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Vol. 18, No. 11
November 2006
307
Original Research
Exploring the Effects of Silver in
Wound Management—What is Optimal?
Richard White, PhD,
1
and Keith Cutting, MN, RN, Dip N, Cert Ed
2
From the
1
Department of Tissue Viability, Aberdeen Royal Infirmary, Aberdeen, Scotland, and
2
Buckinghamshire
Chilterns University College Buckinghamshire, United Kingdom
WOUNDS 2006;18(11):307–314
Abstract: There has been a vast increase in the last 5 years in the number of available silver-con-
taining dressings. Their use has seen a corresponding rise in the number of publications referring to sil-
ver and its potential benefits. It is important that recognition is also given to the potential pitfalls of use,
particularly in relation to toxicity. These factors have been recently reviewed. This article will explore
what happens once the body absorbs silver, discuss the relevance of the carrier dressing to efficacy of
silver, and review the clinical relevance of microbial kill time.
I
I
n recent years, use of silver in medical
healthcare devices has seen a vast increase.
This increase has been largely dominated by
wound dressings. Silver sulfadiazine, which has
been available for approximately 40 years, pro-
vides broad-spectrum antimicrobial activity and
has been widely used, particularly as a topical
cream to manage burn infection. In the last 5
years, the number of available silver-containing
dressings has increased. These dressings are used
primarily on chronic wounds and in clinical prac-
tice are regularly applied for periods of time up
to and in excess of 4 weeks. As silver dressings
may be used in clinical situations other than as a
temporary option, it is important that potential
toxicity be considered, particularly in relation to
the type and amount of silver, and as regards the
risk of selecting for bacterial resistance. These fac-
tors have been recently reviewed.
1
This article will consider what happens once
the body absorbs silver and discuss the levels of
silver required to exert a toxic effect on bacteria.
Address correspondence to:
Keith F. Cutting, MN, RN, Dip N, Cert Ed, Buckinghamshire Chilterns University College, Buckinghamshire, Chalfont
St. Giles, HP8 4AD United Kingdom
Phone: 011 44 1494 605172; Fax: 011 44 1494 605174; E-mail: info@healthdirections.co.uk
In addition, it will explore the relevance of the
c
arrier dressing to efficacy of silver and the clini-
cal relevance of microbial kill time. It is preferable
that any testimony made in respect of silver
should be clinically relevant. In order to do this,
data should be drawn from clinical (in-vivo) stud-
ies wherever possible. Unfortunately, few such
studies exist, so much data will be drawn from
available
in-vitro, ex-vivo, and animal studies.
Metabolic fate of topical silver. Silver, as a
component of wound dressings, antibiotic cream,
and first-aid plasters, comes into contact with
intact skin and breached skin on an increasingly
regular basis. The penchant for silver as an
antimicrobial has seen it incorporated into simple
adhesive dressings for minor cuts and abrasions
and is no longer reserved for “serious” wound
management. Potential repercussions associated
with these applications need to be acknowledged
and explored. Apart from increasing the risk of
contact dermatitis and selecting for resistance,
there will be concerns about possible systemic
and cutaneous toxicity. The interaction of metallic
silver with intact skin does not cause any
detectable increase in blood levels and is not of
great toxicological interest. However, the recent
increase in the use of silver-based wound treat-
ments raises some concerns about the systemic
effects of silver and warrants a toxicological
review. Several factors influence the capacity of a
metal to produce either local or systemic toxic
effects. These factors include 1) the degree of
absorption as influenced by solubility of the
metal or its compounds, 2) the ability to bind to
biological sites, and 3) the degree to which the
metal complexes are sequestered, metabolized,
and ultimately excreted.
Silver is applied to open, dermal wounds in
the form of inorganic silver salts (eg, silver
nitrate), metallic silver, or as organic compounds,
such as silver sulfadiazine (SSD).
2
The chemical
nature of the applied silver will influence its
absorption, distribution, and metabolism. Studies
on “background” or environmental silver levels
in human tissues have been conducted.
