The compatibility of INTRASITE Gel and ACTICOAT : An In-Vivo and In-Vitro assessment. *smith&nephew

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1 The compatibility of INTRASITE Gel and ACTICOAT : An In-Vivo and In-Vitro assessment *smith&nephew

2 An In-Vivo and In-Vitro assessment of the compatibility of ACTICOAT and ACTICOAT 7 with INTRASITE Gel dressings in the management of chronic wounds Introduction ACTICOAT and ACTICOAT 7 (with SILCRYST TM Nanocrystals) are effective antimicrobial barrier dressings which are indicated for use on partial and full thickness wounds such as pressure ulcers, venous ulcers, diabetic ulcers, burns, donor and recipient graft sites. In-Vitro data has demonstrated that the nanocrystalline coating of silver rapidly kills a broad spectrum of bacteria in as little as 30 minutes. ACTICOAT must be kept moist to be effective. When exposed to moisture it can maintain bactericidal activity for at least 3 days. With ACTICOAT 7 bactericidal activity can be maintained for up to 7 days. This bactericidal activity will help to prevent and reduce infection of wounds. Keeping ACTICOAT and ACTICOAT 7 dressings moist, may require rewetting of the dressing with sterile water. However, some clinicians are using INTRASITE Gel/Conformable together with ACTICOAT and ACTICOAT 7 in order to keep the dressings, and the wound moist for longer periods of time. Case studies have been undertaken to show the effectiveness of this combination in the treatment of chronic wounds. To support these two invitro tests have been carried out to investigate the compatibility of the two dressings.

3 Dr. Juan Carlos López Gutierrez Hospital Infantil La Paz- Cirugía Pediátrica Pº de la Castellana, Madrid, Spain The use of ACTICOAT on a severe trauma wound in a paediatric patient This case study demonstrates the use of ACTICOAT in combination with reconstructive surgery and tissue replacement in a paediatric patient with severe trauma. The patient was a 3 and a half year old boy with a trauma wound as a result of a traffic accident. Originally, the patient suffered an open femur fracture to the left leg with injury to the femoral artery, femoral vein and sciatic nerve. Figure 1 After reconstruction of the sciatic nerve and blood vessels, the patient presented with a blood clot of the femoral artery and tissue destruction of the muscles of the thigh, lower leg and the front of the foot (Figures 1, 2 & 3). Treatment ACTICOAT was applied along with INTRASITE Conformable for 8 days to avoid desiccation and infection of the bone (Figures 4 & 5). IntegraTM was applied (Figure 6) and covered with ACTICOAT to prevent infection. After 5 months of treatment (Figures 7 & 8), despite sciatic paralysis, the patient could walk without assistance. Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 TM Johnson & Johnson

4 Marcus Guergen, Senior consultant surgeon Head of Outpatient Wound Clinic, Dept. of Surgery, Sørlandet Sykehus HF, Flekkefjord, Norway The effect of ACTICOAT 7 and INTRASITE Gel on a mixed aetiology leg ulcer Fig1 - The wound at commencement of treatment. Background The patient was a 67 year-old female with a small ulcer on the top of her right foot, which had been present for approximately 6 months. On examination on 19th December 2001, the ulcer measured 2.0cm x 1.5cm x 0.4cm, with slough present in the ulcer bed. The skin surrounding the ulcer, measuring approximately 16cm x 10cm was reddened. Considerable pain was experienced by the patient. The cause of the ulcer was classified as a combination of arterial and venous disease, complicated by an allergic reaction around the ulcer. Treatment The ulcer was first debrided under local anaesthetic. Following debridement the ulcer site was treated with INTRASITE Gel and ACTICOAT 7, whilst the allergic reaction was treated with hydrocortisone 1% ointment. The dressing was removed, and the ulcer assessed once a week. The Outcome On examination of the ulcer on 19th January 2002, granulation tissue was present in the wound bed, and the ulcer had reduced in size to 1.0cm x 0.8cm x 0.1cm (see fig. 2). The reddening of the skin surrounding the ulcer had improved considerably, and the patient experienced less pain. Figure 2 - The wound at 17th January 2002 A further examination on the 25th February 2002 showed that the ulcer had further reduced in size, and now measured 0.3cm x 0.3cm with granulation tissue reaching the edges of the ulcer (see fig. 3). The reddened skin surrounding the ulcer had shown further improvement, and the patient no longer was experiencing any pain. At this point, the treatment with ACTICOAT 7 was stopped, and local therapy continued using hydrocolloid dressings. At a final examination on 16th April 2002 the ulcer had healed completely with just a scar and signs of hyper-pigmentation present. An ulcer which earlier had not shown any signs of progression, despite various treatment therapies, progressed well, and without complications when ACTICOAT 7 (in conjunction with INTRASTE Gel) was used. This treatment regime provided a high degree of patient comfort. Figure 3 - The wound at 25th February 2002 Fig 4 - The wound at 16th April 2002

