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Introduction to The Wound Infection Evidence Matrix
The development of a structured survey of the evidence for wound infection was one of the principal outputs agreed by the International
Wound Infection Institute at its inception. This process began with a simple listing of references (to be found in our “useful documents”
section) and will conclude with a comprehensive list of reviewed, surveyed and abstracted papers on wound infection and its treatment. We
see the provision of an evidence matrix as the next step along the route. The current version of the matrix is incomplete, but we believe that it
is at an appropriate stage to be reviewed by our members. We welcome all of your comments.
One of the main features that we wanted to include was a rating system for the evidence. This is always problematic. The literature reveals
multiple classifications and evidence hierarchies for ranking evidence 1,2,3,4,5. However, these evidence classifications and hierarchies contain
many inconsistencies in interpretation and ranking. Although the gold standard for best evidence is generally considered to be a meta analysis
or systematic review of double blinded randomised controlled trials, few, if any, such reviews are to be found in regards to the diagnosis or
treatment of wound infection. Our rating system is focussed towards the levels of evidence as follows:
1. Meta analysis and systematic reviews
2. Randomised controlled trials
3. Non randomised controlled trials, case control trials, prospective cohort studies, animal studies, evidence summaries or evidence
guidelines
4. Case reports, case series
5. Expert opinion, other literature reviews
Highly influential pieces have been published within all the above levels, some of which have contributed to changes in practice. Therefore we
are considering the addition of an “impact” rating, separate to the evidence rating, based on the importance or significance of certain papers.
We hope that you find this draft of the evidence matrix to be useful. Equally importantly, please give us your opinion on how to improve and
add to this document. In particular we would like your feedback on the following:
International Wound Infection Institute – Evidence Matrix
Page 1 of 53

How useful is the evidence matrix as provided?

What other papers should be included?

What impact score would you give to significant pieces?
Please let us know what you think. All comments will be gratefully received at [email protected]
Keryln Carville, Chair, Evidence sub-committee, April 2009
References:
1. Upshur, R. (2003). “Are all evidence-based practices alike? Problems in the ranking of evidence”. CMAJ, 169(7), downloaded
http://www.cmaj.ca/cgi/content/full/169/7/672
2. Brown JP, Josse RG; Scientific Advisory Council of the Osteoporosis Society of Canada. 2002 clinical practice guidelines for the diagnosis
and management of osteoporosis in Canada. CMAJ 2002;167(Suppl 10):S1-34.
3. Centre for Evidence-Based Medicine. Levels of evidence and grades of recommendation. Oxford: The Centre. Available:
www.cebm.net/levels_of_evidence.asp
4. Wright PJ, English PJ, Hungin AP, Marsden SN. Managing acute renal colic across the primary–secondary care interface: a pathway of
care based on evidence and consensus. BMJ 2002;325:1408-12.
International Wound Infection Institute – Evidence Matrix
Page 2 of 53
5. Evans, D. (2003). “Heirarchy of evidence: A framework for ranking evidence evaluating healthcare interventions.” Journal of clinical
Nursing. 12(1), 77-84.
The Wound Infection Evidence Matrix – April 2009
Author, date
Comment
Title
Key points
Grade
Wound
microbiology
and associated
approaches to
wound
management.
A thorough review of the literature on wound infection published up until 2001. Key points:
all wounds are colonised and progression to infection is as much due to host factors as to
the type and number of bacteria present; most open wounds are polymicrobial, with
anaerobic bacteria constituting 50% of the species present in infected wounds; swab
sampling is easy to carry out but results can be misleading and this should only be carried
out if there are clinical signs of infection, if the wound fails to heal or is deteriorating;
antibiotics induce bacterial resistance and antiseptics are preferred if topical treatment is
required; debridement is an essential part of infection control. In my opinion a literature
review as is stated in the conclusion
The Calgary
biofilm device:
new technology
for rapid
Biofilms have an inherent lack of susceptibility to antibiotics. Ceri et al describe the Calgary
Biofilm Device (CBD) which is a method for the rapid and reproducible assay of biofilm
susceptibility to antibiotics.
Bacteria, biofilms and wound healing
(Bowler, Duerden
et al. 2001)
(Ceri, Olson et al.
1999)
Outlines new
technology for
selecting effective
antibiotics in the
International Wound Infection Institute – Evidence Matrix
The paper describes the formation of biofilms and confirmation of their presence using
Page 3 of 53
5
3
Author, date
Comment
Title
Key points
Grade
treatment of
biofilms
determination
of antibiotic
susceptibilities
of bacterial
biofilms.
quantitative microbiology and SEM, followed by the rigorous testing and assessment of the
CBD assay using NCCLS reference strains of E coli, P aeruginosa and S aureus. Growth curves
demonstrated that biofilms grew uniformly in each of the 96 wells.
Antibiotic susceptibility testing demonstrated that, compared to planktonic forms of the
same bacteria, 100 to 1000 times the concentration of an antibiotic was required to
eradicate the biofilm. The authors claim that the CBD provides a method for the rational
selection of antibiotics effective against microbial biofilms.
(Costerton,
Stewart et al.
1999)
A good review of
biofilms
Bacterial
biofilms: a
common cause
of persistent
infections.
A good and well-referenced review of biofilms. The review explains how biofilms form and
develop, how they differ from planktonic bacteria, the importance of quorum sensing as a
possible target for interfering with their development.
5
(Davies, Parsek et
al. 1998)
The importance of
signalling in biofilms
is described and it is
suggested this could
be a way to control
biofilms.
The
involvement of
cell-to-cell
signals in the
development of
a bacterial
biofilm.
This study demonstrates that a cell-to-cell signal (quorum sensing) is required for the
differentiation of individual cells of P aeruginosa into complex biofilms. When
differentiation is hindered by a mutation, the biofilm becomes abnormal and is sensitive to
a detergent biocide (SDS). Without the signalling device, the biofilms were not able to grow
with the proper architecture and did not leave sufficient space between colonies.
3
International Wound Infection Institute – Evidence Matrix
The authors suggest that inhibition of the quorum sensing signals could be possible ways to
control biofilms, given their resistance to most antibiotics.
Page 4 of 53
Author, date
Comment
Title
Key points
Grade
(Dow, Browne et
al. 1999)
Review
Infection in
chronic wounds:
controversies in
diagnosis and
treatment.
A thorough review that includes: definitions of contamination, colonization and infection;
the pathogenesis of wound infection and how the inflammatory response can delay wound
healing; diagnosis of wound infection; quantification of bacterial burden.
5
Regarding bacterial burden, the authors caution that there is no hard cut-off figure above
which colonization turns to infection and that the level of microbial burden alone can not be
used to define infection. They stress the importance of bacterial species and variety, and
the capacity of the host to tackle infection. They warn of the difficulties of quantitative
biopsy and argue the case for semi-quantitative assessment.
The paper also provides a detailed critique of specimen collection and culture techniques
and concludes with a thorough overview of treatment options including mechanical
(debridement), antiseptics and the role of antibiotics. A useful table summarises the
antimicrobial options for empiric therapy.
A small number of the concepts have been challenged over the years since the publication
of this review, but on the whole it is a thorough and valuable resource on the subject of
wound infection.
(Dowd, Sun et al.
2008)
Highly significant
study
Survey of
bacterial
diversity in
chronic wounds
using
Pyrosequencing,
DGGE and full
International Wound Infection Institute – Evidence Matrix
This study used specific techniques to identify the major populations of bacteria that occur
in the biofilms found in three types of chronic wound: diabetic foot ulcer, venous leg ulcer
and pressure ulcer. The techniques were: three separate I 6S-based molecular
amplifications, followed by pyrosequencing, shotgun Sanger sequencing and denaturing
gradient gel electrophoresis.
All chronic wound types contained certain specific major populations of bacteria:
Page 5 of 53
3
Author, date
Comment
Title
Key points
Grade
ribosome
shotgun
sequencing.
Staphylococcus, Pseudomonas, Peptoniphilus, Enterbacter, Stenotrophomonas, Finegoldia
and Serratia species. However, each of the wound types showed marked differences in their
bacterial populations.
For example, in venous ulcers over 80% of the bacteria were facultative anaerobes,
compared with 62% in diabetic foot ulcers, and just over 20% in pressure ulcers. Pressure
ulcers on the other hand comprised over 60% of strict anaerobes, compared with nearly
30% in diabetic foot ulcers and virtually none in venous ulcers.
Different wound types also showed a different level of oxygen tolerance amongst their
bacterial populations. The authors suggest that this may imply each wound type has a
distinct pathophysiology that affects the ecology of the wound environment determiging
which bacteria can develop.
Results were compared with those from traditional culture-based analyses. In only one
wound type did the culture methods correctly identify the primary bacterial population.
Standard culturing techniques are inherently flawed as they only examine the 1% of
microorganisms that are able to grow rapidly in pure culture. Also, certain populations may
never be cultured in the laboratory due to reduced metabolic activity, obligate cooperation
with other bacteria, need for specialized nutrients or environmental conditions.
The paper gives full details of the bacteria identified.
(Hill, Davies et al.
