SILVER DRESSINGS DOES THEIR EFFECT ON MICROBES JUSTIFY THE EXPLOSION IN THEIR USE?

1. SILVER DRESSINGSDOES THEIR EFFECT ON MICROBES JUSTIFY THE EXPLOSION IN THEIR USE? OCTOBER 2005 – ADELAIDE ASSOCIATE PROFESSOR MICHAEL WOODWARD AUSTIN HEALTH

2. HISTORY OF SILVER • Precious & heavy metals have attracted health interest through the ages • Silver coins used to purify water in middle ages • Silver in many salves and ointments • Silver nitrate recognised as antiseptic in 19th century • SSDC first used in 1968 • Allowed more extensive use than silver nitrate • Less skin discolouration • Revolutionised burns management

3. WEAKNESSES OF SSDC • Ag+ rapidly binds to tissue Cl- , creating AgCl ,which is inactive • So need to apply large quantities,and frequently • Pseudo-eschar formed • Binds tightly to wound surface • Removal necessary but painful • Can macerate wound

4. NEW SILVER PRODUCTS • Prolong the release of ionic silver • Or absorb wound fluid into silver-impregnated product • Utilize modern wound management principles • Most based on existing modern products,with silver added

5. SILVER DRESSINGS AVAILABLE IN AUSTRALIA

6. HOW DOES SILVER ENHANCE WOUND HEALING? • Controls microbial burden • Other effects • Controls inflammation • Alters proteases • Promotes apoptosis

7. EFFECTS OF MICROBES ON WOUND HEALING 1. Contaminate all wounds 2. Critical colonisation • Delays healing • May lead to : 3. Infection

8. MICROBES & WOUND HEALING • Contamination may be helpful to wound healing • Promotes beneficial inflammation • Increases blood flow • Critical clonisation/infection delays healing • Bacterial endotoxins elevate cytokines (eg IL-1 and TNF),causing increased proteases and reduced growth factors • Vessels occluded • Bacteria spread to and damage adjacent healthy tissue

9. BIOFILMS • Microbes on wound surfaces usually form a biofilm • Complex community embedded in a polysaccharide matrix • Resembles a single organism • Excretes via channels,attracts and shares nutrients,resists external threats • Bacteria within can reduce metabolism (“hibernate”)

10. BIOFILMS • Bacteria in a biofilm up to 1000 times more resistant to antibiotics • Protected by the matrix • Reduced metabolism • So factors which aim to control bacterial burden must work on biofilms

11. CONTROLLING MICROBIAL BURDEN ANTIBIOTICS • May be effective for infection • But increasing resistance • In critical colonisation, often ineffective • Biofilm resistance • Multiple organisms • Too late • In surgery, giving Ab after operation increases infection rate

12. CONTROLLING MICROBIAL BURDEN ANTISEPTICS • Much less resistance • as short acting and locally acting • Penetrate and control biofilms COMMONLY USED ONES: • Chlorhexidine • Alcohol • Iodine • Silver

13. EFFECTS OF SILVER ON MICROBES • Attracted to the proteoglycans in cell walls • mammalian cells lack these • Denatures microbial proteins • esp. those involved in respiration • Also affects microbial DNA

14. RESISTANCE TO SILVER • Extremely rare • One mechanism: microbes develop ability to pump silver out • Not seen in bacteria resistant to multiple antibiotics • Not shown to spread between patients

15. EVIDENCE FOR EFFICACY OF SILVER PRODUCTS 1. In Vitro 2. Animal Models 3. Human Studies

16. IN VITRO STUDIES Bowler et al • Foetal calf serum • Inoculated with various organisms - At 0,4 and 9 days • Small piece of Aquacel Ag or control hydrofiber added • Cultured for persistent organisms Bowler PG et al.J Burn Care & Rehab 2004,25:192-60

17. BOWLER ET AL - RESULTS • Single piece of Aquacel Ag nearly completely eliminated microbes up to 9 days later • Despite reinoculations • Effective against • Pseudomonas • MRSA • VRE • anaerobes • fungi/yeasts

18. IN VITRO STUDIES • Wright et al • Inoculated organisms onto dressings coated with 3 different silver forms • Nanocrystalline • SSDC • Silver nitrate • then extracted surviving organisms 30 minutes later • Results: • Nanocrystalline silver most effective • SSDC partly effective Wright BJ et al.Am J Infect Control 1998;26:572-7

19. IN VITRO STUDIES

20. IN VITRO COMPARATIVE STUDIES • Recent study compared antimicrobial effect of 4 products • Acticoat most rapid • Contreet slower but effective against same broad range of bacteria • Actisorb only effective within product(not at wound surface) • Avance not effective Thomas et al J Wound Care 2003;12:101-7

21. ANIMAL STUDIES • Porcine contaminated wound model • wounds created in young pigs • contaminated with Ab-resistant bacteria • then dressed • then cultured and biopsied Wright et al. Wound Repair Regeneration 2002;10:141-9

22. PORCINE MODEL - RESULTS • Nanocrystalline silver dressing improved healing • Better quality granulation tissue on inspection • Better graft uptake • 6/6 • compared to 0/6 control wounds • Reduced metalloproteinases on Bx in silver-treated wounds • Increased apoptosis after silver Rx • “healthy” cell death • the other, necrosis, causes inflammation and tissue damage

