BIP Central Venous Catheter (BIP CVC)

To prevent device related healthcare associated infections: Bactiguard’s mission To prevent device related healthcare associated infections: Reduce healthcare cost Reduce the use of antibiotics – to prevent spread of multi-resistant bacteria Save lives

CLABSI/CRBSI Prevalence and cost of complications due to CVCs Catheter related blood stream infection (CRBSI) is the most frequent complication and risk associated with the use of CVCs Prevalence ranges from 4-6% and a mortality between 12 to 25% One case of CRBSI costs in average 16 550 dollar Morbidity and Mortality Weekly Report (MMWR), Vital Signs: Central Line--Associated Blood Stream Infections --- United States, 2001, 2008, and 2009, CDC Wolf HH, et all; Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Central venous catheter-related infections in hematology and oncology : guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol. 2008 Nov;87(11):863-76. [Warren DK, Quadir WW, Hollenbeak CS, Elward AM, Cox MJ, Fraser VJ .Attributable cost of catheter-associated bloodstream infections among intensivecare patients in a nonteaching hospital. Crit Care Med. 2006 Aug;34 CLABSI Central Line Associated Blood Stream Infection CRBSI Catheter Related Blood Stream Infection

Prevention of microbial adhesion and biofilm formation Our mechanism of action Microbes adhere and multiply. When enough have developed, they form a biofilm. Uncoated surface Less microbes adhere to and colonize on the surface, preventing biofilm formation and subsequent infection. Bactiguard coated surface

How does it work? The galvanic effect – effective and safe Bactiguard coated surface Bactiguard coated surface Release of substances, such as silver ions, chlorhexidine or antibiotics, killing microbes. Short effect due to release Potential harm to tissue Releasing coatings The Bactiguard Infection Protection (BIP) technology is based on applying an extremely thin noble metal coating, consisting of gold, silver and palladium, to medical devices. The Bactiguard® coating is firmly bound to the surface of the device and reduces the adhesion and growth of microbes. The three noble metals in the Bactiguard coating – gold, silver and palladium, cause a galvanic effect which leads to a micro current that prevent the bacteria to adhere to the surface. The solution is unique. As opposed to coating technologies, which depend on the release of toxic substances e.g. silver ions or antibiotics, the Bactiguard coating is non-toxic and non-pharmacologic. To date, more than130 million Bactiguard® coated urinary catheters have been sold for patient use, with no reported adverse events related to the coating. The noble metals Au, Ag and Pd cause a galvanic effect when in contact with fluid. The micro current on the surface create an unfavorable environment for microbial adhesion. No toxic release of antimicrobial agents Tissuefriendly Biocompatible

In vitro data BIP CVC Average % reduction In vitro data 3 relevant microbial strains reduction of bacterial adhesion BIP CVC compared to uncoated CVC

Clinical evidence BIP CVC Goldschmidt et al. Reduction in catheter related infections No patients 236 Patient type Haematologic and oncologic diseases Median time for catheterization : 13,3/12,7 days Design Prospective, randomized Site University of Heidelberg, Germany Primary outcome Catheter related infection Other Local catheter infection Catheter related bacteremia Additionally The risk for thrombosis was evaluated by Harter et al who found no increased risk in the Bactiguard group 52% 50% 44% Goldschmidt et al at the University Hospital in Heidelberg Germany, compared the infections rates on oncology and hematology patients using a CVC. During the 17 month study time, 233 CVCs were evaluated of which 113 were standard (uncoated) and 120 were coated with Bactiguard coating. They found that patients with the Bactiguard coated CVC only developed half has many infections as the uncoated CVC group. In an analysis by Harter et al, it was also concluded that the Bactiguard coated group (1 case) had no increased risk of trombosis vs the standard group ( 3 cases), but the cases were to few for statisitcal significance. To summarize, the Bactiguard coated catheter showed a decreased risk for infection, while no increased risk for trombosis. Goldschmidt H, et al. Prevention of catheter-related infections by silver coated central venous catheters in oncological patients. Zentralbl Bakteriol. 1995 Dec;283(2):215-23. Harter et al Catheter-related infection and thrombosis of the internal jugular vein in hematologic-oncologic patients undergoing chemotherapy: A prospective comparison of silver-coated and uncoated catheters. Cancer. 94 (1):245-251 (2002). Goldschmidt H.et al., Zbl. Bakt.1995; 233: 215-223

Catheter related thrombosis has the same prevalence as CLABSI and is life threatening 4% CLABSI 4-6% Mortality 12-25% 3 terms: pro-thrombotic – create clots and gives risk of thrombosis (all devices inserted into blood are pro-thrombotic) Non-thrombotic – do not create clots, do not give risk for thrombosis Anti-thrombotic – dissolves present clots, decrease risk for thrombosis Morbidity and Mortality Weekly Report (MMWR), Vital Signs: Central Line--Associated Blood Stream Infections --- United States, 2001, 2008, and 2009, CDC Wolf HH, et all; Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Central venous catheter-related infections in hematology and oncology : guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol. 2008 Nov;87(11):863-76. [Warren DK, Quadir WW, Hollenbeak CS, Elward AM, Cox MJ, Fraser VJ .Attributable cost of catheter-associated bloodstream infections among intensivecare patients in a nonteaching hospital. Crit Care Med. 2006 Aug;34