2003)
Molecular analysis
reveals a much
greater diversity of
Molecular
analysis of the
microflora in
International Wound Infection Institute – Evidence Matrix
Culture analyses of CVLU generally reveal staphylococci, streptococci, enterococci and
facultative Gram-negative bacilli. However, anaerobic isolation techniques and prolonged
incubation reveal the presence of fastidious and slow-growing anaerobic species such as
Page 6 of 53
3
Author, date
Comment
Title
Key points
Grade
microflora in chronic
wounds than do
culture techniques.
chronic venous
leg ulceration.
Fusobacterium and peptostreptococci. Cultivation-dependent methods for characterising
the microflora of chronic wounds are limited.
The authors describe the analysis using 16S rDNA sequences of tissue from a CVLU which
demonstrated significantly greater bacterial diversity than culture methods. Sequences
even suggested novel species of bacteria. This technique can clearly not be used routinely
so the clinical application is limited but may inform treatment in deteriorating or longlasting wounds.
The study states that this was one patient and one wound that was analysed? Would that
make it a 4?
(James, Swogger
et al. 2008)
Well-designed and
highly significant
study revealing that
biofilms may be
present in at least
60% of chronic nonhealing wounds
Biofilms in
Chronic wound specimens were taken from 77 subjects and acute wound specimens from
chronic wounds. 16. All specimens were cultured using standard techniques and in addition, light and
scanning electron microscopy were used to analyse 50 chronic and 17 acute specimens.
Molecular analyses were performed on the other 27 chronic specimens.
There was a statistically significant difference between the chronic and acute specimens in
terms of presence of biofilm: 60% of the chronic but only 6% of the acute (p<0.001).
Molecular analysis showed that there were polymicrobial communities and bacteria,
including strictly anaerobic, that were not revealed by culture.
The study shows that biofilms are not necessarily capable of detection using standard
clinical techniques.
International Wound Infection Institute – Evidence Matrix
Page 7 of 53
3
Author, date
Comment
Title
Key points
Grade
(Laato, Niinikoski
et al. 1998)
This paper suggests
a mechanism to
explain why S aureus
sometimes appears
to accelerate wound
healing.
Inflammatory
reaction and
blood flow in
experimental
wounds
inoculated with
Staphylococcus
aureus
This paper is often quoted as it demonstrated that certain low levels of bacteria in a wound
could actually enhance healing, through stimulating inflammation which in turn would
enhance local blood flow.
3
P aeruginosa can
enlarge ulcers and
delay healing. S
aureus and
haemolytic strep
also delay healing
Bacterial
colonisation and
healing of
venous leg
ulcers.
Fifty-nine patients with VLUs were followed with frequent semi-quantitative culture of
bacteria from the ulcer surface for 180 days. The ulcer area was also measured. At 90 and
180 days the authors found that ulcers colonised with P aeruginosa were significantly larger
than those without; and significantly fewer of them healed completely during the
observation period.
Suggested that 105
bacteria per gram of
tissue was a critical
level for infection.
The effect of
microbial
contamination
on
musculocutaneo
(Madsen, Westh
et al. 1996)
(Murphy, Robson
et al. 1986)
In an animal experiment, wounds were created and sponge implants were used as a matrix
to encourage growth of granulation tissue. The implants were injected either with saline
(control), or S aureus at concentrations of 102 or 105 microorganisms/ml. Implants
inoculated with 105 organisms developed infection with pus formation, while implants
inoculated with 102 showed no signs of infection but had an enhanced local blood flow.
3
Ulcers with S aureus or haemolytic streptococci healed significantly more slowly than those
without.
International Wound Infection Institute – Evidence Matrix
Granulating wounds were inoculated with varying levels of bacteria per gram of tissue: 10 4,
105 or 106 and were then covered with musculocutaneous or random flaps or left
uncovered. Bacterial proliferation was evident in all the heavily contaminated wounds (106)
while in the minimally contaminated wounds (104) both types of flap achieved wound
healing and decreased the bacterial level in the wound. In the intermediate group (105)
Page 8 of 53
3
Author, date
Comment
Title
Key points
Grade
us and random
flaps.
musculocutaneous flaps lowered the bacterial count and allowed wound closure, whereas
random flaps failed.
This study is relevant to clinicians beyond the field of surgery as it established that the 10 5
level of bacteria was an important tipping point in the development of infection – all other
things being equal.
Significant impact
(Ovington 2003)
Low evidence but
useful piece
Bacterial toxins
and wound
healing.
An educational piece that describes critical colonisation as a stage of colonisation that
occurs before invasive infection. The current view is that critical colonisation is actually the
presence of biofilm.
The rest of the paper deals with bacterial toxins, describing the nature and effects of exoand endo-toxins. While many educational pieces describe the effects of bacteria in wounds,
this is one of the very few that deals specifically with the actions of bacterial toxins.
The author explains that while antimicrobials may reduce the amount of exotoxin produced
by bacteria, they have no effect on exotoxin that is already in the wound. Also, when Gramnegative bacteria are destroyed, they release endotoxins from their cell wall, so topical
antimicrobials may contribute temporarily to an increase in endotoxin levels. The author
advocates the use of absorbent dressings and activated charcoal to remove toxins from the
wound bed and describes a silver dressing that is based on an activated charcoal cloth
(Actisorb).
International Wound Infection Institute – Evidence Matrix
Page 9 of 53
5
Author, date
Comment
Title
Key points
Grade
(Robson and
Heggers 1970)
An influential paper
that established 105
bacteria per gram of
tissue as a cut-off
level for
uncomplicated
healing of wounds.
Delayed wound
closures based
on bacterial
counts.
At the time of publication of this paper, there was much debate about the effect of
bacterial burden on the healing process and whether it was possible to predict successful
wound closure based on the bacterial count. The aim was to find a method of predicting
success that would therefore allow delayed closure of contaminated non-traumatic
wounds. In 1969 Heggers developed a rapid smear method for bacterial quantification and
in this study, Robson aimed to use the technique prospectively in a series of wounds to see
if bacterial burden, as identified by the swab method, could predict wound closure.
3
Ninety-five cases were studied in which closure had been delayed through, for example,
removal of sutures or drainage of surgical abscess. During the period of delay, the wound
was inspected and cleaned daily, and debrided if necessary. Quantitative and qualitative
cultures were performed at the time of surgery and at attempted closure. An aseptic tissue
sample is prepared and examined under a microscope. The authors claim that the process
takes no more than one hour. Once a wound had 105 or fewer bacteria per gram, delayed
closure was performed. The only exceptions were wounds involving β-haemolytic
streptococci.
Eighty-nine incisions closed when the bacterial count was less than 10 5 and progressed to
rapid healing. Only one of the four cases containing more than this level was successful. The
authors suggest that this bacterial level can be used to predict closure with 96% accuracy.
The paper “Predicting skin graft survival” deals with the same concept. (Robson and Krizek
1973)
International Wound Infection Institute – Evidence Matrix
Page 10 of 53
Author, date
Comment
Title
Key points
Grade
(Robson 1997)
Interesting but not
highly practical.
Wound
infection: a
failure of
healing caused
by an imbalance
of bacteria.
A summary of the state of knowledge at the time about the healing process in surgical,
acute and chronic wounds.
5
Qualitative
bacteriology
and leg ulcer
healing.
The bacterial profile of leg ulcers in 52 patients were investigated to identify whether
specific bacterial groups delay healing, whether the bacterial flora changes as ulcers heal,
and whether the changes influence healing.
(Trengove, Stacey
et al. 1996)
Study that
established the
number of bacterial
species was more
important than the
type in delaying
healing.
Unlike other reviews, such as those by Dow, this is not highly practical, but does contain
some interesting background in a number of areas that are not always included in other
reviews. In particular, the review collects together and summarises earlier work by Robson
and others in the field of surgical research into bacterial burden.
3
The authors found that delay in healing did not appear to be associated with any specific
bacterial group; rather, it was the number of types of bacteria that was most strongly
associated with delayed healing. The presence of four or more bacterial groups was
statistically significantly associated with delayed healing.
There was no apparent connection between the change in flora and wound healing.
Significant impact
(Wheat, Allen et
al. 1986)
Outlines the
importance of a
“reliable” wound
swab technique
Diabetic foot
infections:
bacteriologic
analysis.
International Wound Infection Institute – Evidence Matrix
Diabetic foot infections were evaluated by taking 54 specimens of tissue and avoiding
contamination with foot ulcer. A further 94 “unreliable” specimens were also taken. In the
reliable specimens, the most common isolates were staph species, enterococcus species,
corynebacterium species and various enterobacteriaecae. Anaerobic isolates included
Page 11 of 53
3
Author, date
Comment
Title
Key points
Grade
Peptostreptococcus magnus and prevotii, and bacteroides species.
The results of cultures on the unreliable specimens were similar. When “reliable” and
“unreliable” specimens were taken simultaneously from 26 patients, the results agreed in
only seven patients, however, the antibiotics that would have been selected in 24 cases
would have adequately covered all the pathogens whichever specimen was used.
The authors conclude that diabetic foot infections usually contain mixed bacterial flora and
that uncontaminated specimens are to be preferred.