3,5,6
Normal
silver concentration is very low. Concentrations
of silver in blood, urine, liver, and kidney of sub-
jects without industrial or medicinal exposure are
< 2.3 µg/L, 2 µg/day, 0.05 µg/g wet tissue, and
0.05 µg/g wet tissue, respectively.
3
Reference val-
u
es quoted by Guys and St. Thomas’ Hospital
Toxicology Laboratory (London, UK) are < 3
nmol/L (approx. 0.32 µg/L) for blood and < 8
nmol/L (~ 0.86 µg/L) for urine.
4
Most studies on
the metabolic fate of topically applied silver have
been in patients with burns treated with SSD
cream.
5,6
In SSD cream-treated burn patients, plas-
ma concentrations may be as great as 50 µg/L
within 6 hours of treatment, dependent upon the
area that was treated, and can reach a maximum
of 310 µg/L. Silver in urine may reach a maxi-
mum of 400 µg/day. After absorption, silver has
been found in various tissues. Silver concentra-
tions in a burn patient who died of renal failure
after 8 days of treatment were 970 µg/g, 14 µg/g,
and 0.2 µg/g wet tissue in the cornea, liver, and
kidney, respectively.
3
This equates to liver con-
centration that is 280 times background. Renal
toxicity from silver has been reported after topi-
cal application, leading the authors to conclude
that topical SSD should not be used for long peri-
ods on extensive wounds.
7
Lansdown and
Williams
8
acknowledge that the use of topical sil-
ver in burns and chronic ulcers can lead to sys-
temic absorption and subsequent deposits in the
organs; however, they conclude that the risk is
low. Studies on the fate of SSD using radiolabeled
silver (Ag
110
) showed that label accumulation
occurred in superficial layers and in a short time
period after exposure (2–8 hours)—clearance was
complete in 28 days.
9
This indicates that silver
binds superficially and has low absorption from
single application. Few reported data on systemic
absorption of silver from sources other than topi-
cal SSD exist; thus, it must be assumed that under
normal conditions of use, the modern silver-con-
taining wound dressings are safe in this respect.
10
Chen et al
11
have reported increased serum and
urine silver levels and mild hepatic dysfunction
in patients with burns treated with a silver dress-
ing but concluded that it was safe on small to
medium partial-thickness burns. However, Trop
et al
12
reported silver-related hepatotoxicity and
argyria-like symptoms in a case of a silver-coated
dressing used on a child with 30% total body sur
-
face area burns. Elevated plasma and urine silver
levels of 107 µg/kg (~ 104 µg/L) and 28 µg/kg (~
27 µg /L) were measured, as were elevated liver
308 WOUNDS: A Compendium of Clinical Research and Practice
WHITE AND CUTTING
enzymes (AST, ALT, and GGT). These abnormali-
t
ies eventually resolved after cessation of silver
treatment.
The limits of exposure to silver in industrial
conditions have been reviewed and document-
ed.
1
3
Silver compounds and metal ionize, largely
to the monovalent cation Ag+; there are other
cations, but these are very reactive and short-
lived. Ag+ has a high affinity for thiol groups and
binds to reduced glutathione
14
; it also binds to the
amino-, sulphydryl, carboxyl, and phosphate
groups of nucleic acids.
15
Reduced glutathione is
important in erythrocyte function and in the elim-
ination of organic peroxides,
1
4
and any chemical
alteration to nucleic acids is likely to result in
transcription errors.
In-vitro, ex-vivo, and animal evaluation of silver
toxicity. The cytotoxicity of topically applied
agents, such as antimicrobials, has been evaluat-
ed using skin cells in vitro,
16–19
reconstituted
human epithelium (RHE),
20
and in grafted skin
substitutes.
21
The risk-benefit of cytotoxicity ver-
sus antimicrobial activity for agents applied topi-
cally to wounds has been discussed.
