Topical Antimicrobial Agents for Burn Wounds David G. Greenhalgh,

Topical Antimicrobial
Agents for Burn Wounds
David G. Greenhalgh, MD
KEYWORDS
Burns Antimicrobial Antibiotics
Infection Bacteria Sepsis
OPTIMIZING BURN WOUND HEALING
Superficial Burns
The ultimate goal for all burns is to allow for the
wound to heal with the least amount of scarring.
The management of the burn wound depends on
the depth of injury.1 Each type of burn wound
should have a different management strategy. It
is well known that first-degree burns do not require
any form of treatment other than possibly a moisturizer. Superficial partial-thickness (or seconddegree) burns have lost the epidermis but have
an adequate density of skin adnexa (hair follicles,
sweat and oil glands) to re-epithelialize the wound.
A partial-thickness burn wound that heals within 2
to 3 weeks would not be expected to result in
significant scarring. Second-degree burns that
take longer than 2 to 3 weeks to heal frequently
develop hypertrophic scarring.2 Therefore, the
goal of treating these superficial wounds is to optimize the extent of re-epithelialization to allow the
wound to heal as fast as possible.
Numerous studies have proved that re-epithelialization proceeds more rapidly if the wound
remains moist.3 Keratinocytes migrate across the
viable wound surface more rapidly if there is no
barrier to interfere with travel. After the wound
dries and forms a scab (made of fibrin, neutrophils,
and debris), the epithelial cells must digest this
fibrinous exudate using fibrinolytics and proteases
to resurface the wound. Because this digestion
slows epithelial cell migration, the time to healing
is delayed. Any topical agent that maintains a moist
environment allows for more rapid epithelial healing and reduces the chances of scarring. The
simplest option, an ointment, maintains the moist
environment and allows for more rapid healing.
An ointment is a water-in-oil preparation in which
the amount of oil exceeds the amount of water in
the emulsion. Topical antimicrobial ointments
such as bacitracin or neomycin maintain a moist
healing environment and are commonly used for
superficial wounds. These topical ointments need
to be washed off and reapplied twice a day, which
can be painful.
Deep Burns
Deep partial-thickness and full-thickness burns
require different treatment strategies because the
wounds will not re-epithelialize unless they are
very small. Deep burns of any size will scar less if
they are treated using excision and grafting, so
the intention when using topical agents is to minimize bacterial colonization until grafting occurs.
Shriners Hospitals for Children Northern California, Department of Surgery, University of California, Davis,
2425 Stockton Boulevard, Sacramento, CA 95817, USA
E-mail address: [email protected]
Clin Plastic Surg 36 (2009) 597–606
doi:10.1016/j.cps.2009.05.011
0094-1298/09/$ – see front matter ª 2009 Published by Elsevier Inc.
plasticsurgery.theclinics.com
Every time a patient receives a burn, it is expected
that the burn will be treated using some type of
ointment or cream. Many physicians know little
beyond the fact that a burn must be treated using
some form of topical antimicrobial agent.
However, treatment of the burn wound has
changed markedly in the last couple of decades,
so topical antimicrobial agents play a different
role today than they did in the past. In the past,
burns were treated expectantly. Now, burns are
treated more aggressively, using early excision
and grafting. This philosophical change must influence the topical management of burns. This article
discusses what role topical agents have in
managing burn wounds. The basics of burn wound
healing, how topical agents influence the burn
wound, and the wide variety of different available
topical agents are reviewed.
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Greenhalgh
Obviously, if the burn is excised and grafted within
a few days after injury, then there is little colonization. Many caregivers will treat these wounds
using a broad-spectrum topical cream such as
silver sulfadiazine to minimize colonization. A
cream is an oil-in-water emulsion in which the
amount of water exceeds the amount of oil. They
are usually water miscible. Agents such as silver
sulfadiazine were originally designed to cover
large third-degree burns for weeks in the era prior
to the adoption of early surgical excisional techniques. The goal at that time was to minimize
infection while the eschar spontaneously separated. Eschar, the coagulated protein of burned
skin and other tissues, adheres very tightly to the
underlying tissue. To separate it from the wound
bed, bacteria must invade the nonviable tissue
and the body must lay down a barrier of granulation tissue. The bacteria lyse the nonviable tissue
using proteases. So bacteria must be present for
spontaneous separation to occur. In the past, it
was hoped that the patient did not succumb to
sepsis from bacteria invading the burn wound.