Diagnosis of infection
(Bowler 2003)
Contribution to the
debate on the
significance of the
105 figure as a
determinant of
critical colonisation
The 105
bacterial growth
guideline:
reassessing its
clinical
relevance in
wound healing.
International Wound Infection Institute – Evidence Matrix
The microbiology of wounds is a key determinant in healing and clinicians generally accept
that a level of microbial (ie, bacterial) growth greater than 100,000 viable organisms per
gram of tissue can be used to diagnose infection. Although other factors that predispose a
wound to infection are widely recognized, today's wound care practitioners are influenced
primarily by the 105 guideline, with treatment being based on the microbial count in deep
or superficial tissue. However, to appropriately manage microbially challenged wounds (eg,
heavily colonized and clinically infected), a more balanced awareness of the broader issues
relating to micro-organisms and wounds is needed. The types of micro-organisms, their
interactions with each other and with the wound environment, the local conditions, and
host resistance are all key factors that collectively influence healing. From a microbiological
perspective, successful wound healing is dependent on maintaining a host-manageable
bioburden. If local conditions favor microbial growth, a wound may fail to heal and become
infected, requiring topical antiseptics or antibiotics to supplement the host inflammatory
response and restore balance in favor of the host. This paper provides a critical examination
Page 12 of 53
5
Author, date
Comment
Title
Key points
Grade
of the 105 guideline to enhance clinician understanding and utilization of a commonly
applied diagnostic consideration.
(Ceri, Olson et al.
1999)
(Cutting and
Harding 1994)
A method is
described for the
rapid assessment of
biofilm susceptibility
A useful and
influential paper
that had a
widespread effect
on clinical practice
The Calgary
biofilm device:
new technology
for rapid
determination
of antibiotic
susceptibilities
of bacterial
biofilms.
Biofilms have an inherent lack of susceptibility to antibiotics. Ceri et al describe the Calgary
Biofilm Device (CBD) which is a method for the rapid and reproducible assay of biofilm
susceptibility to antibiotics.
Criteria for
identifying
wound
infection.
Useful source of background information from various audits about wound infection rates
and the cost to healthcare systems of managing infections.
The paper describes the formation of biofilms and confirmation of their presence using
quantitative microbiology and SEM, followed by the rigorous testing and assessment of the
CBD assay using NCCLS reference strains of E coli, P aeruginosa and S aureus. Growth curves
demonstrated that biofilms grew uniformly in each of the 96 wells.
Antibiotic susceptibility testing demonstrated that, compared to planktonic forms of the
same bacteria, 100 to 1000 times the concentration of an antibiotic was required to
eradicate the biofilm structure. The authors claim that the CBD provides a method for the
rational selection of antibiotics effective against microbial biofilms.
However, the authors note that traditional criteria for identifying wounds, such as the
presence of pus or inflammation may not be adequate in some circumstances. They support
this by citing figures showing high percentages of infection becoming evident in patients
only after they had been discharged.
The authors provide a list of criteria for identifying wound infection. This includes the
International Wound Infection Institute – Evidence Matrix
3
Page 13 of 53
3
Author, date
Comment
Title
Key points
Grade
traditional criteria (abscess, cellulitis, discharge) but also some additional criteria that
should alert a clinician to the possibility of infection (delayed healing, discolouration, friable
granulation tissue, unexpected pain or tenderness, pocketing or bridging at the wound
base, abnormal smell and wound breakdown). Some of these criteria were suggested on the
basis of other studies, and some were based on empirical data from a large,
multidisciplinary practice (clinical experience).
(Cutting 1998)
Inter-rater reliability
testing of clinical
wound infection and
validity testing of
pre-determined
criteria
The
identification of
infection in
granulating
wounds by
registered
nurses.
The author carried out a study to validate the criteria for wound infection he had proposed
in an earlier paper (1994). Twenty ward nurses were asked to view wounds and make a
decision on the infection status using their own criteria. A researcher also viewed the
wounds using the 1994 Cutting and Harding criteria and a microbial assay was also taken via
wound swab. A total of 40 different patients were viewed and the findings suggested that
the 1994 criteria had a high degree of validity. All but one of the decisions made by the
researcher were corroborated by the wound swab culture.
(Cutting and
White 2005)
Extremely valuable
resource, often used
in other studies
Criteria for
identifying
wound infection
- revisited.
A 1994 paper by Cutting and Harding proposed a set of criteria which could be used to
5
identify wound infection. These were based on observations made in a large clinical practice
and were subsequently validated by Cutting (1998) and Gardner (2001).
The authors acknowledge that a weakness of the original criteria is that they do not
differentiate between wounds of different types which might make them less applicable in
some cases.
Using a review of the literature, Cutting and White have generated a list of infection criteria
that are applicable to various types of wound: acute, surgical, diabetic foot ulcer, venous
and arterial leg ulcer, pressure ulcer and burn. The paper includes a table listing the criteria
International Wound Infection Institute – Evidence Matrix
Page 14 of 53
3
Author, date
Comment
Title
Key points
Grade
for each of these wound types.
Cutting KF, White
RJ, Mahoney P,
Harding KG.
Reinforces and
validates the Cutting
& White 2005
criteria for wound
infection.
This article appears
in the
EWMA Position
Document.
Identifying criteria
for
wound infection.
London: MEP
(Dowd, Sun et al.
2008)
Very important
study revealing the
short-comings of
traditional culture
techniques in
identifying biofilms.
Clinical
identification of
wound
infection: a
Delphi
approach.
A multidisciplinary Delphi group of 54 expert members was used to generate and rank
infection criteria for acute wounds, arterial and venous leg ulcers, burns, diabetic foot
ulcers and pressure ulcers. Cellulitis, malodour, pain, delayed healing or deterioration of the
wound and/or wound breakdown were determined to be the common criteria for infection
amongst all six wound types.
5
This study used specific techniques to identify the major populations of bacteria that occur
in the biofilms found in three types of chronic wound: diabetic foot ulcer, venous leg ulcer
and pressure ulcer. The techniques were: three separate I 6S-based molecular
amplifications, followed by pyrosequencing, shotgun Sanger sequencing and denaturing
gradient gel electrophoresis.
3
In: EWMA
Position
Document.
Identifying
criteria for
wound infection.
London: MEP
Ltd, 2005.
Survey of
bacterial
diversity in
chronic wounds
using
Pyrosequencing,
DGGE and full
ribosome
International Wound Infection Institute – Evidence Matrix
All chronic wound types contained certain specific major populations of bacteria:
Staphylococcus, Pseudomonas, Peptoniphilus, Enterbacter, Stenotrophomonas, Finegoldia
Page 15 of 53
Author, date
Comment
Title
Key points
Grade
shotgun
sequencing.
and Serratia species. However, each of the wound types showed marked differences in their
bacterial populations.
For example, in venous ulcers over 80% of the bacteria were facultative anaerobes,
compared with 62% in diabetic foot ulcers, and just over 20% in pressure ulcers. Pressure
ulcers on the other hand comprised over 60% of strict anaerobes, compared with nearly
30% in diabetic foot ulcers and virtually none in venous ulcers.
Different wound types also showed a different level of oxygen tolerance amongst their
bacterial populations. The authors suggest that this may imply each wound type has a
distinct pathophysiology that affects the ecology of the wound environment determiging
which bacteria can develop.
Results were compared with those from traditional culture-based analyses. In only one
wound type did the culture methods correctly identify the primary bacterial population.
Standard culturing techniques are inherently flawed as they only examine the 1% of
microorganisms that are able to grow rapidly in pure culture. Also, certain populations may
never be cultured in the laboratory due to reduced metabolic activity, obligate cooperation
with other bacteria, need for specialized nutrients or environmental conditions.
The paper gives full details of the bacteria identified.
(Gardner, Frantz
et al. 2001)
A useful and
frequently cited
article.
The validity of
the clinical signs
and symptoms
used to identify
International Wound Infection Institute – Evidence Matrix
Following on from the publication in 1994 of suggested criteria for wound infection (Cutting
and Harding 1994) Gardner et al carried out a study to validate these suggested criteria.
Thirty-six chronic wounds were assessed for the 12 signs and symptoms of infection. Five
Page 16 of 53
3
Author, date
Comment
Title
Key points
Grade
localized chronic nurses were trained in identifying the criteria.
wound
The wounds were then quantitatively cultured via biopsy to identify correlation between
infection.
the assessment and infection. The presence or absence of signs and symptoms was
compared with the infection status as defined by the culture results.
The authors found that although each sign and symptoms was valid to some degree, four
items: increasing pain, friable granulation tissue, foul odour and wound breakdown were
valid criteria based on four parameters – sensitivity, specificity, discriminatory power and
positive predictive value.
They also suggest that in chronic wounds the signs specific to secondary wounds (as
proposed by cutting and Harding) were better indicators of chronic wound infection than
the classic signs.
The authors also found that inter-observer reliability ranged from 0.53 to 1.00 suggesting
that the check-list could be used reliably by a variety of people. Inter-clinician variability was
not assessed and the authors did not attempt to discriminate by wound type but
nonetheless the results were sufficiently robust to warrant inclusion in routine wound
assessment.
(Hill, Davies et al.
2003)
Molecular
analysis of the
microflora in
chronic venous
leg ulceration.