22
The toxicity
of silver in cells and tissues has been assessed
using silver nitrate, silver sulfadiazine, and silver
dressings. In a study on cultured human dermal
fibroblasts, silver nitrate exposure to various
quantities of fetal calf serum (resembling physio-
logical conditions) produced cytotoxic effects at
8.2 nmol/L after 8 and 24 hours.
18
In similar
experiments using monolayer cultures of 3T3
fibroblasts and keratinocytes from surgical dis-
cards, silver from silver nitrate and from a silver
dressing was found to be cytotoxic (lethal to sil-
ver nitrate at 50 x 10
-4
% after 3 hours as well as
the dressing). The same silver dressing was eval-
uated for cytotoxicity using cultured skin substi-
tutes
in vitro and in vivo after grafting.
21
Results
showed the dressing was cytotoxic in vitro within
1 day, but the in-vivo dressing was not after 1
week. These results suggest that in-vitro cytotoxi-
city is more sensitive than in vivo, as there is no
means of reducing toxicity via blood circulation,
tissue reservoir, metabolism, or by dilution
effects. It is justifiable to conclude that in-vivo or
ex-vivo studies are more likely to reflect the possi-
ble toxicity in routine clinical use.
The oligodynamic nature of silver. Bacteria in
wounds, notably chronic wounds, exist as both
p
lanktonic and sessile organisms. The latter are
attached to a surface (eg, biofilm form) that is
postulated, but not yet confirmed, as a feature of
chronic wounds.
23
Bacteria behave differently in
each of these 2 forms. This behavior becomes rel-
evant to bioburden control measures when the 2
forms exist contemporaneously in the wound.
Bacteria in planktonic form are freely available to
topical antimicrobial agents, whereas in biofilms,
bacteria are less susceptible.
24
The antimicrobial
activity of silver has been known for many years,
and numerous publications report its action
against a wide variety of organisms
in vitro.
2
5
It is
generally accepted that silver is active as the
monovalent cation Ag+ and that this species is
active at low concentrations (parts per billion
[ppb] or µg/L, to parts per million [ppm] or
mg/L) in aqueous solutions.
26
The term oligody-
namic, meaning active in small quantities, has
been used in this context in much research over
the last century.
27–31
In a review directed at SARS
(severe acute respiratory syndrome), Rentz
30
referred to the work of von Näegeli
27
who found
Ag+ to be an active biocide at concentrations
between 9.2 x 10
-
9
and 5.5 x 10
-
6
M, (ie, 9.2 ppb and
5.5 ppm). Rentz
3
0
cited a 1987 study by Cliver
3
2
that reported Ag+ was active at 250 ppb in 2
hours. The efficacy of silver ion disinfection has
been illustrated by the following calculation:
At a concentration of 10
4
cells/mL and 50 ppb
(4.7 x 10
-7
mol/L) metal ions, there are approxi-
mately 2.8 x 10
10
metal ions per cell.
25,32
This calculation represents a typical bacterial
concentration in wound exudate and a “low”
level of silver dissolution from a silver-containing
dressing. However, exudate will have an influ-
ence on silver ion activity by virtue of its anion
content (eg, Cl
-
), which bind the Ag+ ion. The
effects of protein on the binding and bioavailabil-
ity of silver ions have been investigated using an
oral bacterium, Porphyromonas gingivalis
33
; the
frequent presence of silver in the mouth from
dental amalgam
34
is known to select for resistance
and casts some doubt on the validity of these
observations.
35
According to Bechert et al,
29
“the
oligodynamic activity of silver ions is not reduced
by pre-incubation with albumin and fibrinogen.”
Currently, not much information is available that
Vol. 18, No. 11 November 2006 309
WHITE AND CUTTING
relates to the effects of silver on wound clinical
i
solates in the presence of common anions and
protein (ie, an exudate equivalent environment).
However, Bowler et al
36
addressed this situation
and challenged a silver dressing with clinical iso-
lates tested in a simulated wound fluid. Their
findings suggest that the silver-containing dress-
ing is likely to provide a barrier to infection.