Fortunately, this slow and painful process has
been replaced by aggressive excision and grafting
procedures that reduce the patient’s exposure to
inflammatory mediators. Topical agents are now
provided during the short time until excision and
grafting has been performed. The principal of
aggressive excision and grafting has led to the
need for topical antimicrobial agents to minimize
bacterial colonization at the graft site. Usually,
topical solutions are used for this purpose
because the goal is to reduce the chances for
infection while minimizing toxicity to the stressed
skin graft.
INFECTION AND WOUND HEALING
To make rational choices concerning the use of
topical antimicrobial agents, it is essential to
understand how bacteria influence the healing of
a wound. One usually assumes that any presence
of bacteria in a wound leads to impaired healing.
However, decades ago, researchers applied
different types of bacteria on wounds and tested
the tensile strength and time required for closure.
To their surprise, many wounds contaminated
with bacteria actually healed faster than noncontaminated wounds.4–7 At other times, especially
when bacterial concentrations were greatly
increased, wounds had delayed healing. Contamination with lower numbers of bacteria stimulates
an inflammatory response that activates the resident macrophages to augment healing through
the release of growth factors and other cytokines.
If the concentration of bacteria exceeds
a destructive threshold or if the bacteria are overly
cytotoxic, then damage to the wound may occur.
Classically in the burn wound, a bacteria concentration of more than 105 per gram of tissue tends
to be destructive and lead to impaired graft take,
whereas a density of fewer than 105 per gram of
tissue does little to impair burn wound healing.7
All wounds will have some bacterial colonization. It is not possible to completely eliminate all
organisms from a burn wound. Our bodies are
covered with bacteria that coexist and are in
many ways beneficial.8 Elimination of these
commensurate microorganisms allows for the
numbers of pathologic organisms to increase.
One must always ask if the routine use of antimicrobial agents is necessary or even harmful. Antibiotic resistance has become a major problem in
our time. Elimination of one population of bacteria
clears the way for a different population. These
evolutionary forces have led to major resistance
problems related to many pathologic microorganisms. The rational use of topical and systemic antimicrobial agents should be considered of the
utmost importance.
Because the dominant commensal skin organisms are gram-positive cocci,8 organisms such
as Streptococcus and Staphylococcus aureus
tend to be early colonizers and infectors of the
burn wound. Over time, especially if topical agents
that act against gram-positive organisms are
used, gram-negative organisms become dominant. One of the more common gram-negative
organisms is Pseudomonas aeruginosa, which
tends to leave a fluorescent yellow/green exudate
on the wound. If gram-negative organisms are
controlled, then yeast (Candida) may appear
next. Finally, more resistant bacteria and fungi
will invade a wound if the host’s resistance is
impaired and eschar remains on the unhealed
wound.
Methicillin-resistant Staphlococcus aureus
(MRSA) has emerged as a major cause of burn
wound infection. Of further concern, multiresistant
gram-negative organisms of the Acinetobacter
genus have become a major cause of infection in
burn units. Previously uncommon fungi such as
Aspergillus are also being seen more often.
Viruses such as Herpes simplex are also a problem
in some units.
A recent American Burn Association Consensus
Conference9 classified burn wound infections.
Most burn wounds are colonized with bacteria
and usually produce an exudate that does not
signify infection.10 The important clinical signs of
a burn wound infection include redness and
swelling (typical of streptococcal cellulitis) and
discoloration or premature separation of eschar.
Topical Antimicrobial Agents for Burn Wounds
Healed donor sites that have their new epithelium
‘‘melt’’ away may be indicative of ‘‘burn wound
impetigo,’’ which is typically a staphylococcal
infection. Invasive Pseudomonas infection is manifested by purple, punched-out lesions in burns or
donor sites, usually accompanied by signs of
sepsis or septic shock. Candida infections typically result in small, white pustules on the skin.
Herpes simplex infections leave punched-out
holes (2–3 mm) in previously healing skin. Infections in a skin graft are manifested by graft loss,
with purulence being found beneath the original
graft. When obvious infections occur, systemic
therapy and surgical intervention are indicated,
which are topics not covered in this article.
