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

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SILVER DRESSINGS AVAILABLE IN AUSTRALIA
PRODUCT RANGE SILVER FORMULATION SILVER CONCENTRATION (per cm3)
CONTREET (2 products) Low-release ionic 47 mg
AVANCE Very low-release 1.6 mg
ACTICOAT (3 products) Nanocrystalline 107 mg
AQUACEL Ag Low-release ionic 8.3 mg
ATRAUMAN Ag Moderate-release 35 mg
ACTISORB PLUS Very low-release 3 mg
POLYMEM SILVER Very low-release 12.4 mcg
URGOTULLE SSD Moderate release 3.7 SSD
ARGLAES Very low-release 100 mcg
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

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CONTROLLING MICROBIAL BURDEN

• ANTISEPTICS
• Much less resistance
• as short acting and locally acting
• Penetrate and control biofilms
• COMMONLY USED ONES
• Chlorhexidine
• Alcohol
• Iodine
• Silver

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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 2004,25192-60
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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

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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 199826572-7
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IN VITRO STUDIES
STRAIN NANOCRYSTALLINE SILVER NANOCRYSTALLINE SILVER SSDC SSDC SILVER NITRATE SILVER NITRATE
STRAIN CONTROL 30 mins CONTROL 30 mins CONTROL 30 mins
Staph aureus 7.3 lt2.0 7.3 4.8 7.3 4.3
E faecalis 7.2 2.7 7.2 7.0 7.7 7.7
Pseudo- monas 7.0 lt2.0 7.0 5.6 7.0 7.0
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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 200312101-7
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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
200210141-9
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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

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CONTOP
ULCER TYPE ULCER TYPE
VENOUS LEG ULCER 45
MIXED ARTERIAL/ VENOUS LEG ULCER 22
PRESSURE ULCERS 10
DIABETIC FOOT ULCERS 7
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CONTOP
DRESSING USED DRESSING USED
FOAM/ALGINATE 45
HC/FILM 15
GUAZE 4
ANTISEPTIC - Contreet 48 - Other 52 30
OTHER 6
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P0.006
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CONTOP
OUTCOME CONTREET FOAM STANDARD CARE STATISTICAL SIGNIFICANCE
ODOUR None by week 2 None by week 3 P.003
PAIN (0-10) CHANGE/BETWEEN 1/1 2/2 P.008/P.02
EASE OF USE Very easy Easy P.0001
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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

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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

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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

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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

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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

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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 200312351-4
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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 200413421-3
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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 200413145-8 2.Caruso
et al J Burn Care Rehab 20042589-97
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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 200514109-14
38
IS THIS EVIDENCE SUFFICIENT?

• By comparison to other areas of health practice
• POSSIBLY
• By comparison to pharmaceutical research
• DEFINITELY NOT

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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 sponsors 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

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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

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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