TauroSept ®

1. TauroSept® Maria Scheuermann DDS MPH Medical Advisor

2. TauroSept® • What are Catheter Related Blood Stream Infections (CRBSI)? • How much do they cost our health care? • What is TauroSept®? • How can TauroSept® be used against CRBSI?

3. What are Catheter Related Blood Stream Infections (CRBSI)?

4. Number of catheters used per year • US 3 million CVCs • Germany 1,75 million CVCs • France 1 million CVCs • Italy 0.5 million CVCs • UK 0.24 million CVCs Tacconelli E et al. Epidemiology, medical outcomes and costs of catheter- related bloodstream infections in intensive care units of four European countries: literature- and registry-based estimates The Lancet conferences, CDC/gov

5. Catheters • Venous access is important for1. Parenteral nutrition and hydration2. Haemodialysis3. Chemotherapy4. Analgesic therapy5.Treatment of infections6. Repetitive laboratory sample taking • Different kind of catheters 1. Central venous catheters2. Port-a-cath3. Peripherally inserted central catheters (PICC)

6. Catheter Related Blood Stream Infections Haematogenous Intra luminal Extra luminal Transmissionroutes for CRBSI

7. Pathophysiology W.R.Jarvis, M.D. Community and Hospital Infection Control Association (CHICA) Feb 24, 2009

8. External transmission routes for CRBSI • Nosocomial Infections (hospital-acquired infection) 1. Direct contact transmission (infected hands) 2. Indirect contact transmission (needles, vials, catheter) 3. Droplet transmission (coughing, sneezing, talking) 4. Airborne transmission (droplets, dust, particles) 5. Common vehicle transmission (food, water, medications, devices and equipment)

9. Infectiousorganisms • Coagulase-negative Staphylococcus eg. S. epidermidis • Enterococcus (VRE) • Staphylococcus aureus (MRSA) • Pseudomonas • Yeasts eg. Candida albicans • Enterobacter • Klebsiella • Corynebacterium • Escherichia coli

10. Incidence of CRBSI KISS (2008) Raisin (2007) NHSN (2008) Shapey et al. NAO (2009) E. Tacconelli et al. Journal of Hospital Infection (2009) CDC/gov

11. Clinical Facts • ICU-acquired bloodstream infections (BSI) occurred on average in 3.0 % (mean of ICU cumulative incidences 3.2 %; median 2.4 %) of patients staying more than two days in the ICU. • Bloodstream infections were catheter-associated (defined as a primary bloodstream infection with central line use in the 48 hours preceding the infection) in 56 %. • Central venous catheter annually cause hundreds of thousands of bloodstream infections (BSI) all over the world, resulting in thousands of deaths. Annual epidemiological report on communicable diseases 2009 SURVEILLANCE REPORT European Centre for Disease Prevention and Control, WHO (Patient safety program)

12. Mortality Cdc/gov, Tacconelli T et al. Epidemiology, medical outcomes and costs of catheter-related bloodstream infections in intensive care units of four European countries: literature-and registry-based estimates

13. Annual costs related to CRBSI NHS Litigation Authority 2008, CDC/gov, Raisin, KISS,

14. Government’s and organization’s emphasis on patient security • “the cost of CVC-associated BSI is substantial”. “To improve patient outcome and reduce health-care costs, strategies should be implemented to reduce the incidence of these infections. This effort should be multidisciplinary,” (CDC U.S.) • World Alliance for Patient Safety was established in 2004, Central venous catheter annually cause hundreds of thousands of bloodstream infections (BSI) all over the world, resulting in thousands of deaths. Preventing bloodstream infections from central line venous catheters is a new project (WHO)

15. Whatis TauroSept®?

16. Introduction TauroSept®, a catheter lock solution for the treatment and prevention of catheter sepsis, is a medical device according to EC Directive 93/42/EEC

17. Introduction Taurolidin [bis-(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)methane] is a derivative of the non-essential aminoethyl-sulphonic acid taurine. Empirical formula: C7H16N4O4S2 Molecular weight: 248.37 Description: white, crystalline, odourless substance Solubility: approx. 2% in water, pH-value of the aqueous solution 6.9 – 7.0 pH of TauroSept®: 7.0 – 7.6

18. Background • The commercial solutions Taurolin® and TauroSept® contain 2% Taurolidin and 5% Povidone (Polyvinylpyrrolidone, PVP) as stabiliser. • In aqueous solution, taurolidin forms an equilibrium with taurultam and N-hydroxymethyl taurultam, with taurinamide being a downstream derivative. This equilibrium has been reported to be mainly on the side of taurultam and N-hydroxymethyl taurultam, so that taurolidin is estimated to exist in low concentrations (2-10%) in aqueous solution.