COMMON TOPICAL AGENTS
Antimicrobial Ointments
As stated previously in this article, for more superficial burns, the goal of topical agents is to maximize epithelialization while reducing the
colonization of pathologic bacteria (Table 1). Ointments maintain a moist environment while acting
as a media for antimicrobial agents.11–14
Bacitracin
Bacitracin is one of the most commonly used
topical antimicrobial agents for small, superficial
burn wounds. Bacitracin is a mixture of similar
cyclic polypeptides produced by a strain of
Bacillus subtilis. It interferes with dephosphorylation of a component of the bacterial cell wall. It is
not an effective oral agent but works well topically.
It is typically placed in a white-petroleum ointment
and applied over the wound two or three times per
day. The antimicrobial agent is effective against
gram-positive cocci and bacilli and seems to be
relatively unlikely to develop resistance to organisms. The topical agent is safe patients of all
ages. Bacitracin is frequently used for treating
burned faces, which are not amenable to the use
of silver sulfadiazine or mafenide acetate. The
main problem with the agent is that it is not effective against gram-negative organisms or yeast. It is
not uncommon for people to develop a rash with
prolonged use, especially on re-epithelialized
wounds, which is frequently related to Candida
overgrowth. The rash resolves quickly after
discontinuation of the bacitracin ointment.
Polymyxin B sulfate
Polymyxin B is an antimicrobial agent obtained
from B polymyxa, and it also is placed in a whitepetroleum ointment. It acts as a detergent-like
agent that binds to the cell membrane and makes
it more permeable. It is a bactericidal agent
against gram-negative organisms (including
Pseudomonas and coliforms), but it has little effect
on gram-positive organisms because the cell wall
prevents it from obtaining access to the
membrane. Patients may develop hypersensitivity
reactions, but absorption across the wound is
infrequent. Exposing large surface areas may
lead to systemic absorption and expose the
patient to neurotoxicity and renal acute tubular
necrosis.
Neomycin and other aminoglycosides
Neomycin is produced by the bacterium Streptmyces fradiae and acts like all other aminoglycosides
that interrupt protein synthesis by binding to the
30S subunit of the bacterial ribosome. It can be
prepared as an ointment, cream, or eye drops. It
has excellent activity against gram-negative
organisms and some limited activity against
gram-positive bacteria. There is a greater
tendency for bacteria to develop resistance to
this antimicrobial agent than to some of the other
ointments. There is also a relatively high incidence
of hypersensitivity reactions (5%–8%). If large
areas are exposed, there are risks for ototoxicity
and nephrotoxicity, as there are with all aminoglycosides. Gentamicin, which is synthesized by
Micromonospora purpurea, is a common systemic
aminoglycoside that is available as an ointment or
a cream. It is difficult to use to regulate systemic
absorption, and it is not recommended for topical
use. Amikacin, a derivative of kanamycin A, is also
available in some countries as a topical aminoglycoside, but should probably be saved for intravenous treatment of systemic gram-negative
infections.
Combination ointments
Because many ointments are only effective
against gram-positive or gram-negative bacteria,
many are combined as broader-acting commercial products. Polysporin (Johnson & Johnson,
New Brunswick, New Jersey) is a combination of
polymyxin B sulfate and bacitracin. Neosporin
(Johnson & Johnson) combines three topical
agents: neomycin, bacitracin, and polymyxin B.
These combinations should have broader
coverage of bacteria, but no clinical trials have
demonstrated their superiority over single agents.