International Wound Infection Institute – Evidence Matrix
Culture analyses of CVLU generally reveal staphylococci, streptococci, enterococci and
facultative Gram-negative bacilli. However, anaerobic isolation techniques and prolonged
incubation reveal the presence of fastidious and slow-growing anaerobic species such as
Fusobacterium and peptostreptococci. Cultivation-dependent methods for characterising
Page 17 of 53
3
Author, date
Comment
Title
Key points
Grade
the microflora of chronic wounds are limited.
The authors describe the analysis using 16S rDNA sequences of tissue from a CVLU which
demonstrated significantly greater bacterial diversity than culture methods. Sequences
even suggested novel species of bacteria. This technique can clearly not be used routinely
so the clinical application is limited but may inform treatment in deteriorating or longlasting wounds.
Topical treatments: antiseptics and antibiotics
(Cooper, Laxer et
al. 1991)
(Drosou, Falabella An important review
et al. 2003)
which collected
together and
explained the
The cytotoxic
effects of
commonly used
topical antimicrobial agents
on human
fibroblasts and
keratinocytes.
An in vitro study which assessed the effect of a number of topical antimicrobials on human
dermal fibroblasts and epidermal keratinocytes. The agents studied were: polysporin,
bacitracin, polymyxin B, GU irrigant, neomycin, gentamicin, sulfamylon, betadine, acetic
acid and modified Dakins solution.
The authors conclude that many antimicrobial agents have adverse effects on fibroblasts
and keratinocytes. However, subsequent animal and human studies found that the in vivo
situation was different (see Drosou).
Antiseptics on
A significant review article which attempted to resolve the controversy about the use of
wounds: an area antiseptics on open wounds. Some authors had argued against their use, citing cytotoxicity
of controversy.
data in support; other investigators found no evidence of adverse effects on healing.
International Wound Infection Institute – Evidence Matrix
3
Page 18 of 53
5
Author, date
Comment
Title
various animal and
human studies into
antiseptics. This
paper helped to
dispel the view that
antiseptics were
cytotoxic in vivo.
Key points
Grade
The review begins with a useful section on antiseptics, and their use on intact skin, before
providing a rationale for their use in wounds, which includes their ability to kill many
different types of bacteria and the very low possibility that bacteria will develop resistance
against them.
Balancing this, the authors summarise the arguments against using antiseptics in open
wounds. This includes the possible cytotoxicity demonstrated by in vitro studies, and the
possibility that antiseptics will be largely inactivated by wound fluids. The article then
reviews the animal and human studies of antiseptics and ignores the in vitro studies, on the
basis that the laboratory studies can not take into account the physiological effects
pertaining to actual wounds. The article reviews povidone-iodine, cadexomer iodine,
hydrogen peroxide, acetic acid, chlorhexidine and silver.
Povidone-iodine. Animal studies found little benefit but only used a single application or
applications more than three hours after wounding. Most human trials proved the efficacy
of povidone-iodine in burns, sutured lacerations, non-infected venous leg ulcers, surgical
wounds (1%, not 5%). Other studies could not confirm these results. The reported effects
on wound healing are conflicting which may be due to differences in the parameters
evaluated, the assessment times, the concentrations, the diversity of wounds and, in animal
experiments, the type of animal. Most clinical studies showed no adverse effects on the
wound healing rate when a 1% solution is used.
Cadexomer iodine. Positive results have been found both in animal and human studies (see
section on Iodine for details). Animal studies suggest that cadexomer iodine increased
epidermal regeneration and epithelialisation but has no effect on granulation tissue
formation, neovascularisation or wound contraction. In clinical studies cadexomer iodine
International Wound Infection Institute – Evidence Matrix
Page 19 of 53
Author, date
Comment
Title
Key points
Grade
has not been found to have any detrimental effects on wound healing, and may even have
beneficial effects.
Hydrogen peroxide. The situation with hydrogen peroxide is less clear-cut with some
conflicting results. Overall it appears that it does not negatively affect wound healing, but is
not very effective. The effervescent effect may provide some mechanical benefit in
loosening debris.
Acetic acid. In vivo studies did not confirm the cytotoxic effects found in in vitro studies.
Chlorhexidine. Chlorhexidine appears to be relatively safe with little effect on wound
healing but there are insufficient results to draw conclusions about its utility in open
wounds.
Silver. Silver compounds do not have a negative effect on wounds and may accelerate
wound healing. See the section on silver compounds as many papers in this area have been
published since the Drosou paper.
The paper contains very comprehensive tables listing all the studies reviewed.
(Fumal, Braham
et al. 2002)
The beneficial
toxicity paradox
of
antimicrobials in
leg ulcer healing
impaired by a
International Wound Infection Institute – Evidence Matrix
Two lesions in each of 51 patients with chronic leg ulcers were studied. The ulcers were
long-standing but were not apparently infected. The two target ulcers were randomised to
receive saline rinse and hydrocolloid (control) or control plus antimicrobial. The test
antimicrobials were: 10% povidone-iodine, 1% silver sulfadiazine (SSD) or 5% chlorhexidine.
After six weeks, the healing rate was slightly improved with SSD and chlorhexidine, but was
Page 20 of 53
2
Author, date
Comment
Title
Key points
Grade
polymicrobial
significantly improved with povidone-iodine (p<0.01).
flora: a proof-ofBased on histological analysis, the authors suggest that the beneficial effect of povidoneconcept study.
iodine is not due just to an antimicrobial effect but to a positive effect on biological
mechanisms.
(Gruber, Vistnes
et al. 1975)
Very influential
study which refuted
the suggestion that
antiseptics are
detrimental to
healing
The effect of
commonly used
antiseptics on
wound healing.
An animal and clinical study to evaluate the effect of some common antiseptic agents on
wound contraction, epithelialisation, and migration of epidermis across the wound surface.
Three agents were studied: acetic acid (25%), povidone-iodine (Betadine), hydrogen
peroxide (3%) and saline control. The agents were applied to partial and full-thickness
wounds in 60 rats, or to donor sites in 40 patients until full epithelialisation had taken place.
Serial microscopy was used to study the effect of the agents.
3
No delay of epithelialisation compared to saline control was noted either macroscopically or
microscopically with any of the agents. In fact, hydrogen peroxide shorted the healing time
(defined as a pink surface, without scab). The authors suggest this may be due to the
effervescent action of hydrogen peroxide allowing earlier separation of the scab. This may
also be responsible for some bullae which developed on the donor site.
(Kucan, Robson et
al. 1981)
Comparison of
silver
sulfadiazine,
povidone-iodine
and physiologic
saline in the
treatment of
International Wound Infection Institute – Evidence Matrix
2/3
The presence of bacteria and local infection is an important factor in the local management
of chronic pressure ulcers. For successful closure of the ulcer, the bacterial count should be
105 or less per gram of tissue in the granulating wound. In a prospective randomized study
of 45 (eventually 40) hospitalized patients, silver sulfadiazine (Silvadene) cream and
Page 21 of 53
Author, date
Comment
Title
Key points
Grade
chronic pressure
ulcers.
povidone-iodine (Betadine) solution were compared to physiologic saline for effectiveness
in preparing pressure ulcers for closure. Quantitative bacteriologic techniques on tissue
biopsy specimens were used for objective evaluation. In 100 percent of the ulcers treated
with silver sulfadiazine cream (15 patients) the bacterial counts were reduced to 10(5) or
less per gram of tissue within the three-week test period, compared to 78.6 percent in
those treated with saline (14 patients) and 63.6 percent in those treated with povidoneiodine solution (11 patients). Moreover, the ulcers treated with silver sulfadiazine cream
responded more rapidly, with one-third showing bacterial levels of less than 10(5) within
three days, and half within a week (Published abstract).
(Lineweaver,
Howard et al.
1985)
A paper that has
often been cited as
proof that antiseptic
agents adversely
affect wound
healing. Later
studies, using
sustained release
preparations,
suggested
otherwise.
Topical
antimicrobial
toxicity.
International Wound Infection Institute – Evidence Matrix
Three topical antibiotics and four antiseptics were applied to cultured human fibroblasts to 3
quantitatively assess their cytotoxicity. The antibiotics used were bacitracin, 1% neomycin
sulphate and 2% kanamycin sulphate; while the antiseptics were 1% povidone-iodine, 0.25%
acetic acid, 0.5% sodium hypochlorite and 3% hydrogen peroxide.
At full strength, none of the antibiotics was toxic to fibroblasts. The four antiseptics were
found to be cytotoxic [at these concentrations]. Serial dilutions showed that the cytotoxic
effects of hydrogen peroxide and acetic acid exceeded their bacterial effects, whereas it
was possible to prepare dilutions of non-cytotoxic povidone-iodine and sodium
hypochlorite.
The antiseptic agents and saline control were also applied to animal wounds three times a
day, and the size of the unepithelialised area of the wounds was recorded at 4, 8, 12 and 16
Page 22 of 53
Author, date
Comment
Title
Key points
Grade
days after wounding. At four days, wounds irrigated with 1% povidone-iodine were
significantly weaker than wounds irrigated with saline, other topical agents, or unirrigated
wounds. Wound epithelialisation was significantly retarded at four days by povidone-iodine
and acetic acid, at eight days by povidone-iodine, acetic acid and sodium hypochlorite and
at 16 days by sodium hypochlorite.