19. Mode of action and metabolism of taurolidine

20. Mechanism of action - general • In contrast to most antibiotics Taurolidin acts by a non selective chemical reaction • The active principle of the Taurolidin molecule are methylol derivatives of Taurultam and Taurinamide, which react with the bacterial cell wall as well as with primary amino groups (LPS) of endo- and exotoxins • Pro-inflammatory cytokines and enhanced TNF-α levels are reduced • Elimination half-life in plasma for Taurultam is 2 h and 5h for Taurinamide

21. Mechanism of actionanti-adherence • Adherence of pathogens and biofilm formation is inhibited due to destruction of the fimbriae and flagella • Decreasesadherence of bacteria and fungi to host cells, maximum reduction of adherence with concentrations < 0.5% W/V Taurolin® Cells of E. Coli before exposure to Taurolin Cells of E.Coli after exposure to 2% Taurolin

22. Treatment time and concentration of TaurolinGorman, S. P., D. F. McCafferty, et al. (1987).

23. Mechanism of action anti-bacterial • The methylol derivatives of Taurultam and Taurinamide react irreversibly with the mesh- like Peptidoglycan (murein) of the cell wall • Fimbriae and flagellae of Gram(-) bacteria are first compressed along the cell surface and then reduced • The ability to divide is limited • The cell form of Gram (-) bacteria is first elongated and then dissolved. • The spherical cell wall structure of Gram(+) bacteria is immediately dissolved • The killing time is >30 minutes

24. Antimicrobial spectrum

25. Antimicrobial spectrum Bacterial resistance against taurolidin has never been observed and is unlikely to occur because of the mechanism of action of taurolidin, i.e. chemical reaction with cell wall. • Taurolidine is active against: • MRSA (Methicillin resistant Staph. aureus), including CA-MRSA • VRE (Vancomycin resistant Enterococci) • VISA (Vancomycin intermediate susceptible Staph. aureus) • VRSA (Vancomycin resistant Staph. aureus)

26. Mechanism of action anti-toxin • Highly toxic Bacteria endotoxins Lipopolysaccharides (LPS) found in the outer membrane of various Gram (-) bacteria are deactivated by cross linking with methylol derivatives of Taurultam and Taurinamide • Polypeptide exotoxins attached by receptors to the bacteria (eg. S.aureus) cell wall, equally cross link with methylol derivatives over - OH groups which alters the toxic property of the exotoxins. • Antibiotic-induced endotoxins are inactivated by Taurolin; no Herxheimer reaction • Taurolin slowly destroys the bacteria and simultaneously inactivates the endo- and exotoxins irreversibly when released

27. TauroSept® 6 ml and 10 ml

28. How can TauroSept®be used against CatheterRelated Blood Stream Infections (CRBSI)?

29. Indications for TauroSept® • For intensive care and other patients who are using singular or permanent intracorporal silicone or polyurethane central-based devices for • Parenteral nutrition (TPN-HPN) • Haemodialysis • Oncology • Port catheter systems (e.g. Port-a-Cath) • TauroSept® is meant to be used as a catheter lock solution (CLS). It can be used daily and repeatedly for months and is to be instilled into the device before and at the termination of a catheter session. It should be withdrawn prior to initiating subsequent catheter use. • Port catheter systems too can be repeatedly instilled.

30. Indicationsfor TauroSept® TauroSept® is meant to be instilled into intracorporal catheters between treatments in order to • treat and prevent bacterial and fungal growth • avoid biofilm formation ( DNA, Proteins and Polysaccharides) with followingmicrobialinfection in the catheter lumen • maintain patency • prevent Staphylo-coagulase biofilm and clottingThe solution should remain at least 15 to 30 min within the system TauroSept® has no fibrinolytic activity; therefore it will not lyse existing clots.

31. Instruction for use • Flush the catheter with 10 ml sterile physiological saline solution before instillation of TauroSept® . • Transfer the required volume of TauroSept® from the vial with a syringe and fill the lumen of the catheter with TauroSept®. • Follow the manufacturer's instructions for the particular catheter utilized. Specific catheter volumes are associated with each device and must be strictly followed. • It must always be ensured that the entire cavity of the catheter is filled and under filling should be avoided. • Allow TauroSept® to remain inside the catheter for at least 30 minutes or until the next treatment. • Withdraw and discard TauroSept® before the next use of the catheter.

32. Frequency of catheter-related bacteremia with antimicrobial locks versus heparin locks. (Allon 2008)

33. Thank you for your attention