Staff members in the units where the author works
often add other agents to expand the coverage of
bacitracin. They add 1 part silver sulfadiazine to 3
parts bacitracin to cover gram-positive and gramnegative bacteria. In addition, they mix equal
amounts of bacitracin, silver sulfadiazine, and
nystatin to cover bacteria and yeast. They usually
apply the ointments using a nonsticky dressing
such as Adaptic (Johnson & Johnson) to reduce
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Table 1
A brief listing of currently available topical antimicrobial agents
Agent
Ointments
Bacitracin
Neomycin
Polymyxin B
Neosporin
Polysporin
Mupiricin
Povidone-iodine
Gentamicin or amikacin
Xeroform
Repithel
Scarlet red
Creams
Silver sulfadiazine
Silver sulfadiazine/cerium nitrate
Silver sulfadiazine/chlorhexidine
Silver sulfadiazine lipidocolloid
Mafenide acetate
Mafenide/nystatin (Clotrimazole)
Nystatin
Clotrimazole
Ciclopirox
Solutions
Silver nitrate (0.5%)
Mafenide acetate (5%)
Mafenide acetate/nystatin
Mafenide acetate/miconazole
Genitourinary irrigant
Triple-antibiotic solution
Dakin’s solution
Acetic acid (0.5%)
Chlorhexidine digluconate
Abbreviations:
Formulation
Organisms Covered
Bacitracin
Neomycin
Polymyxin B
Neomycin/bacitracin/polymyxin B
Polymyxin B/bacitracin
Bactroban
Betadine
Aminoglycosides (rarely used)
Pre-prepared dressing (bismuth)
Povidone-iodine in hydrogel
Scarlet red and fine mesh gauze
gram
gram
gram
gram
gram
gram
gram
gram
gram
gram
gram
Silvadene, Flammazine
Flammacerium
Silverex, Silvazine
Urgotol SSD
Sulfamylon
Formulated in pharmacy
Nystatin
Lotrimin
Loprox
gram 1, gram
gram 1, gram
gram 1, gram
gram 1, gram
gram 1, gram
gram 1, gram
yeasts
yeasts, fungi
gram 1, gram
–, yeasts, fungi
0.5% (made in pharmacy)
Sulfamylon solution
5% Sulfamylon/nystatin powder
5% Sulfamylon/miconazole powder
Neomycin/polymyxin B
Neomycin/polymyxin B/bacitracin
0.25% or 0.5% sodium hypochlorite
0.5% (made in pharmacy)
0.05%
gram
gram
gram
gram
gram
gram
gram
gram
gram
–, yeasts, fungi
–
–, yeasts
–, yeasts
–
–
–, yeasts, fungi
–
–, yeasts, fungi
1
–
–
1,
1,
1,
1,
–
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
1,
gram –
gram –
MRSA
gram –, yeasts, fungi
gram –, yeasts
gram –, yeasts
gram –
gram
gram
gram
gram
gram
gram
gram
gram
gram
–, yeasts
–, yeasts, fungi
–, yeasts, fungi
–, yeasts
–
–, yeasts
, negative; 1, positive.
the possibility of the dressing sticking to the
wound.
Mupiricin
Mupiricin (Bactroban, GlaxoSmithKline, Middlesex, United Kingdom) has become a popular
topical agent since the development of increasing
incidence of MRSA infections. Mupiricin is derived
from a strain of P fluorescens, and it inhibits transfer-RNA activity. It is now the topical treatment of
choice for use against MRSA infections.15 The
agent is also used intranasally to treat carriers of
MRSA. Some burn units are using intranasal
mupiricin to reduce the risk for Staphlococcus
infections.15,16 There is a potential for developing
resistance to the antimicrobial agent, so it should
not be used for more than 10 days.
Other ointments
There are other ointments that are less frequently
used. Povidone-iodine solution is well-known as
an antiseptic used to prepare surgical wounds.
The ointment is available as a topical agent for
burns, but is rarely used because of a potential
for toxicity to fibroblasts and keratinocytes. It
has a broad spectrum of activity, covering
Topical Antimicrobial Agents for Burn Wounds
gram-positive and gram-negative bacteria, yeast,
and fungi. It can cause contact dermatitis and
may be tied to metabolic acidosis. There are also
reports that the agent may be inactivated by
wound exudates. It should not be used during
pregnancy or in small children, or in any patient
who has thyroid disease. In addition, different
formulations of macrolides (erythromycin), quinolones, hydroxyquinolines, tetracyclines, metronidazole, clindamycin, chloramphenicol, azelaic
acid, gramicidin, nitrofurazone, rifaximin, and retapamulin are available but rarely used for burn
patients.11
There are some topical antimicrobial agents that
are not available in the United States. For instance,
fusidic acid, which is derived from the fungus Fusidium coccineum, interferes with bacterial protein
synthesis by preventing the translocation of elongation factor G from the ribosome. Fusidic acid
is effective against gram-positive organisms and
is used in combination with mupiricin for severe
Staphylococcus infections. Resistance to the antimicrobial agent develops rapidly.