(Mertz, Alvarez et
al. 1984)
(Viljanto 1980)
Fairly useful study
which showed that
one single
application of an
antiseptic agent has
limited antibacterial
effect.
Useful
A new in vivo
model for the
evaluation of
topical
antiseptics on
superficial
wounds: the
effect of 70%
alcohol and
povidone-iodine
solution.
Six partial thickness wounds in each of nine pigs were inoculated with S aureus and were
then treated with 0.1ml of either 70% alcohol, 10% povidone-iodine solution or distilled
water control. The agents were rubbed into the wound for 30 seconds. The agents were left
on the wounds for one minute, three minutes or 24 hours and were cultured for bacteria.
Disinfection of
surgical wounds
without
inhibition of
normal wound
healing.
While intact skin can withstand very strong disinfective agents, the cells of a fresh surgical
wound are much more susceptible to damage.
International Wound Infection Institute – Evidence Matrix
3
After one minute, neither solution reduced the number of pathogens. After three minutes,
both agents produced a slight reduction, and after 24 hours, povidone-iodine slightly
reduced the number of pathogens. After 24 hours, neither agent reduced the number of
pathogens below 105 CFU per ml.
The authors conclude that single applications of these agents only provide limited efficacy
against pathogens in superficial wounds. This treatment design was chosen as it mimics the
usual emergency treatment of abrasions.
Povidone-iodine solutions (5% and 1%) or no disinfectant were applied to the surgical
wounds of 294 paediatric patients, 283 of whom had undergone appendectomy. The
disinfectant was applied to the wound by a nurse without the surgeon knowing which
Page 23 of 53
3
Author, date
Comment
Title
Key points
Grade
patient would be treated.
Regardless of the state of the appendix there was a significant increase in wound infections
in the 5% group compared to the control (p<0.001). Using a cellstic method, it was found
that the 5% solution inhibited leukocyte migration. Most of the nuclei were pyknotic and
the chromatin often appeared to lack structure. No cell aggregates or fibroblasts were seen.
The 1% solution allowed better cellular movement and attachment, and some cell
aggregates were visible. Cell morphology was very similar to that in the saline control.
No wound infections developed in the patients disinfected with 1% solution; 8.5% of
patients in the saline control developed infections. Although 1% povidone-iodine is useful in
local disinfection of the wound, where infection progressed beyond the appendix, such as in
peritonitis, local disinfection was inadequate.
Iodine
(Apelqvist and
Ragnarson 1996)
Cavity foot
ulcers in
diabetic
patients: a
comparative
study of
cadexomer
iodine ointment
and standard
treatment. An
41 patients with deep exudative diabetic foot ulcers were included in a 12 week, open,
randomized, comparative study comparing cadexomer iodine treatment with standard
treatment.
International Wound Infection Institute – Evidence Matrix
Page 24 of 53
No clinical difference between Iodosorb and other treatments: gentamicin solution,
stretodornase/streptokinase, dry saline gauze.
2
Author, date
Comment
Title
Key points
Grade
economic
analysis
alongside a
clinical trial.
(Danielsen,
Cherry et al.
1997)
(Hansson 1998)
Large study, but the
section on infection
is weak as little
detail is given.
Cadexomer
iodine in ulcers
colonised by
Pseudomonas
aeruginosa.
An open, uncontrolled, multi-centre pilot study in three countries (Sweden, Denmark, UK) in 3
19 patients with venous leg ulcer.
The effects of
cadexomer
iodine paste in
the treatment
of venous leg
ulcers compared
with
hydrocolloid
dressing and
paraffin gauze
dressing.
Cadexomer
Iodine Study
Group.
A 12 week randomized, open, controlled, multicenter study with 153 patients with
exudating venous leg ulcers who were treated with cadexomer iodine paste, hydrocolloid
dressing, or paraffin gauze dressing, combined with short-stretch compression bandages.
International Wound Infection Institute – Evidence Matrix
Bacterial cultures for growth of Ps aeruginosa were carried out regularly. After one week of
treatment, 11/17 ulcers had negative culture for Ps aeruginosa, and 6/8 at 12 weeks.
The authors report that wound infection was more common with hydrocolloid and paraffin
gauze than with the cadexomer iodine paste but give no detail as to how infection was
assessed or recorded.
At weeks 4 and 8, wounds treated with cadexomer iodine had significantly lower levels of
slough than those treated with paraffin gauze, but there was no significant difference
between cadexomer iodine and hydrocolloid.
Page 25 of 53
2
Author, date
(Hillström 1988)
(Holloway,
Johansen et al.
1989)
Comment
Title
Key points
Grade
Iodosorb
compared to
standard
treatment in
chronic venous
leg ulcers - a
multicenter
study.
Multi-centre study with 93 patients.
3
Multicenter trial
of cadexomer
iodine to treat
venous stasis
ulcer.
Controlled, cross-over study in the US with 75 patients assigned to cadexomer iodine or
standard treatment (saline, wet-to-dry compression) for venous stasis ulcers.
The number of isolates of S aureus was significantly lower after application of cadexomer
iodine. Ps aeruginosa and other organisms were also significantly reduced.
Cleansing action was assessed visually on scales that assessed the amount of exudate, pus
and debris on the ulcer surface. Cadexomer iodine appeared to be more effective but not to
the level of statistical significance.
Nothing is specifically mentioned about antimicrobial action but slough removal was more
effective with cadexomer iodine.
International Wound Infection Institute – Evidence Matrix
Page 26 of 53
3
Author, date
Comment
Title
Key points
Grade
(Mertz, Davis et
al. 1994)
Well-conducted
study but small
numbers
Can
antimicrobials
be effective
without
impairing
wound healing?
The evaluation
of cadexomer
iodine ointment.
An animal study in which partial thickness wounds infected with S aureus or Ps aeruginosa
were treated with cadexomer iodine ointment, ointment base or no treatment.
2
At 24, 48 and 72 hours there were significantly fewer numbers of S aureus recovered from
cadexomer-iodine treated wounds compared to the other two groups (p<0.03).
In wounds inoculated with Ps aeruginosa, the number of microbes recovered from all
wounds fell markedly between 24 and 72 hours. Only at 48 hours did cadexomer iodine
ointment reduce bacterial levels compared to no treatment, but not to the ointment base.
There was a sustained effect against S aureus, but the low numbers of Ps aeruginosa seen in
all wounds suggests that no treatment group provided ideal conditions for its growth.
In addition to the antimicrobial action demonstrated in this study the authors showed that
there no trade-off with healing. They found that cadexomer iodine had no deleterious
effect on epithelialisation, indeed it accelerated healing compared to air-exposed wounds.
(Mertz, OliveiraGandia et al.
1999)
The evaluation
of a cadexomer
iodine wound
dressing on
methicillin
resistant
Staphylococcus
aureus (MRSA)
in acute
International Wound Infection Institute – Evidence Matrix
An animal study in which partial thickness wounds were infected with MRSA and were
treated with either cadexomer iodine or the vehicle dressing without iodine, or with no
treatment.
The cadexomer iodine dressing significantly reduced MRSA and total bacteria compared to
wounds with either no treatment or the inactive dressing.
Page 27 of 53
3
Author, date
Comment
Title
Key points
Grade
Controlled trial
of Iodosorb in
chronic venous
ulcers.
Randomised, optional cross-over trial of 61 out-patients with venous ulcers using
cadexomer iodine or standard dressings.
3
Bactericidal
activity and
toxicity of
iodinecontaining
solutions in
wounds.
Complexing iodine with povidone (polyvinylpyrrolidone) or surfactants significantly limits
the quantity of free iodine. Reduction of the free iodine level eliminates the adverse
properties of staining, instability, and irritation and also alters bactericidal activity. Addition
of detergents to create surgical scrub solutions further reduces the activity of iodine. In
vitro testing indicated that the bactericidal activity of iodophors was inferior to that of
uncomplexed aqueous iodine. In vivo tests proved that aqueous iodine significantly
potentiated the development of infection. Although the povidone iodophor did not
enhance the rate of wound or infection, it offered no therapeutic benefit when compared
with control wounds treated with saline solution. Addition of detergents to the povidone
iodophor was deleterious, with the wounds exposed to this combination displaying
significantly higher infection rates than untreated control wounds. Based on these results,
aqueous iodine solutions and iodophor surgical scrub solutions should not be used on
broken skin. Aqueous iodophors can be used in wounds, but no therapeutic benefit from
such use was found in this study (Published abstract).
wounds.
(Ormiston,
Seymour et al.
1985)
(Rodeheaver,
Bellamy et al.
1982)
Good trial
International Wound Infection Institute – Evidence Matrix
No significant effect on bacterial colonisation. A wide and changing variety of organisms
were cultured, and there was no consistent trend towards eradication of particular
pathogens, irrespective of the treatment or response of the ulcer.
Page 28 of 53
3
Author, date
Comment
Title
Key points
Grade
(Skog, Arnesjö et
al. 1983)
Well-conducted
A randomized
trial comparing
cadexomer
iodine and
standard
treatment in the
out-patient
management of
chronic venous
ulcers.