The authors are unaware of any published
studies on the mutant selection window (MSW)
and mutant prevention concentration (MPC) for
silver.
37,38
The MSW has been developed using
antibiotics, so its value in antiseptic studies is a
matter for conjecture. The principles are never-
theless intriguing and further research is neces-
sary. Mutant selection window (ie, 2 concentra-
tions of antimicrobials, usually antibiotics), at the
lower level, blocks the majority of susceptible
bacteria growth. The upper limit of the window is
the concentration of antimicrobials that blocks the
growth of the least susceptible bacteria. Resis-
tance is rarely expected to develop when drug
concentrations are kept above the upper bound-
ary of the MSW. This expectation led to the upper
boundary being designated as the MPC.
The results of such studies would be highly
desirable before making assertions on the likeli-
hood of selection for resistance through the use of
dressings delivering different amounts of silver
in everyday clinical practice.
39
While claims have been made that a rapid kill
rate is essential in order to avoid resistance and
biofilm formation,
40
there is no supporting MSW
data. It is known that silver has the capacity to
disrupt the biofilm matrix at a low dose (50
ppb).
41
It could, therefore, be argued that such
claims are made more for commercial advantage
than for the advancement of clinical intervention.
Silver ions at low ppb concentrations are effec-
tive antibacterial agents against most planktonic
bacteria.
26
This level (50 ppb) has also been found
effective in destabilizing biofilms of Staphylococ-
cus epidermidis in vitro.
41
In an in-vivo study using
a biofilm-forming Staphylococcus epidermidis,
Illingworth et al
42
showed that a silver-coated
heart valve cuff exerted bactericidal activity. This
implies that the (probable) biofilm formation on
the cuff does not protect from silver ions. Thus, it
is reasonable to conclude that in the case of silver
ions, oligodynamic equates to bactericidal activi-
t
y at nanomolar (ppb) concentrations.
Dressing Association with the
Wound Bed
Sibbald
4
3
highlighted the important relation-
ship of effective wound bed preparation and the
management of wound infection through use of
antimicrobial agents. He stated that the selection
of any product should account for microbial sen-
sitivity, low allergenicity, and low cellular toxici-
ty and should not be a systemic agent. These
important considerations should not be disputed.
Irrespective of the type of antimicrobial silver
used in any medical device (eg, salts or metallic),
the form of silver delivered to the wound should
remain consistent (ie, Ag+) and not change irre-
spective of the carrier dressing. However, it is
generally recognized that silver efficacy is influ-
enced by the amount of silver and its availability,
which are dependent on the chosen product.
However, Parsons et al
44
stated that efficacy is
unrelated to the total amount of silver in the
dressing. One additional factor that impinges on
antiseptic efficacy and is not related to the form
of silver used or the dosage but should not be
overlooked is the ability of the carrier dressing to
conform to the wound bed. High conformability
helps ensure that areas of noncontact between the
dressing and the wound bed are minimized thus
reducing the formation of voids (dead space)
where bacteria may flourish. Dead space has been
identified as an impediment to successful wound
healing and efforts should be made to avoid their
occurrence.
45
A dressing that gels in contact with
wound fluid by internally binding water is more
likely to achieve high conformability with the
wound bed than one that does not conform and is
relatively inflexible. Fibrous dressings maintain
an excellent absorptive capacity yet can be
removed from the wound atraumatically while
remaining intact and retaining the additional ben-
efit of avoiding dead space formation in the
wound.
46,47
Additionally, the ability of a dressing
to maintain a high tensile strength while binding
water would seem to be advantageous.
The value of fibrous dressings in wound man-
agement has been enhanced by the silver ion
310 WOUNDS: A Compendium of Clinical Research and Practice
WHITE AND CUTTING
incorporation, resulting in an absorptive, antimi-
c
robial dressing.
48
S
uch dressings are known to
achieve and maintain intimate contact with the
wound bed—this is deemed advantageous in
wound healing because these dressings avoid cre-
ating dead space. Avoiding dead space creation
at the wound bed/dressing interface can be
demonstrated through
in-vitro methods.