Antimicrobial Creams
Silver sulfadiazine
Silver sulfadiazine is the most well-known topical
agent for the treatment of burns. The cream was
introduced in the 1970s and it continues to be
the most popular cream for the treatment of burns
worldwide.17 It is a water-miscible cream that
contains 1% insoluble silver sulfadiazine in
micronized form. The active component is
a mixture of silver nitrate and sodium sulfadiazine.
The silver is complexed to propyleneglycol, stearyl
alcohol, and isopropyl myrisolate. The silver atom
substitutes for a hydrogen atom in the sulfadiazine
molecule. The original name for this compound
was Silvadine, but Marion Corporation, the original
manufacturer, no longer exists. It now comes in
several other trade names. Many caregivers automatically treat any burn with this agent. It is the
most commonly used topical antimicrobial agent
for superficial and deep burns. It is extremely
popular because it is very soothing and has broad
antimicrobial coverage. It is both a sulfa drug and
an agent that slowly elutes silver. It is a bactericidal
agent that is effective against gram-positive
bacteria (eg, Staphlococcus aureus), gram-negative bacteria (eg, Escherichia coli, Enterobacter,
Klebsiella, Pseudomonas), and some yeasts (eg,
C albicans) and viruses. The activity of silver as
an antimicrobial agent in itself will be covered later
in this article.
There are minimal problems with silver sulfadiazine, which explains its popularity. One must avoid
its use in patients who have sulfa allergies. If the
sulfa allergy is questionable or mild, the author places a small test patch on a nonburned area to
determine if a rash would develop. It rarely causes
discomfort and is soothing for most people. Mild
cutaneous sensitivities may develop. It may turn
a gray color, but rarely discolors tissues or clothing
(unlike silver nitrate solution). The main downside
of the agent is that it has been reported to impair
re-epithelialization, so its use for superficial
partial-thickness burns is questionable. The cream
also has some toxicity to fibroblasts in vitro.
Whether these in vitro activities actually impair
wound healing is less clear. It also leaves a whitish,
yellowish-to-greenish exudate on the wound,
which is the caused by the product mixing with
the serum proteins of the wet scab. This exudate
will lift off when the wound epithelializes, just as
for any other scab.
The classic concern for silver sulfadiazine is for
a brief leukopenia that occurs 3 to 5 days after
the burn.18 Although one study suggested that
the agent could have some myelosuppressive
activities,19 most physicians believe that the drop
in white blood cell count is related more to margination of the leukocytes to the wound rather than to
bone marrow suppression.20 The leukopenia
always resolves spontaneously, despite continuation of treatment using silver sulfadiazine. In addition, the cream is not recommended for faces
because of the potential for ingestion and eye irritation or injury. The sulfonamide component is also
associated with kernicterus, so the agent should
not be used during pregnancy or in infants.
Mafenide acetate
Mafenide acetate 11.1% cream (Sulfamylon,
Mylan Laboratories, Canonsburg, Pennsylvania)
is a methylated sulfonamide (sulfa drug) that
competes with para-aminobenzoic acid, thus preventing its incorporation into dihydrofolic acid and
blocking normal folic acid metabolism. This action
is not typical of other sulfonamides because paraaminobenzoic acid does not antagonize its
activity. It is active against gram-positive and
gram-negative bacteria, although there are
concerns that it may not be as effective for some
Staphlococcus strains. It was especially chosen
for its efficacy against P aeruginosa, an organism
that used to commonly kill burn patients by
invading the burn wound. It has no activity against
yeast, and thus has a tendency to lead to yeast
overgrowth in wounds if left for too long. It is
known for its excellent ability to penetrate tissues
such as eschar. This ability has also made it
a favorite topical agent for use in deep ear burns
because it effectively prevents invasive chondritis
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of the ear. It is prone to cause pain on application
and, like other sulfa drugs, can lead to allergic
reactions. The tendency to cause rashes is the
result of allergic tendencies in the patient or to
the agent’s propensity to allow for yeast overgrowth, which can lead to the development of
small, white papules on the skin. It is classically
known as a carbonic anhydrase inhibitor, and its
use over large surface areas can lead to metabolic
acidosis. The metabolic acidosis may lead to
a compensatory increase in respiratory rate to
maintain a normal pH level. Like many topical
creams, the agent inhibits neutrophil and lymphocyte activity in vitro.