A randomized trial in 93 out-patients comparing cadexomer iodine and standard treatment
in the treatment of chronic venous leg ulcers.
2
In-patient
treatment of
chronic varicose
venous ulcers. A
randomized trial
of cadexomer
iodine versus
standard
dressings.
2
A total of 67 patients with treatment resistant chronic venous ulcers were admitted to
hospital for 6 weeks of bed rest and daily dressings. The patients came from a rural area in
Poland with poor socioeconomic conditions. They were randomized to treatment with
either standard dressings or with cadexomer iodine. After 6 weeks all but four patients had
shown a clear reduction of ulcer area; the mean reduction was 54% within the former group
and 71% with cadexomer iodine. The latter treatment was significantly more effective than
the standard hospital dressings in debriding the ulcer, accelerating healing and reducing
pain. Elevation of serum concentrations of protein-bound iodine occurred after treatment
with cadexomer iodine in patients with large ulcers, but tests of thyroid function showed no
changes associated with the use of cadexomer iodine.
(Laudanska and
Gustavson 1988)
Cleansing effect of cadexomer iodine was significantly greater than that of standard
treatment (p<0.005).
Cadexomer iodine significantly reduced infection with S aureus, Ps aeruginosa, and other
organisms such as: Streptococcus, Proteus, Enterobacteria and Klebsiella.
It is concluded that cadexomer iodine significantly accelerates the healing of chronic,
infected, treatment-resistant, venous ulcers in hospitalized patients.
International Wound Infection Institute – Evidence Matrix
Page 29 of 53
Author, date
Comment
Title
Key points
Grade
Chlorhexidine
(Drosou, Falabella
et al. 2003)
Antiseptics on
A significant review article which attempted to resolve the controversy about the use of
wounds: an area antiseptics on open wounds.
of controversy.
They found that chlorhexidine appears to be relatively safe with little effect on wound
healing but there are insufficient results to draw conclusions about its utility in open
wounds.
5
Previously reviewed
(Fumal, Braham
et al. 2002)
The beneficial
toxicity paradox
of
antimicrobials in
leg ulcer healing
impaired by a
polymicrobial
flora: a proof-ofconcept study.
International Wound Infection Institute – Evidence Matrix
Two lesions in each of 51 patients with chronic leg ulcers were studied. The ulcers were
long-standing but were not apparently infected. The two target ulcers were randomised to
receive saline rinse and hydrocolloid (control) or control plus antimicrobial. The test
antimicrobials were: 10% povidone-iodine, 1% silver sulfadiazine (SSD) or 5% chlorhexidine.
After six weeks, the healing rate was slightly improved with SSD and chlorhexidine, but was
significantly improved with povidone-iodine (p<0.01).
Based on histological analysis, the authors suggest that the beneficial effect of povidone-
Page 30 of 53
2
Author, date
Comment
Title
Key points
Grade
iodine is not due just to an antimicrobial effect but to a positive effect on biological
mechanisms.
Previously reviewed
(Wu, Crews et al.
2008)
Use of
chlorhexidineimpregnated
patch at pin site
to reduce local
morbidity: the
ChIPPS Pilot
Trial.
This study evaluated the use of chlorhexidine impregnated polyurethane dressings applied
to pin sites for external fixation devices in 20 patients compared with 20 controls. There
was a significantly lower rate of pin tract infections in patients who were fitted with the
chlorhexidine dressings.
3
BACKGROUND: Nanocrystalline silver has both antimicrobial and anti-inflammatory
properties. However, the exact mechanisms underlying these activities are not known.
3
Silver, basic science and lab experiments
(Bhol and
Schechter 2005)
Topical
nanocrystalline
silver cream
suppresses
inflammatory
cytokines and
induces
International Wound Infection Institute – Evidence Matrix
OBJECTIVES: The objectives of this study were to assess the anti-inflammatory effects of
nanocrystalline silver using a murine model of allergic contact dermatitis, compare the
effects with those of tacrolimus and a high potency steroid, and to relate the effects to
Page 31 of 53
Author, date
Comment
Title
Key points
Grade
apoptosis of
inflammatory
cells in a murine
model of allergic
contact
dermatitis.
modulation of pro-inflammatory cytokines and apoptosis of inflammatory cells. METHODS:
Dermatitis was induced on the ears of BALB/c mice using dinitrofluorobenzene. Topical
treatment, including vehicles, 1% nanocrystalline silver cream, tacrolimus ointment and a
high potency steroid, was applied once a day for 4 days. Ear swelling was measured and the
erythema was evaluated daily. After 4 days of treatment the mice were killed and samples
from the ears were collected for histological and immunohistochemical examination,
terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labelling
(TUNEL) staining and extraction of total RNA for reverse transcriptase polymerase chain
reaction (RT-PCR). RESULTS: Significant reductions of ear swelling, erythema and
histopathological inflammation in mice ears were observed after 4 days of treatment with
1% nanocrystalline silver cream, tacrolimus ointment or a high potency steroid with no
significant difference among them. Both RT-PCR and immunohistochemical staining of
sections from ear biopsies demonstrated that nanocrystalline silver, tacrolimus and steroid
significantly suppressed the expression of tumour necrosis factor (TNF)-alpha and and IL-12
and induces apoptosis of inflammatory cells; mechanisms by which nanocrystalline silver
may exert its anti-inflammatory effects (Published abstract).
(Burd, Kwok et al.
2007)
A comparative
study of the
cytotoxicity of
International Wound Infection Institute – Evidence Matrix
Over the past decade, a variety of advanced silver-based dressings have been developed.
There are considerable variations in the structure, composition, and silver content of these
Page 32 of 53
3
Author, date
Comment
Title
Key points
Grade
silver-based
dressings in
monolayer cell,
tissue explant,
and animal
models.
new preparations. In the present study, we examined five commercially available silverbased dressings (Acticoat, Aquacel Ag, Contreet Foam, PolyMem Silver, Urgotul SSD). We
assessed their cytotoxicity in a monolayer cell culture, a tissue explant culture model, and a
mouse excisional wound model. The results showed that Acticoat, Aquacel Ag, and Contreet
Foam, when pretreated with specific solutes, were likely to produce the most significant
cytotoxic effects on both cultured keratinocytes and fibroblasts, while PolyMem Silver and
Urgotul SSD demonstrated the least cytotoxicity. The cytotoxicity correlated with the silver
released from the dressings as measured by silver concentration in the culture medium. In
the tissue explant culture model, in which the epidermal cell proliferation was evaluated, all
silver dressings resulted in a significant delay of reepithelialization. In the mouse excisional
wound model, Acticoat and Contreet Foam indicated a strong inhibition of wound
reepithelialization on the postwounding-day 7. These findings may, in part, explain the
clinical observations of delayed wound healing or inhibition of wound epithelialization after
the use of certain topical silver dressings. Caution should be exercised in using silver-based
dressings in clean superficial wounds such as donor sites and superficial burns and also
when cultured cells are being applied to wounds (Published abstract).
(Dunn and
Edwards-Jones
The role of
Acticoat with
nanocrystalline
International Wound Infection Institute – Evidence Matrix
Silver is an effective antimicrobial agent, but older silver-containing formulations are rapidly
inactivated by the wound environment, requiring frequent replenishment. These older
formulations may also be pro-inflammatory and may delay healing. Acticoat (Smith &
Page 33 of 53
4
Author, date
Comment
2004)
(Fong, J. 2005).
(Fraser, Bodman
et al. 2004)
A comparison of
standard burn
treatment (SSD)
compared to
nanocrystalline
silver dressings
Title
Key points
silver in the
management of
burns.
Nephew, Hull, UK) is a relatively new form of silver antimicrobial barrier dressing which
helps avoid the problems of earlier agents. It has rapid and sustained bactericidal activity,
and because of this may reduce inflammation and promote healing. Despite extensive
testing and clinical experience, no evidence has emerged of resistance or cytotoxicity to
nanocrystalline silver. This article collects together a number of presentations that were
given at the 2003 European Burns Association Meeting on the use of Acticoat in the
management of burns (Published abstract).
The use of silver
products in the
management of
burn wounds:
Change in
practice for the
burn unit at
Royal Perth
Hospital.
An in vitro study
of the antimicrobial
efficacy of a 1%
silver
sulfadiazine and
0.2%
chlorhexidine
Details before and after patient care audits conducted in a burns unit in 2000 and 2002. The
outcome variables were burn wound cellulitis, antibiotic use and cost of treatment. The two
regimes audited were twice daily showers or washes with chlorhexidine 4% soap followed
by the application of silver sulphadiazine cream or nanocrystalline silver (Acticoat™). The
audit demonstrated reduced incidence of infection and antibiotic use as well as cost savings
in the treatment of burns with nanocrystalline silver as compared to SSD.
4
Burn sepsis is a leading cause of mortality and morbidity in patients
with major burns. The use of topical anti-microbial agents has helped
improve the survival in these patients. There are a number of anti-
3
International Wound Infection Institute – Evidence Matrix
Grade
microbials available, one of which, Silvazine (1% silver sulphadiazine
(SSD) and 0.2% chlorhexidine digluconate), is used only in Australasia.
