seen in early-stage clinical investigations using the drug to treat gastrointestinal malignancies and tumors of the central nervous system.[3]

Taurolidine is the active ingredient of anti-microbial catheter lock solutions for the prevention and treatment of catheter related blood stream infections (CRBSIs)[4][5][6][7][8][9] and is suitable for use in all catheter based vascular access devices. Bacterial resistance against taurolidine has never been observed in various studies.[10]

Taurolidine acts by a non selective chemical reaction. In aqueous solution, the parent molecule taurolidine forms equilibrium with taurultam and N-hydroxymethyl taurultam, with taurinamide being a downstream derivative.

The active principle of taurolidine are N-methylol derivatives of taurultam and taurinamide, which react with the bacterial cell wall, cell membrane, proteins as well as with the primary amino groups of endo- and exotoxins. Microbes are killed and the resulting toxins are inactivated; the destruction time in vitro is 30 minutes.

Pro-inflammatory cytokines and enhanced TNF-α levels are reduced when used as a catheter lock solution.[11]

Taurolidine decreases the adherence of bacteria and fungi to host cells by destructing the fimbriae and flagella and thus prevent the biofilm formation.

Dose of 5g over 2 hours every 4 hours for at least 48 hours were given intravenously for the treatment of various sepsis condition.[12]

Pharmacokinetic properties

Absorption is rapid, with maximum concentrations of taurultam occurring between 10 and 15 minutes, and the half-life being less than one hour. Maximum plasma taurinamide concentration occurs between 0.5 and 2 hours, and the Taurolidine is metabolised with a short half-life to taurine, carbon dioxide and water. Elimination half-life lies between 5 and 5.5 hours. Urinary estimations show excretion of taurinamide accounts for 25% of the Taurolidine dose.

Pharmacodynamic properties

Following administration of taurolidine, the bactericidal and antiendotoxin activity of the taurolidine molecule is conferred by the release of three active methylol (hydroxymethyl) groups as taurolidine is rapidly metabolized by hydrolysis via taurultam and methylol taurultam to methylol taurinamide and taurine. These labile methylol groups react with the bacterial cell-wall resulting in lysis of the bacteria, and by inter- and intramolecular cross-linking of the lipopolysaccharide-protein complex, neutralization of the bacterial endotoxins which is enhanced by enzymatic activation.[13] This mechanism of action is accelerated and maximised when Taurolidine is pre-warmed to 37 °C. Taurolidine inhibits the formation of postoperative adhesions, and in vitro has been shown to reduce the adherence of micro-organisms to mucosal epithelium.

The chemical mode of action of taurolidine via its reactive methylol groups confers greater potency in vivo than indicated by in vitroMIC (minimum inhibitory concentration) values, and also appears to preclude susceptibility to resistance mechanisms.

Taurolidine is highly active against the common infecting pathogens associated with peritonitis; this activity extends across a wide-spectrum of aerobic/anaerobic bacteria and fungi (with no diminution of effect in the presence of biological fluids, e.g. blood, serum, pus.

Contraindications

Taurolidine should not be used systemically in neonates, infants and children under 10 years of age. Taurolidine should be used with caution in patients with renal impairment for systemic use.

Pregnancy and Breastfeeding

Taurolidine has shown no evidence of teratogenicity in animal studies, but administration to pregnant women should only be undertaken if the clinician considers it essential.

Side effects

No systemic side effects have been identified. The safety of taurolidine has also been confirmed in clinical studies with long-term intravenous administration of high doses (up to 20 g daily). In the body, taurolidine is metabolized rapidly via the metabolites taurultam and methylol taurinamide, which also have a bactericidal action, to taurine, an endogenous aminosulphonic acid, CO2 and H2O. Therefore, no toxic effects are known or expected in the event of accidental injection.[12]

Catheter lock solution in hemodialysis (HD)

The combination of taurolidine with the anticoagulant citrate (4%) and Heparin (500IU/mL) may help to decrease the incidence and occurrence of catheter-related blood stream infections (CRBSI) in hemodialysis patients (HD).[11][14][17][19][20][21][22]

Catheter lock solution in oncology

Catheter-or port-a-cath-related bloodstream infections are a common problem in cancer patients. The use of taurolidine/citrate lock solution is associated with a significant reduction in bloodstream infections in immune compromised (pediatric) patients.[23][24][25][26][27]

Catheter lock solution in home parenteral nutrition (HPN) / total parenteral nutrition (TPN)

CRBSI remains the most common serious complication associated with long-term parenteral nutrition HPN/TPN. The use of taurolidine/citrate as a catheter lock solution shows a significant reduction of CRBSI in adult patients and in pediatric patients.[28][29][30][31][32][33][34][35][36]