Approximately 20 years ago, a 5%-solution
formulation was developed, and it is still
commonly used as an antimicrobial solution to
reduce infection in skin grafts. The tendency to
allow for yeast overgrowth has been dealt with
by adding nystatin or miconazole to the solution.
There have been debates as to whether the antifungal properties are as effective in the mafenide
acetate solution, but the combination is being
used in the author’s units and in many others.21,22
Cerium nitrate and silver sulfadiazine
Cerium nitrate has been added to silver sulfadiazine as a commercial product (Flammacerium,
Solvay, Israel) with broad coverage of gram-positive and gram-negative bacteria and fungi.23,24
The combination of the two agents leads to synergistic activities, at least in vitro. Cerium acts by
interfering with calcium-dependent enzymes, and
it also may affect immune function. It hardens the
eschar while still having excellent penetrating abilities. Although the product is used in Europe, it is
not available in the United States. There is some
question as to whether it is more effective than
silver sulfadiazine alone. It also has the potential
for causing methemoglobinemia.
Antimicrobial Solutions
Antimicrobial solutions can be used to cover burns
but are more commonly used to provide prophylaxis to newly applied skin grafts and skin substitutes. Solutions are especially useful for meshed
grafts because they maintain a moist environment
to optimize epithelialization of the mesh interstices
and minimize bacterial overgrowth.
Mafenide acetate
Mafenide acetate 5% solution was mentioned
previously in this article and is commonly used to
prevent infection, especially Pseudomonas infections in skin grafts. In addition, many centers add
nystatin or miconazole to prevent yeast
overgrowth.
Silver nitrate
Silver nitrate 0.5% solution is one of the older solutions available for topical treatment of burns and
grafts. It covers Staphlococcus species, Pseudomonas, and some yeasts. There are limitations to
its coverage of other gram-negative bacteria. The
mechanism of its action is discussed in the later
section of this article that covers other methods
of supplying silver to wounds. Silver ion precipitates when it is bound to chloride to form
a brownish-black residue that stains the patient’s
tissues and anything else it contacts (including
caregivers and patient’s rooms). After the silver is
precipitated, the wound is exposed to water,
thus hyponatremia and hypochloremia can result.
Electrolytes should be monitored if large surface
areas are treated. Methemoglobinemia is a very
infrequent complication.
Genitourinary irrigant
A genitourinary irrigant that consists of a mixture of
neomycin and polymyxin B is available to treat skin
grafts, but it is less effective against Pseudomonas
than mafenide acetate solution. In a comparison
study reported to the American Burn Association,
there were increased wound infections in skin
grafts when using this agent than when using
a mafenide acetate solution.25 A variation on this
combination is a triple-antibiotic solution that is
a combination of bacitracin (50,000 U), polymixin
B (200,000 U), and neomycin (40 mg) in 1 liter of
saline. Again, the downfall of this solution is its
relative ineffectiveness against Pseudomonas.
Sodium hypochlorite (Dakin’s solution)
Another very old topical agent is 0.5% or 0.25%
sodium hypochlorite solution (NaOCl, Dakin’s
solution), which essentially is dilute bleach. There
are more dilute concentrations available. The solution has made a return to the author’s unit because
workers there have had problems with occasional
fungal (Aspergillus or Mucor) invasion in the burn
wound. Dakin’s solution has efficacy against
bacteria, fungi, and viruses. There are concerns
about its toxicity to the cells in the healing wound.
The agent has been reported to dissolve clots and
could increase postgraft bleeding, but this
problem has not been noticed in the author’s
burn unit.
Other Antimicrobial Solutions
Acetic acid 0.5% is another antimicrobial solution
that is relatively inexpensive and effective against
gram-positive and gram-negative bacteria,
including Pseudomonas. This solution is not used
very frequently in the United States. Chlorhexidine
gluconate solution (0.05% in distilled water) is
Topical Antimicrobial Agents for Burn Wounds
another agent that has in vitro activity against
many organisms. The experience with its use for
burn wounds is limited. The solution is used as
a mouthwash to control bacterial numbers. Chlorhexidine gluconate also is usually used as soap
to wash patient’s wounds and now, when used
with alcohol, is the preferred preparation for
central lines. Because it is used as soap and in
preparations, another agent should probably be
used for prolonged contact to minimize the potential for resistance development.