49
Howev-
er, the clinical benefit obtained through the
appropriate use of such dressings is not in the
absolute bactericidal impact (ie, achieving sterili-
ty) but in the reduction of bacterial bioburden to
a level where the host immune response can
respond and regain control.
Topical antimicrobials have an important role
to play in managing wound bioburden,
50
and
product selection should take into account not
just those issues related to antimicrobial activity,
such as sensitivity, allergenicity, and cellular toxi-
city, but should consider the physical relationship
of the carrier vehicle (dressing) to the wound bed.
High conformability will help ensure the effec-
tiveness of the antimicrobial component at the
dressing/wound bed interface.
49
Not only may
the delivery of silver ions to the wound bed be
enhanced through the close proximity of the
dressing but wound bed bioburden may also be
reduced through bacterial sequestration. Walker
et al
51
demonstrated the value of sequestration in
managing bacterial pathogens using scanning
electron microscopy. Their investigations showed
that as the fibrous dressing became hydrated and
formed a cohesive gel, bacteria absorbed into the
dressing matrix were immobilized and retained
within the gel structure. This dressing property
immobilizes the bacteria and compliments the
bactericidal activity of the silver ions by reducing
the wound bed bioburden through the mecha-
nism of sequestration.
An issue related to silver and antimicrobial
efficacy that has acquired a degree of attention is
time to kill. Diametrically opposite views may be
found in the literature regarding the relevance of
time to kill in the control of wound pathogens.
40,44
A recent publication listed dressing products
with their comparative silver content
52
and
should not be interpreted as though a higher
level of silver leads to a shorter kill time or that
silver efficacy is primarily time/dose related. In a
review of silver biocides in dressings, Silver et al
53
s
tated that conclusions as to one product being
more effective than another during in-vitro tests
have little bearing on the efficacy of these prod-
ucts in human medicine. Choice of an apposite
antibacterial dressing should be based on the clin-
ical results (impact) and not on any single labora-
tory limitation.
44,53
Although the comparative tab-
ular approach is helpful (it provides a hierarchy
of silver content by product), the problem arises
that much supporting evidence is usually gener-
ated following in-vitro testing, and the clinical rel-
evance of such data requires exploration. It also
should be put into context of resistance selection
and the MSW. Some authors have published data
related to a single dressing type extolling the
apparent benefits of rapid time to kill. So this is
not viewed as an aspect of dressing performance
where products are differentiated for marketing
purposes, it must be established whether or not
time to kill due to topically applied antimicro-
bials is clinically relevant. The latter may be
applicable where such studies use type cultures
and not clinical isolates. Of equal or perhaps
greater importance is that the test model must
represent clinical use (eg, saline, serum, exudate,
dead cells).
Furthermore, the balance between antimicro-
bial dressings and systemic antibiotics also needs
to be established—when is a topical antimicrobial
dressing adequate and when should topical treat-
ment be supplemented with systemic antibiotics?
Conclusion
The appropriate use of topical silver in wound
care is not as clear-cut as some publications tend
to imply. A number of key areas still need to be
resolved. The clinical result is the ultimate test of
a silver dressing (ie, does it work in practice?). It
is likely that most silver dressings are being used
on chronic wounds as opposed to acute wounds,
such as burns. It remains to be established if data
from these 2 wound types can be reliably trans-
posed. The evidence is now clear that resistance
exists in a number of organisms.
53
The argument
over levels of silver and risks of resistance result-
ing from inadequate dosing is unresolved. It is
apparent that marketing and commercial inter-
Vol. 18, No. 11 November 2006 311
WHITE AND CUTTING
ests are clouding scientific debate. This requires
t
hat clinicians be collectively diligent in the clini-
cal use of silver dressings. There is no compelling
evidence regarding the extrapolation of in-vitro
data on bacterial activity to the in-vivo clinical sit-
uation. No data exists to support dressings
according to their silver “dosage.” Silver dress-
ings when used responsibly are of great clinical
value.
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