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Liu H., Liu H., Deng J., Chen L., Yuan L., Wu Y. (2014). Preventing Catheter-Related Bacteremia with Taurolidine-Citrate Catheter Locks: A Systematic Review and Meta-Analysis. Blood Purif 37: 179-187
  5. ↑ Liu Y., Zhang A.-Q., Cao L., Xia H.-T., Ma J.-J. (2013). Taurolidine Lock Solutions for the Prevention of Catheter-Related Bloodstream Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLOS ONE 8(11): e79417. doi:10.1371/journal.pone.0079417
  6. ↑ Mermel LA. (2001). New technologies to prevent intravascular catheter-related bloodstream infections. Emerg Infect Dis. Mar-Apr; 7(2): 197–9
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Bouza E.,et al. (2004) . A European perspective on intravascular catheter-related infections: report on the microbiology workload, aetiology and antimicrobial susceptibility (ESGNI-005 Study). Clin. Microbiol. Infect.10: 838–42.
  10. ↑ Olthof E.D., Rentenaar R.J., Rijs A.J.M.M., Wanten G.J.A. (2013). Absence of microbial adaption to taurolidine in patients on home parenteral nutrition who develop catheter related bloodstream infections and use taurolidine lock. Clin Nutr 32: 538-542
  11. ↑ 11.0 11.1 Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ 12.0 12.1 Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ • Waser P.G., Sibler E. et al. (1985). Pharmakologie und Toxikologie von Taurolin. In: Taurolin – Ein neues Konzept zur antimikrobiellen Chemotherapie chirurgischer Infektionen. Hrsg.: Brückner W.L. und Pfirrmann R.W., Urban & Schwarzenberg Verlag.
  14. ↑ 14.0 14.1 Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ 17.0 17.1 Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ V. Filiopoulos, D. Hadjiyannakos, I. Koutis, S. Trompouki, T. Micha, D. Lazarou, D. Vlassopoulos (2011). Approaches to Prolong the Use of Uncuffed Hemodialysis Catheters: Results of a Randomized Trial, Am J Nephrol; 33: 260-268.
  20. ↑ Solomon LR., Cheesbrough JS., Bhargava R., Mitsides N., Heap M., Green G., Diggle P. (2012). Observational Study of Need for Thrombolytic Therapy and Incidence of Bacteremia using Taurolidine-Citrate-Heparin, Taurolidine-Citrate and Heparin Catheter Locks in Patients Treated with Hemodialysis, Seminars in Dialysis; 25(2), 233-238.
  21. ↑ R. Zwiech, M. Adelt, S. Chrul (2013). A Taurolidine-Citrate-Heparin Lock Solution Effectively Eradicates Pathogens From the Catheter Biofilm in Hemodialysis Patients, Amer J Therap.
  22. ↑ Murray E.C., Deighan C., Geddes C., Thomson P.C. (2014). Taurolidine-citrate-heparin catheter lock solution reduces staphylococcal bacteraemia rates in haemodialysis patients. QJMed2014
  23. ↑ Haag G.-M., Berger A.-K., Jäger D. (2011). Treatment of long-term catheter related bloodstream infections with taurolidine block: a single cancer center experience, J Vasc Access 12, 244-247
  24. ↑ Querfeld U., Dümichen M. J., Seeger K., Lode H. N., Kühl J. S., Ebell W., Degenhardt P., Singer M., Geffers C. (2012). Randomized controlled trial of taurolidine-citrate versus heparin as catheter lock solution in paediatric patients with hematologic malignancies, J Hosp Infect 80, 304-309
  25. ↑ Handrup M. M., Fuursted K., Funch P., Moeller J. K., Schroeder H. (2012). Biofilm formation in long term central venous catheters in children with cancer: a randomized controlled open-labelled trial of taurolidine versus heparin, APMIS 120: 794-801
  26. ↑ Schroeder H., Handrup M. M., Moller J. K. (2013). Central venous catheters and catheter locks in children with cancer: a prospective randomized trial of taurolidine versus heparin, Pediatr. Blood Cancer 60: 1292-1298
  27. ↑ Ince E., Oğuzkurt P., Temiz A., Ezer S. S., Özkan Gezer H., Yazici N., Hiçsönmez A. (2014). Complications of total implantable access ports and efficacy of Taurolidine-citrate lock solution against catheter-related infections, Afr J Paediatr 11: 138-142
  28. ↑ Bradshaw J. H., Puntis J. W. L. (2008). Taurolidine and Catheter-related Bloodstream Infections: A Systematic Review of the Literature, J Pediatr Gastroenterol Nutr 47, 179-186
  29. ↑ Cullis P. S., McKee R. F. (2011). Taurolidine Lock – Experience from the West of Scotland, Clin Nutr 30: 399-400
  30. ↑ Chu H.-P., Brind J., Tomar R., Hill S. (2012). Significant Reduction in Central Venous Catheter-related Bloodstream Infections in Children on HPN After Starting Treatment with Taurolidine Line Lock, JPGN 55, 403-407
  31. ↑ Toure A., Lauverjat M., Peraldi C., Boncompain-Gerard M., Gelas P., Barnoud D., Chambrier C. (2012). Taurolidine Lock solution in the secondary prevention of central venous catheter-associated bloodstream infection in home parenteral nutrition patients, Clin Nutr. 31, 567-570
  32. ↑ Olthof D., Rentenaar R. J., Rijs A. J. M. M., Wanten G. J. A. (2013). Absence of microbial adaption to taurolidine in patients on home parenteral nutrition who develop catheter related bloodstream infections and use taurolidine lock, Clin Nutr 32, 538-542
  33. ↑ Diamanti A., Capriati T., Iacono A. (2014). Recurrent catheter related bloodstream infections by Candida glabrata: Successful treatment with taurolidine, Clin Nutr 33, 367
  34. ↑ Saunders J., Naghibi M., Leach Z., Parsons C., King A., Smith T., Stroud M. (2014). Taurolidine locks significantly reduces the incidence of catheter-related blood stream infections in high-risk patients on home parenteral nutrition, Eur J Clin Nutr 2014.
  35. ↑ Al-Amin H., Sarveswaran J., Wood J. M., Burke D. A., Donnellan C. F. (2013). Efficacy of taurolidine on the prevention of catheter-related bloodstream infections in patients on home parenteral nutrition, J. Vasc. Access 14: 379-382
  36. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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