Silver as an Antimicrobial Agent
Silver has a long history as an antimicrobial agent,
and there are excellent reviews describing the
history of its use.26,27 There are descriptions of
using silver to make water potable from 1000
BC, and some accounts state that it was used as
early as 7000 years ago without knowledge of its
effects. Alexander the Great only drank out of
silver vessels. Silver was used by the Romans as
a medicine. Paracelsus (1493–1541 AD) wrote
about the benefits of silver as an agent to help
healing. Silver nitrate was used to treat fractures,
ulcers, and suppurating wounds in the nineteenth
century. German obstetrician K.S.F. Crede introduced the use of silver nitrate drops in the eyes
of newborns to prevent gonorrheal infection in
1884. The synergistic effects of the combination
of silver with low-voltage direct current electricity
was also recognized soon after the discovery of
electricity. The famous surgeon William Halstead
introduced the use of silver foil as an antimicrobial
dressing, which was used until antibiotics replaced it during World War II. Silver has been
used for dental fillings for decades, providing
a possible reduction of further dental caries. Silver
is now used in urinary catheters, central lines,
endotracheal tubes, and even in clothing and
shoes to reduce odors from organisms. There
are manufacturers of silver-coated washing
machines, silver colloids are applied to vegetables
in Mexico, and silver is used for water purification.
Whether silver is needed for such products is not
clear.
The mechanism of silver’s action is not totally
clear.28–30 All heavy metals are toxic to bacteria
and other cells. The silver ion (Ag1) is highly reactive and binds to negatively charged moieties such
as DNA, RNA, negatively charged proteins, and
other ions. To be biologically active, Ag1 or clusters of Ago must be soluble in solution. Ago is the
metallic and uncharged form of silver that is found
in crystalline and nanocrystalline forms. In solution
it must exist in less than eight atom (subcrystalline)
groups. Its activity depends on the amount of
soluble silver delivered to the wound. In vitro
activity frequently does not correlate with in vivo
activity because Ag1 usually binds to proteins in
the serum or tissues. Delivery of the ion is thus
very important. Maintenance of a steady level of
silver is also very important. In the complex fluids
of a wound, silver concentrations of more than
50 ppm must be maintained. This is why most
topical creams are applied twice a day. Eluting
agents, therefore, must have prolonged release
for continued efficacy.
The metal form is inert and poorly absorbed by
bacterial or mammalian cells. When Ago interacts
with cellular fluids and enzymes, it becomes
ionized and then is highly reactive, binding to
proteins and cell membranes. It may affect cellular
permeability and interfere with cell membrane
transport and enzyme activities by interfering with
protein functions. Like other heavy metals, Ag1
interacts with thiol groups on the respiratory chain
molecules to interfere with cellular energy use.
Ag1 interacts with free sulphydryl groups and interferes with the enzyme phosphomannose isomerase. The ion also interferes with RNA and DNA
activities. Silver, in itself, has activities against
bacteria, yeasts, and molds. Ag1 is effective
against MRSA and vancomycin-resistant enterococci if delivered in adequate concentrations.
Some of the early uses of silver in the 1970s
included using silver-coated fabrics that were connected to a direct current of electricity.31 The initial
treatments were for bone infections and appeared
to be effective. Since then, several authors have
examined the benefits of treating burn wounds
using silver cloth and DC electricity.32 The use of
electrically charged silver cloths has not become
popular in the clinical world.
The most recent fad for topical agents has been
the development of dressings that elute silver.
These products frequently use nanocrystalline
silver in the dressing. Nanocrystalline silver is
a metastable, high-energy form of elemental silver
prepared by using ‘‘physical vapor deposition
reactive sputtering,’’ which creates crystals of
oxidized silver (Ag2O and Ag2CO3) and metallic
silver. Normally, silver does not dissolve in water,
but the nanocrystalline form dissolves to produce
70 ppm of both Ag1 and Ago. A plethora of
silver-eluting products with different delivery
methods are now available. These products are
used for different aspects of burn wound care.
Many are used for split-thickness donor sites and
partial-thickness burns. The silver-eluting materials are also used for deeper burns and to provide
antimicrobial coverage over dermal substitutes
such as Integra (Integra, Plainsboro, New Jersey).