No study, in vitro or clinical, had compared Silvazine with the new
dressing Acticoat. This study compared the anti-microbial activity of
Page 34 of 53
Author, date
Comment
Title
Key points
digluconate
cream, 1% silver
sulfadiazine
cream and a
silver coated
dressing.
Silvazine, Acticoat and 1% silver sulphadiazine (Flamazine) against eight
common burn wound pathogens. METHODS: Each organism was
prepared as a suspension. A 10 microl inoculum of the chosen bacterial
Grade
isolate (representing approximately between 10(4) and 10(5) total
bacteria) was added to each of four vials, followed by samples of each
dressing and a control. The broths were then incubated and 10 microl
loops removed at specified intervals and transferred onto Horse Blood
Agar. These plates were then incubated for 18 hours and a colony count
was performed. RESULTS: The data demonstrates that the combination
of 1% SSD and 0.2% chlorhexidine digluconate (Silvazine) results in the
most effective killing of all bacteria. SSD and Acticoat had similar
efficacies against a number of isolates, but Acticoat seemed only
bacteriostatic against E. faecalis and methicillin-resistant
Staphylococcus aureus. Viable quantities of Enterobacter cloacae and
Proteus mirabilis remained at 24h. CONCLUSION: The combination of
1% SSD and 0.2% chlorhexidine digluconate (Silvazine) is a more
effective anti-microbial against a number of burn wound pathogens in
this in vitro study. A clinical study of its in vivo anti-microbial efficacy is
required (Published abstract).
International Wound Infection Institute – Evidence Matrix
Page 35 of 53
Author, date
(Lam, Chan et al.
2004)
Comment
Title
Key points
Grade
In vitro
cytotoxicity
testing of a
nanocrystalline
silver dressing
(Acticoat) on
cultured
keratinocytes.
Acticoat is a polyethylene mesh coated with nanocrystalline silver. It has been used widely
as a dressing for chronic wounds, acute partial-thickness burn wounds and donor sites. In
this study, the in vitro cytotoxicity of Acticoat on cultured keratinocytes is tested. Human
3
keratinocytes are cultivated on a pliable hyaluronate-derived membrane (Laserskin) using
dermal fibroblasts as the feeder layer. When the cultured Laserskin (CLS) is subconfluent it
is covered by Acticoat, which is exposed to water (Group 1), phosphate-buffered saline
(Group 2) or culture medium (Group 3). The control group is not exposed to the Acticoat.
After 30 minutes incubation at 37 degrees C, the inhibitory effect of the nanocrystalline
silver on keratinocyte growth is measured by an MTT assay. Compared with the control, the
relative viability of the CLS dropped to 0%, 0% and 9.3%, respectively. Thus, Acticoat is
cytotoxic to cultured keratinocytes and should not be applied as a topical dressing on
cultured skin grafts
(Lansdown,
Jensen et al.
2003)
Contreet Foam
and Contreet
Hydrocolloid: an
insight into two
new silvercontaining
dressings.
International Wound Infection Institute – Evidence Matrix
In vitro laboratory tests and preliminary clinical trials have found that two silver-containing
dressings, Contreet Foam and Contreet Hydrocolloid, promote healing in infected and
chronic venous leg ulcers and diabetic foot ulcers
Page 36 of 53
4
Author, date
(Muller, Winkler
et al. 2003)
(Paddle-Ledinek,
Nasa et al. 2006)
Comment
Title
Key points
Grade
Antibacterial
activity and
endotoxinbinding capacity
of Actisorb
Silver 220.
Actisorb Silver 220 wound dressing demonstrated a high in vitro endotoxin-binding capacity 3
combined with a marked bactericidal activity without releasing Pseudomonas aeruginosa
endotoxins into the environment, and so may be beneficial in the treatment of infected
Effect of
different wound
dressings on cell
viability and
proliferation.
Keratinocyte cultures were exposed for 40 hours to extracts of Acticoat, Aquacel-Ag,
Aquacel, Algisite M, Avance, Comfeel Plus transparent, Contreet-H, Hydrasorb and SeaSorb
with silicone extract as a reference. Cell survival and proliferation were measured.
wounds, particularly colonization by Gram-negative bacteria..
3
The authors found that extracts of silver-containing dressings were most cytotoxic. Extracts
of Hydrasorb were less cytotoxic but affected keratinocyte proliferation and morphology.
Extracts of alginate-containing dressings had high calcium concentrations which markedly
reduced keratinocyte proliferation and affected morphology. Aquacel and Comfeel
inhibited keratinocyte proliferation to a small but significant degree.
The authors conclude that silver dressings should not be used in the absence of infection.
(Poon and Burd
2004)
In vitro
cytotoxicity of
silver:
implication for
International Wound Infection Institute – Evidence Matrix
In this study, we look at the cytotoxic effects of silver on keratinocytes and fibroblasts. We
have assessed the viability of monolayer cultures using the MTT and BrdU assays. The
composition of the culture medium and also the culture technique were modified to assess
Page 37 of 53
3
Author, date
Comment
Title
Key points
Grade
clinical wound
care.
the effects of culture 'environment' on the susceptibility of the cells to the toxic action of
silver. Further in vitro, experiments were performed using tissue culture models to allow
cellular behavior in three dimensional planes which more closely simulated in vivo behavior.
The silver source was both silver released from silver nitrate solution but also
nanocrystalline silver released from a commercially available dressing. The results show that
silver is highly toxic to both keratinocytes and fibroblasts in monolayer culture. When using
optimized and individualized culture the fibroblasts appear to be more sensitive to silver
than keratinocytes. However, when both cell types were grown in the same medium their
viability was the same. Using tissue culture models again indicated an 'environmental effect'
with decreased sensitivity of the cells to the cytotoxic effects of the silver. Nevertheless in
these studies the toxic dose of skin cells ranging from 7 x 10(-4) to 55 x 10(-4)% was similar
to that of bacteria. These results suggest that consideration of the cytotoxic effects of silver
and silver-based products should be taken when deciding on dressings for specific wound
care strategies. This is important when using keratinocyte culture, in situ, which is playing
an increasing role in contemporary wound and burn care
(Silver, Phung et
al. 2006)
Silver as
biocides in burn
and wound
dressings and
International Wound Infection Institute – Evidence Matrix
Silver products have been used for thousands of years for their beneficial effects, often for
hygiene and in more recent years as antimicrobials on wounds from burns, trauma, and
diabetic ulcers. Silver sulfadiazine creams (Silvazine and Flamazine) are topical ointments
Page 38 of 53
5
Author, date
Comment
Title
Key points
Grade
bacterial
resistance to
silver
compounds.
that are marketed globally. In recent years, a range of wound dressings with slow-release Ag
compounds have been introduced, including Acticoat, Actisorb Silver, Silverlon, and others.
While these are generally accepted as useful for control of bacterial infections (and also
against fungi and viruses), key issues remain, including importantly the relative efficacy of
different silver products for wound and burn uses and the existence of microbes that are
resistant to Ag+. These are beneficial products needing further study, although each has
drawbacks. The genes (and proteins) involved in bacterial resistance to Ag have been
defined and studied in recent years (Published abstract).
(Supp, Nelly et al.
2005)
Evaluation of
cytotoxicity and
antimicrobial
activity of
Acticoat burn
dressing for
management of
microbial
contamination
in cultured skin
substitutes
grafted to
athymic mice.
International Wound Infection Institute – Evidence Matrix
This study evaluated the cytotoxicity and microbial efficacy of Acticoat when used with
cultured skin substitutes (CSS) which are often used in the closure of burn wounds. CSS was
grafted to full-thickness wounds in athymic mice. The cytotoxicity of the dressing was
evaluated after one week of exposure during in vitro maturation, or by assessment of
healing on the mice. After four weeks, wound biopsies were evaluated for engraftment of
human cells.
In a subsequent experiment wounds were inoculated with P aeruginosa before application
of CSS.
The authors found that, in vitro, Acticoat was cytotoxic to CSS within one day, but in vivo,
one week of exposure did not injure CSS or inhibit wound healing. Contaminated wounds
treated with Acticoat healed similarly to control treatments, with comparable rates of
engraftment. None of the test strain of P aeruginosa was found in the wound after
Page 39 of 53
3
Author, date
Comment
Title
Key points
Grade
inoculation onto the surface of Acticoat.
They conclude that Acticoat may be effective as a protective dressing to reduce
environmental contamination of CSS, but suggest that additional antimicrobials may be
required to control organisms in the wound (Published abstract)
(Thomas and
McCubbin 2003)
An in vitro
analysis of the
antimicrobial
properties of 10
silver-containing
dressings.
The authors were interested to examine how dressings with different silver content and
composition might release silver in sufficiently high concentrations to exert a significant
antimicrobial effect. An earlier study investigated Acticoat, Actisorb Silver 220, Avance and
Contreet-H and these were included along with six new dressings: Arglaes, Aquacel Ag,
Calgitrol, Contreet Ag, Silverlon, Silvasorb and the test organisms were: S aureus, E coli and
Candida albicans.