5 Marcus Guergen, Senior consultant surgeon Head of Outpatient Wound Clinic, Dept. of Surgery, Sørlandet Sykehus HF, Flekkefjord, Norway The use of ACTICOAT 7 and INTRASITE Gel on a patient s trauma wound with venous insufficiency Background This case study is about an 81 year old lady who fell in her home in March 2002 and suffered a large wound in the area medial to the kneecap. She had previously been a patient at the Outpatient Wound Clinic due to a large ulcer on her right leg. This had been treated with, among other things, skin grafting and treatment was completed on 5 March The patient was known to have venous insufficiency. Wound evaluation The patient came to the Outpatient Wound Clinic on the 15 April 2002 (Figure 1). Examination showed a large necrotic wound medial to the patella with the dimensions 8.0 x 3.5 x 1.5 cm. The ulcer did not probe to bone. There were evident signs of infection. There was no doubt that the wound was in the inflammation stage. The patient was admitted to the hospital. Figure 1 - The wound before commencement of treatment 15 April 2002 Treatment Debridement was performed surgically, and a 10-day course of systemic antibiotic therapy was started. This was done to prevent the infection spreading into the joint. ACTICOAT 7 moistened with sterile water was used in combination with INTRASITE Gel as local therapy. The wound was assessed every other day while the patient was in the hospital, just by lifting up the ACTICOAT 7 dressing. This allowed us full control of the wound. The patient was sent home after one week at the hospital on 22 April 2002 (Figure 2). The wound was now granulating. The treatment continued at the Outpatient Wound Clinic where a new ACTICOAT 7 dressing was applied once a week. The patient reported the dressing as being very comfortable and allowed her to continue her daily activities as normal. Figure 2 - The wound at 22 April 2002 Examination on 27 May 2002 (Figure 3) showed an ulcer reduced from 8.0 x 3.5 x 1.5 cm to 4.0 x 2.2 cm. Granulation tissue was present on the wound bed and there were no signs of infection. The ulcer marginsshowed signs of re-epithelialisation. Skin grafting proved to be unnecessary. Use of ACTICOAT 7 was stopped, and the ulcer was treated locally with ALLEVYN. Conclusion This case study shows the successful use of ACTICOAT 7 on a patient with venous insufficiency and an infected traumatic wound. Figure 3 - The wound at 27th May.

6 In-Vitro assessments of the compatibilty of ACTICOAT and INTRASITE Gel dressings Introduction To support the use of ACTICOAT in conjunction with INTRASITE Gel, two in-vitro tests have been undertaken to investigate the compatibility of the two dressings: Test 1: ACTICOAT bioactivity when used with INTRASITE Gel - to confirm INTRASITE Gel does not affect the activity of ACTICOAT Test 2: The rheological effect of INTRASITE Gel when used with ACTICOAT - to confirm ACTICOAT does not affect the rheology of INTRASITE Gel Test 1: ACTICOAT bioactivity when used with INTRASITE Gel Method Two in-vitro antimicrobial activity tests were used to determine the ability of the dressing to kill a variety of important clinical pathogens. Bacterial Reduction Test (Log) This test is performed to determine the ability of the dressings to kill a wide variety of important clinical pathogens. Inocula of bacteria, suspended in tryptic soy broth, were applied directly to the surface of the dressings. After 30 minutes and 2 hours the bacterial reduction of viable organisms remaining on each of the dressing was compared. The microorganisms used in this experiment were: S. aureus and P. aeruginosa, (two antibiotic resistant strains of these organisms). Corrected zone of inhibition - Specimens of each of the dressings were placed onto a lawn of bacteria (P. aeruginosa) and the zone of no growth surrounding the dressing was determined over a 24 hour incubation period then the specimen was transferred to a fresh lawn of bacteria. This is repeated every 24 hours for a 7 day period and the zone of no growth determined after each incubation. 2.54cm x 2.54 cm pieces of ACTICOAT dressing were coated with 0.7 g of INTRASITE Gel. For comparative purposes, the coated ACTICOAT dressing without wound gel was also tested. ACTICOAT dressing pieces were inoculated with 0.2 ml of a bacterial suspension. An untreated ACTICOAT dressing served as the control. The rest of the test was conducted as per the procedure except that S. aureus samples were eluted in STS with increased NaCl to facilitate elution of the organisms. Results Results from the CZOI tests are shown in Table 1.The results from the Log Reduction Tests are shown in Table 2 Table 1: CZOI of ACTICOAT dressing coated with INTRASITE Gel Sample CZOI (mm) vs P. aeruginosa CZOI (mm) vs S. aureus Test ACTICOAT control Test ACTICOAT control INTRASITE Gel treated dressing Table 2: Log reduction in bacterial load by ACTICOAT dressing coated with INTRASITE Gel Hydrogel Log reduction in Ps.aeruginosa Log reduction in S. aureus 30min incubation 2 hr incubation 30min incubation 2 hr incubation Untreated ACTICOAT 5.6 NT INTRASITE Gel treated dressing NT = Not tested 5.3 NT