Even negative-pressure wound-healing devices
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Greenhalgh
are starting to use silver in their sponges, such as
the GranuFoam Silver sponge (KCI, San Antonio,
TX), which is effective against vancomycin-resistant enterococci.
Some authors state that organisms do not
develop resistances to silver, but recent evidence
suggests that resistances do occur.28,33 The
mechanisms of how resistance develops are also
being discovered. The ability of bacteria to
develop resistance to silver is not surprising
because they develop resistance to almost all antimicrobials agents. Resistance to silver and many
other toxic heavy metals (eg, Cd12, Hg12, Pb12,
Tl1) is at least in part due to the effects of the
genetic machinery. Such resistance genes are
also transferred to other bacteria by plasmids.
Resistant organisms develop an efficient efflux
system that ejects Ag1 from the cell (and thus
avoids toxicity). Some resistant E coli strains are
deficient in outer membrane porin proteins. The
genes produce different proteins, called sil (eg,
silA, silB), which create a complex set of proteins
that eject the silver ion. Other proteins (eg, CusF)
are also encoded in the genetic machinery. The
resistant genes create at least two silver ‘‘pumps’’
that effectively eject the ion.
There are some complications from silver use,
but they are rare. High oral or inhaled doses can
lead to argyria, which is a permanent deposition
of silver in the skin’s microvessels. This problem
has not been reported with topical use of silver
products. There have been reports of absorption
of silver from the use of silver sulfadiazine in burns
over more than 40% of the total body surface area,
so it is conceivable that systemic toxicities could
occur.34–36 Silver nitrate solution and, rarely, nanocrystalline silver products will stain the skin temporarily. The brownish-black precipitate will peel off
after 2 to 3 weeks as the stained epithelium
sloughs.
The final concern with silver products is their
effects on wound healing.28–30,37–39 In vitro studies
have repeatedly demonstrated that silver is toxic
to keratinocytes and fibroblasts. The toxicity
increases with increased concentrations of silver.
The in vitro inhibition has not led to obvious impairments in animal or human healing. Delivery of
lower levels of silver in vivo and the binding of
silver by proteins are likely to limit toxicities to
a healing wound. Silver may also alter the actions
of reactive oxygen species in a wound by
depleting glutathione, but again, this is a theoretic
problem that is unlikely to have profound clinical
effects. Silver has been found to decrease matrix
metalloproteinase levels, which may benefit the
ultimate healing. There was one study that
compared the healing of a wound treated using
a silver-coated dressing (Acticoat; Smith &
Nephew, Hull, England) with the healing of another
wound treated using a non–silver-coated dressing,
and there was a significant delay in the healing of
donor sites in the wound with the silver-coated
dressing.39 The results of that study create
concerns for the use of silver-eluting products on
donor sites. More studies are needed to determine
if silver has significant effects on healing.
Other Novel Antimicrobial Dressings
Probably one of the oldest topical agents is honey.
Reports still indicate that honey is an effective
topical agent for wounds.40 Honey, or even a sugar
paste, probably inhibits bacterial growth because
of its high osmolarity. Honey inhibits bacterial
growth in vitro, so there may also be some inherent
antimicrobial activities. A recent review of the literature suggests that honey is an effective agent for
burn wounds and may even augment healing. The
studies to support this evidence were not
prospective, randomized studies, but they are, at
least, intriguing.
Newer agents are being tested all of the time.
There is a report of a liposomal hydrogel containing povidone-iodine (Repithel, Mundipharma
GmbH & Co, KG, Limburg/Lahn, Germany).41
There are also reports of a silver sulfadiazine–
impregnated lipidocolloid wound dressing (Urgotol
SSD, Laboratories Urgo, Chenove, France).42 A
recent publication described the investigation of
the use of nanofibers in burn wound healing.43
These nanofibers provide a matrix scaffold for
collagen deposition and have the theoretic advantage of being a delivery system for antimicrobial
agents and other healing stimulants (such as
growth factors).
SUMMARY
Topical antimicrobial agents have been used for
decades to successfully decrease the bacterial
load in wounds. Fortunately, early excision and
grafting of the burn wound has replaced the
need for prolonged use of these agents. The latest
interest has been in using dressings that deliver
silver to the wound. The clinical value of these
newer dressings still needs to be proved clinically.
Tests of the efficacy of topical agents are just
starting to be performed and need to be
continued.
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