Clinical evidence BIP CVC: Risk of thrombosis Harter et al Results- Catheter Related Thrombosis No patients 236 Patient type Haematologic oncologic diseases Median time for catheterization : 13,3/12,7 days Design Prospective, randomized Site University of Heidelberg, Germany Primary outcome Thrombosis prevalence Harter et al, Cancer 94(1):245-51 (2002)

Thrombosis- TAT as surrogate markers in clinical study Trombin-Antitrombin complex (TAT)  Increased TAT formation is correlated to activation of coagulation and are surrogate markers for thrombosis Thrombosis is when a blood clot is formed in a vein. This is a serious condition, since the bloood clot can seal of the vessel. The blood clot can break apart, travel throughout the body, and cause blockages in the heart, brain, or lungs, leading to heart attack, stroke, or pulmonary embolism depending on where it ends up. To evaluate the blood compatible properties in the lab, we measure TAT, which is a surrogate marker for thrombosis.

BIP CVC: Ex Vivo assessment of Blood Compatibility Vafa Homann et al. 2015 Problem Catheter related Thrombosis – develops in around 4% of the patients and forms life threatening blood clots Methods Blood from 23 healthy volunteers was examined for compatibility with BIP CVC and standard catheter in the Chandlers- loop model Primary outcome BIP CVC showed less TAT = less activation of coagulation = lower thrombotic risk than non-coated CVC Other BIP CVC showed no hemolysis, while another anti-infective CVC* showed extensive hemolysis. Thus, BIP CVC is unique being both anti-infective and tissue-friendly. *Chlorhexidine Silver Sulfadiazine CVC Tendency to less thrombosis has been seen in vitro, using surrogate marker TAT, and visually Hydrocath Assure – BD Medical Careflow – BD Medical The results of the study revealed that the Bactiguard noble metal alloy coating used for the BIP CVC has potentially improved blood compatibility properties of the catheter in terms of risk of thrombosis compared to a standard uncoated product. The BIP CVC was also superior to the other coated CVC with respect of non-hemolytic properties. This, together with prevention of microbial adhesion and biofilm formation on the catheter, suggests that the Bactiguard coating can be a key approach to battle healthcare associated infections in general and bloodstream infections in particular, in a tissue friendly way. ”Tendency to less Thrombosis” *TAT= Thrombin–Anti-Thrombin complex, depends on activation of coagulation and is used as marker for thrombotic risk Vafa Homann et al. 2015. Improved Ex vivo blood compatibility of Central Venous Catheters with noble metal coating. J of Biomaterial Research Karolinska Institutet, Danderyd Hospital, Bactiguard

Soft tip The superior geometric soft tip design couple with unique soft blended bio-compatible material make insertion safe and easy.

Needles Straight Y valve The BIP CVC kits are available with either straight or the more specialized Y-Valve needle which allows for easy guide-wire insertion while minimizing air embolism and backflow of blood as you can leave the syringe in one of the needle insertion sites while using the other one for the guidewire. It is a very popular and rare feature, often much appreciated by doctors. Straight Y valve

Kink resistant guidewire The guidewire of the BIP CVC has a Nitinol core, preventing it from kinking. If you bend it and then release, it will return to its original shape. This prevents it from getting stuck in the catheter during the insertion procedure.

High flow catheter 703 - Lumen Size is 16G/18G/18G Distal = 16G (1.041 mm) Middle = 18G Proximal = 18G 713 - Lumen Size is 14G/18G/18G Distal = 14G (1.20 mm) 14G > 16G Gauge A special article amongst the BIP CVC products in the product 713 which just as the 703 is a 7 French catheter with 3 lumen. It has however a larger distal lumen, 14G instead of 16G, allowing for more rapid and high volume of fluids & Medication Administration. It is our high flow catheter and very popular. This should not be confused with a high pressure catheter, which is something else and not available in the BIP CVC range of products today.

BIP CVC features Short term (<30 day) use Polyurethane with Bactiguard coating on the outside Y- and straight valve needle options No increased risk for thrombosis Tissue friendly and safe for patient use Catheter size French (Fr/Ch) Lumen Gauge (G) Length (cm) 4 Fr 1 lumen 4 Fr 18 16, 20 4 Fr 2 lumen 22/22 6, 10, 16 5 Fr 1 lumen 5 Fr 16 5 Fr 2 lumen 5,5 Fr 18/18 10, 16, 20 5 Fr 3 lumen 20/20/22 8, 13, 30 7 Fr 1 lumen 7 Fr 14 7 Fr 2 lumen 16/16 16, 20, 30 7 Fr 3 lumen 16/18/18 10, 16, 20, 30 14/18/18 8,5 Fr 2 lumen 8,5 Fr 14/16/16 8,5 Fr 3 lumen 8,5 Fr 4 lumen 14/16/18/18 The BIP CVC is approved for use up to 30 days and available in several sizes. 5FR 3 lumen and kinkresistent guidewire will be launched during 2016.

Bactiguard Infection Protection Effective prevention of healthcare associated infections, through reduction of microbial adherence and growth to medical devices. Reduces the need for antibiotics, and can so limit the spread of multiresistant bacteria. The Bactiguard coating is proven to be a tissue friendly and safe technology. To summarize our offer: - Effective prevention of healthcare associated infections, through reduction of microbial adherence and growth to medical devices. - Reduces the need for antibiotics, and can so limit the spread of multiresistant bacteria. - The Bactiguard coating is proven to be a tissue friendly and safe technology.