7 In-Vitro assessments of the compatibilty of ACTICOAT and INTRASITE Gel dressings cont... ACTICOAT with INTRASITE Gel gave zone sizes similar to the ACTICOAT dressing used alone. Reduction in bacterial count for treated and untreated ACTICOAT dressings are tabulated in Table 2. When P. aeruginosa was used as the inoculum, both plain and treated ACTICOAT dressings reduced the microbial load to a non-detectable levels within 30 minutes. For S. aureus, the gel treated ACTICOAT did display reduced kill rates relative to the regular ACTICOAT dressing. At the 30 minute time point the dressing with INTRASITE Gel still displayed a three log reduction in bacteria, but displayed the same level of kill at 2 hours. A log reduction of 3 or greater is considerable with regard to antimicrobial efficacy. Assuming that 10,000,000 bacteria were present at the outset (equating to 10 7 ) a 3 log reduction would equate to a reduction to 10,000 CFU (Colony Forming Units). If the log reduction was greater than 4 this would equate to less than 1000 CFU remaining and a log reduction of greater than 5 would equates to less than 100 CFU present after the test period. After 2 hours, the log reduction was 4.3 for S.aureus which would equate to less than 1000 CFU present. With P. aeruginosa, the antimicrobial was faster acting. The log reduction of 5.3 would equate to less than 100 CFU after 30 minutes. Discussion No significant impact on zones of inhibition was detected with treating ACTICOAT with INTRASITE Gel. This study showed that the ACTICOAT continued to give a considerable reduction in bacteria at both time points. The results give confidence that the two dressings can be used in combination without comprising the antimicrobial efficacy of ACTICOAT.

8 In-Vitro assessments of the compatibilty of ACTICOAT and INTRASITE Gel dressings cont... Test 2: The rheological effect of INTRASITE Gel when used with ACTICOAT Method Eight samples of ACTICOAT dressing were coated with INTRASITE Gel. INTRASITE Gel was applied at 2mm/cm 2 (equivalent to 20g over a 10x10cm dressing). Samples were aged at 32 o C for up to seven days sealed in light / moisture impregnable foil pouches. After 0, 1, 2 and 7 days, duplicate samples were removed from storage. Samples coated with INTRASITE Gel were scraped and the gel rheology determined. The standard specification oscillation and flow tests were performed in attempts to determine whether the INTRASITE GEL was being adversely affected by anything that the ACTICOAT was excreting or absorbing. In addition, a creep test was performed, measuring the displacement that the sample made under a suitable low load. Also, a more complex oscillation test was used to try and determine the limit of elasticity when oscillated at zero frequency. All tests were performed on TA AR 500 Rheometer with temperature 25oC / Parallel plate with a 2mm (2000um) gap. Results The INTRASITE Gel that was removed from ACTICOAT dressings during the test did become discoloured as it absorbed silver, however this discolouration diminished over time taking on a brownish yellow colour after 7 days. the subjective texture and appearance of the INTRASITE Gel after removal from the acticoat dressings did not feel different from between the fingers of the operator. The rheological data showed that over the course of the test, the INTRASITE Gel did show a slight increase in viscosity and elasticity (see fig 1), but this was not evident subjectively. Figure 1 Figure 1 Elasticity of Intrasite gel after contact with Acticoat dressings for up to 7 days. Elasticity (G ) and Dynamic Viscosity (n 5Hz/50 Pa Discussion There is little noticeable rheological effect on the INTRASITE Gel from being in contact with ACTICOAT for a one day, two day, or seven day period. Over the 7 day period of this experiment, the INTRASITE Gel is subjectively the same to the touch, although rheological data shows it to be slightly thicker and stiffer. The results of this test suggest that ACTICOAT and INTRASITE Gel are compatible for use together.

9 In-Vitro assessments of the compatibilty of ACTICOAT and INTRASITE Gel dressings cont. Conclusions Clinicians do use ACTICOAT and ACTICOAT 7 in conjunction with INTRASITE Gel in the treatment of chronic wounds, and this is supported by both in-vitro and in-vivo data. The in-vitro tests suggest that although discolouration of the gel is observed, the bioactivity is not compromised. The case study results provide in-vivo evidence that when used together, ACTICOAT and ACTICOAT 7 with INTRASITE Gel can provide an effective treatment regime for chronic wounds that may be susceptible to infection.

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12 Wound Management Smith& Nephew Medical Ltd 101 Hessle Road Hull HU3 2NB England TM SILCYRST is a trade mark of NUCRYST Pharmaceutical Corp.; used under licence Trademarks of Smith & Nephew