23. HUMAN STUDIES • No “gold standard” study with silver • Nearest is probably CONTOP • Naturalistic comparator trial • Partly randomised • Silver or standard care which could be silver • 1,000 patients to be enrolled • Findings on first 352 presented at WUWHS meeting, Paris July 2004

24. CONTOP

25. CONTOP

26. P=0.006

27. CONTOP

28. CONTOP • Results on 619 patients at Silver Symposium in Perth, September 2005 • 50% reduction in size at week 4 with Contreet • 34% with standard care

29. INTERPRETING CONTOP • Not published • Not fully randomised • No rater blinding • Outcomes clunky • P values hard to understand • Results apply only to this silver product • and presumably sponsored by manufacturer • but most drug research is

30. CONTREET FOAM vs ALLEVYN • 109 patients with chronic venous leg ulcer or mixed arterial/venous ulcer • 13 Centres • Healing stalled • Less than 30% reduction in size at 4 weeks • Features of critical colonisation • Pain, appearance

31. CONTREET FOAM vs ALLEVYN RESULTS • CONTREET • 45% reduction in size by 4 weeks • ALLEVYN • 25% reduction in size by 4 weeks • OTHER SECONDARY ENDPOINTS IMPROVED WITH CONTREET • less exudate • less leakage

32. RDNS/SILVER CIRCLE STUDY • Planned – 360 patients with wounds not decreasing in size or signs of critical colonisation • Randomise to cadexomer iodine or silver product (Iodosorb or Acticoat) • Follow-up: 3 months; 2-weekly reviews • Endpoints: wound size, use of antibiotics, adherence, wound swabs, nurse and client satisfaction • Results: 2007

33. CHRONIC VENOUS ULCERS • 25 patients with chronic venous ulcers • Contreet foam use led to 56% reduction in ulcer area over 4 weeks • IMPORTANT-not selected for colonization • No comparator group Karlsmark et al J Wound Care 2003;12:351-4

34. CHRONIC WOUNDS • Randomised non-blinded study in chronic wounds with no clinical infection, using an activated charcoal silver dressing • Reduced bacterial levels in 85.1% of 67 silver-treated wounds by day 15 • Compared with 62.1% of 58 control wounds • Healing times not reported Soriano et al J Wound Care 2004;13:421-3

35. SIGNIFICANCE OF THESE LAST 2 STUDIES • These suggest a role for silver even when microbial burden not an obvious factor • Not clear if this influenced dressing selection in CONTOP • probably did • However, role of silver may still be via control of microbes, as last study suggests

36. BURNS STUDIES 1. Open-label non-comparator study with Urgotul SSD • Low rate of Staph aureus colonisation • 1 of 41 subjects 2. Another non-comparative trial with Aquacel-Ag • 17 patients • healed in average 14 days • only one required grafting 1.Carsin et al J Wound Care 2004;13:145-8 2.Caruso et al J Burn Care Rehab 2004;25;89-97

37. DIABETIC FOOT ULCERS • Non-randomised trial of diabetic foot ulcers treated with Contreet in 27 patients • small comparator group of 6 ulcers in same patients not treated with Contreet • average healing 56% over 4 weeks • not reported in comparators • two treated ulcers infected,compared to all 6 comparators Rayman RG et al British J Nursing 2005;14:109-14

38. IS THIS EVIDENCE SUFFICIENT? • By comparison to other areas of health practice • POSSIBLY • By comparison to pharmaceutical research • DEFINITELY NOT

39. COST EFFECTIVENESS DATA • ALWAYS SEEMS TO JUSTIFY EXPENSIVE PRODUCT USE • Use a commonsense approach • And ask - ”can service or patient afford it”, even if cost effectiveness claimed

40. HOW SHOULD THIS EVIDENCE INFLUENCE CLINICAL PRACTICE? • Consider silver dressings for critically colonised wounds • and return to standard dressing once microbial burden controlled • Try a different silver product if initial one fails • But no human head-to-head trials and such trials notoriously unhelpful • always seem to favour sponsor’s product !

41. EVIDENCE-BASED USE OF SILVER • Consider silver product in non-healing and slowly healing wounds • even if no evidence of microbial critical colonisation/infection • could biopsy first to establish such burden, but evidence only exists for value of high counts revealing infection, not lower counts and colonisation • and silver may be effective even with no microbial burden

42. EVIDENCE-BASED USE OF SILVER • Infected wounds need • Antibiotic • Debridement • Silver may add extra benefit • But no human studies • Only support from in-vitro and porcine studies

43. EVIDENCE-BASED USE OF SILVER • Always return to first principles: • Fully and repeatedly assess • Compress if venous • Ensure adequate blood supply • Reduce pressure • Improve nutrition • Treat co-morbidities • Assess social circumstances • Silver is not a panacea

44. THE FUTURE • A Challenge • Design and participate in well-designed and powerful trials • Avoid the temptation of “easy” research only • More case series • No comparator group • Until then, use silver mainly for control of microbial burden • This is where the evidence is currently strongest