3
Four measurements were taken: zone of inhibition, microbial challenge, microbial
transmission and silver content. Full details of the performance of the ten dressings can be
found in the article. As the results vary between test and organism it is impossible to
reproduce all the results here, however, Acticoat, Aquacel Ag, Calgitrol Ag, Contreet-H and
Silverlon generally performed better than other dressings.
The results can be loosely related to silver content, but the form and location of the silver
also have an effect on performance.
(Wright, Lam et
al. 2002)
Early healing
events in a
International Wound Infection Institute – Evidence Matrix
Full thickness wounds on the backs of pigs, contaminated with P aeruginosa, Fusobacterium
species and coagulase-negative staphylococci were covered with dressings, some of which
Page 40 of 53
3
Author, date
Comment
Title
Key points
Grade
porcine model
of contaminated
wounds: effects
of
nanocrystalline
silver on matrix
metalloproteina
ses, cell
apoptosis and
healing.
contained silver.
Comparative
evaluation of
silver-containing
antimicrobial
dressings and
drugs.
Wound dressings containing silver as antimicrobial agents are available in various forms and 3
formulations; however, little is understood concerning their comparative efficacy as
antimicrobial agents. Eight commercially available silver-containing dressings, Acticoat 7,
Acticoat Moisture Control, Acticoat Absorbent, Silvercel, Aquacel Ag, Contreet F, Urgotol
SSD and Actisorb, were tested to determine their comparative antimicrobial effectiveness in
vitro and compared against three commercially available topical antimicrobial creams, a
non treatment control, and a topical silver-containing antimicrobial gel, Silvasorb. Zone of
inhibition and quantitative testing was performed by standard methods using Escherichia
Nanocrystalline silver dressings promoted rapid wound healing, particularly in the days
immediately after injury. There was rapid development of well vascularised granulation
tissue that was able to take a tissue graft four days after injury. Control wounds were not
able to take a graft.
The proteoloytic environment of the wounds dressed with nanocrystalline silver dressings
had reduced levels of matrix metalloproteinases and higher levels of cellular apoptosis. The
authors suggest that nanocrystalline silver may alter the inflammatory events in wounds
and facilitate the early phase of wound healing.
Silver, clinical
(Castellano, Shafii
et al. 2007)
International Wound Infection Institute – Evidence Matrix
Page 41 of 53
Author, date
Comment
Title
Key points
Grade
coli, Pseudomonas aeruginosa, Streptococcus faecalis and Staphylococcus aureus. Results
showed all silver dressings and topical antimicrobials displayed antimicrobial activity. Silvercontaining dressings with the highest concentrations of silver exhibited the strongest
bacterial inhibitive properties. Concreet F and the Acticoat dressings tended to have greater
antimicrobial activity than did the others. Topical antimicrobial creams, including silver
sulfadiazine, Sulfamylon and gentamicin sulfate, and the topical antimicrobial gel Silvasorb
exhibited superior bacterial inhibition and bactericidal properties, essentially eliminating all
bacterial growth at 24 hours. Silver-containing dressings are likely to provide a barrier to
and treatment for infection; however, their bactericidal and bacteriostatic properties are
inferior to commonly used topical antimicrobial agents (Published abstract).
(Holder, Durkee
et al. 2003)
Assessment of a
silver-coated
barrier dressing
for potential use
with skin grafts
on excised
burns.
Acticoat burn dressing is a silver-coated dressing with antimicrobial activity purported to
reduce infection from environmental organisms in partial and full-thickness wounds.
Acticoat was tested for activity as an antimicrobial treatment and as an antimicrobial barrier
dressing in three in vitro assays. It was found that a modified disc assay method gave false
negative results but in an assay in which bacteria were inoculated on top of samples of
Acticoat, bacterial numbers were reduced, over time, with all microorganisms tested.
Acticoat served as a barrier for bacteria, inoculated onto it, from contaminating the surface
of an agar plate under the Acticoat. The data show that Acticoat has: antimicrobial
capabilities, but to be effective hours of contact between Acticoat and the microorganisms
are required; and the capacity to serve as an antimicrobial barrier dressing. These findings
support the conclusion that Acticoat has activity to reduce microbial contamination of
wounds from environmental sources.
International Wound Infection Institute – Evidence Matrix
Page 42 of 53
3
Author, date
(Rustogi, Mill et
al. 2005)
Comment
Title
Key points
Grade
The use of
Acticoat in
neonatal burns.
PURPOSE: To evaluate the safety and efficacy of Acticoat use in primary burn
4
injuries and other skin injuries in premature neonates. PROCEDURES: An audit
of eight premature neonates who sustained burn injuries and other cutaneous
injuries from various agents were treated with Acticoat. Serum silver levels
were measured in three neonates. Wounds were assessed for infection and
blood cultures were taken where sepsis was suspected. FINDINGS: Neonates
ranged from 23 to 28 weeks gestation (weight: 578-1078 g). Causative injury
mechanisms included: alcoholic chlorhexidine, alcoholic wipes, electrode jelly,
extravasated intravenous fluids, artery illuminator, temperature probe and
adhesive tape removal. Total burned body surface area ranged from 1 to 30%.
All neonates were treated with Acticoat dressing changed every 3-7 days. All
wounds re-epithelialised by day 28 and scar management was not required.
There were four mortalities secondary to problems associated with extreme
prematurity. Serum silver levels ranged from 0 to 1 micromol/L. There were no
wound infections or positive blood cultures during the treatment period.
CONCLUSIONS: Acticoat is a suitable dressing for premature neonates who
have sustained burn injury, with the advantage of minimal handling as the
dressing need only be changed every 3-7 days (Published abstract).
International Wound Infection Institute – Evidence Matrix
Page 43 of 53
Author, date
(Tredget,
Shankowsky et al.
1998)
Comment
Title
A matched-pair,
randomized
study evaluating
the efficacy and
safety of
Acticoat silvercoated dressing
for the
treatment of
burn wounds.
International Wound Infection Institute – Evidence Matrix
Key points
Grade
A new silver-coating technology was developed to prevent wound adhesion, limit
2
nosocomial infection, control bacterial growth, and facilitate burn wound care through a
silver-coated dressing material. For the purposes of this article, Acticoat (Westaim
Biomedical Inc, Fort Saskatchawan, Alberta, Canada) silver-coated dressing was used. After
in vitro and in vivo studies, a randomized, prospective clinical study was performed to
assess the efficacy and ease of use of Acticoat dressing as compared with the efficacy and
ease of our institution's standard burn wound care. Thirty burn patients with symmetric
wounds were randomized to be treated with either 0.5% silver nitrate solution or Acticoat
silver-coated dressing. The dressing was evaluated on the basis of overall patient comfort,
ease of use for the wound care provider, and level of antimicrobial effectiveness. Wound
pain was rated by the patient using a visual analog scale during dressing removal,
application, and 2 hours after application. Ease of use was rated by the nurse providing
wound care. Antimicrobial effectiveness was evaluated by quantitative burn wound biopsies
performed before and at the end of treatment. Patients found dressing removal less painful
with Acticoat than with silver nitrate, but they found the pain to be comparable during
application and 2 hours after application. According to the nurses, there was no statistically
significant difference in the ease of use. The frequency of burn wound sepsis (> 10(5)
organisms per gram of tissue) was less in Acticoat-treated wounds than in those treated
with silver nitrate (5 vs 16). Secondary bacteremias arising from infected burn wounds were
also less frequent with Acticoat than with silver nitrate-treated wounds (1 vs 5). Acticoat
dressing offers a new form of dressing for the burn wound, but it requires further
investigation with greater numbers of patients in a larger number of centers and in different
Page 44 of 53
Author, date
Comment
Title
Key points
Grade
phases of burn wound care (Published abstract).
(Wright, Lam et
al. 1999)
Efficacy of
topical silver
against fungal
burn wound
pathogens.
BACKGROUND: Fungal infections of burn wounds have become an important cause of burn- 3
associated morbidity and mortality. The nature of fungal infections dictates aggressive
treatment to minimize the morbidity associated with these infections. Persons with large
total body surface area burns are particularly susceptible to fungal infections and are
treated in such a manner as to minimize their risk of infection. METHODS: This study
examined the in vitro fungicidal efficacy of a variety of different topical agents. By placing
fungal inocula in contact with mafenide acetate, silver nitrate, silver sulfadiazine, and a
nanocrystalline silver-coated dressing, we determined the kill kinetics of these topical
agents against a spectrum of common burn wound fungal pathogens. RESULTS: The topical
antimicrobials that were tested demonstrated varying degrees of efficacy against these
pathogens. CONCLUSION: The nanocrystalline silver-based dressing provided the fastest
and broadest-spectrum fungicidal activity and may make it a good candidate for use to
minimize the potential of fungal infection, thereby reducing complications that delay wound
healing (Published abstract).
International Wound Infection Institute – Evidence Matrix
Page 45 of 53
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Acknowledgements:
The IWII is very grateful to the following members for the development of this matrix:
Dr Keryln Carville, Curtin University of Technology, Australia
Terry Swanson, South West Healthcare, Warrnambool, Victoria, South Australia
Dr Marc Despatis, Cape Breton Health Care Complex, Canada
Jude Douglass, IWII Member, UK
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