SURGICAL INFECTIONS

Volume 21, Number X, 2020 Review Article

ª Mary Ann Liebert, Inc.
DOI: 10.1089/sur.2020.368

Topical Antimicrobial Agents for Burn Wound Care:

History and Current Status

Leopoldo C. Cancio
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Abstract

Background: Infection is the leading cause of death after thermal injury. Optimal prevention and treatment of
burn wound infection is enabled by an in-depth understanding of burn wound treatment modalities not only
from a technical standpoint, but also from the standpoint of the clinical context in which these modalities were
originally developed.
Methods: A review of the historical literature on the topical antimicrobial care of burn wounds was performed.
Results: As our understanding of post-burn infection evolved, and as new products were developed for the
prevention of post-burn wound infection, major advances in post-burn survival occurred. Ultimately, improve-
ments in anesthetic, surgical, and critical care management have permitted early excision and grafting of the burn
wound, decreasing but not eliminating the importance of topical antimicrobial care, and shifting much of the
burden of wound infection prevention to the post-operative period.
Conclusions: The development of effective topical antimicrobial agents for wound care was, arguably, the
single most important advance in the care of the burn patient. Still, many gaps in our ability to treat complicated
burn wounds remain. Fungal infection is an unusual but daunting challenge. Patients with impaired wound
healing and those with advanced age or medical comorbidities may not benefit from early excision, and the
benefits of early excision may not be available in austere or remote locations. For these reasons, research on
optimal topical treatment continues.

Keywords: antibiotic agents; antimicrobial agents; burns; infection; mafenide; silver

A ccording to Basil A. Pruitt, Jr. (1930–2019), burns

should not be viewed as a unique phenomenon but rather
as the ‘‘universal trauma model’’ that exemplifies many of the
Antisepsis
The modern history of topical antimicrobial wound treat-
ment begins with the English surgeon Joseph Lister (1827–
body’s responses to injury, inflammation, and infection [1].
1912), who recognized that micro-organisms, rather than
Indeed, the development of topical antimicrobial agents for
‘‘miasma,’’ were the cause of wound infection. In 1867 he
burn care is a microcosm of the larger campaign to understand
described ‘‘the antiseptic principle in the practice of surgery’’:
and treat surgical infections. The development by Pruitt and
colleagues of effective topical antimicrobial agents for the I arrived.at the conclusion that the essential cause of sup-
prevention of invasive gram-negative burn wound infection puration in wounds is decomposition, brought about by the
was the single most important step in the history of burn care influence of the atmosphere upon blood or serum retained
and led to important and sustained improvements in post-burn within them, and, in the case of contused wounds, upon por-
mortality. This achievement was marked by the introduction to tions of tissue destroyed by the violence of the injury (.)
When it had been shown by the researches of Pasteur that the
the bedside of topical mafenide acetate cream (Sulfamylon,
septic property of the atmosphere depended not on the oxygen,
Mylan, Inc., Canonsburg, PA) in January 1964 [2]. This pivotal or any gaseous constituent, but on minute organisms sus-
event was grounded in years of integrated laboratory and pending in it.it occurred to me that decomposition in the
clinical research and was followed by continued efforts to ad- injured part might be avoided.by applying as a dressing
dress the ever-changing epidemiology of burn wound infection some material capable of destroying the life of the floating
[3]. These efforts are incomplete and continue to this day. particles [4].

U.S. Army Institute of Surgical Research, Fort Sam Houston, Texas, USA.

1
 2 CANCIO
For this purpose, he selected carbolic acid (phenol), be-
cause it was used in the town of Carlisle to reduce the stench
of sewage applied as a fertilizer to pasture land, with the
additional effect of preventing parasitic infections in the
cattle who grazed there [5]. Lister applied it topically to
compound fractures and abscess cavities, he used it to cleanse
the instruments and the surgeon’s gloved hands, and he had
an assistant spray it into the air during surgery [6]. Lister
avoided the ignominious fate of his Hungarian predeces-
sor, Ignaz Semmelweis (1818–1865), in part because of the
contemporaneous work of Louis Pasteur (1822–1895), and in
part because of his travels to communicate his findings to
surgical audiences in Europe and America. Thus, for exam-
ple, Lister was able to convert Henry Bigelow (1818–1890),
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professor of surgery at Harvard University, from a skeptic
who referred to Lister as a practitioner of ‘‘medical hocus-
pocus’’ [6] to a devoted proponent:
But after two years’ experience, I have accepted the new
doctrine with most of its details. I have learned that.the duty
of the surgeon is to act as if all the particles made visible by a
sunbeam were noxious, falling like snow-flakes during every
operation and every dressing.His aim should be to destroy
the actual intruders, and effectually to exclude their thronging
companions [7].
Even so, it is worth noting that Lister in later life discarded
the practice of spraying carbolic acid during surgery [8].
The onset of World War I challenged surgeons with in-
juries of unprecedented severity and number, caused by
machine-gun fire and artillery shells during trench warfare.
Massive wounds, contaminated field conditions, and delayed
evacuation led to a high rate of death from necrotizing
wound infections [9]. Under these circumstances, listerian
principles were questioned. Antiseptic solutions, applied to
the surface of a wound, were incapable of eradicating in-
fection from septic penetrating injuries. Rather, immunolo-
gist Almroth Wright (1861–1947) argued that hypertonic
saline (5%) dressings should be applied to septic wounds in
order to ‘‘attract water’’ from the depths of the wound, thus
producing an ‘‘outflowing current of water’’ and ‘‘drawing
into the tissues from the blood stream lymph inimical to
microbial growth.’’ Thus, his idea was to enhance the body’s
own antimicrobial processes [10].
Meanwhile, French surgeon Alexis Carrel (1873–1944) and
English chemist Henry Drysdale Dakin (1880–1952) devel-
oped a refinement of the antiseptic technique. Dakin tested a
number of chemicals, settling on 0.5% sodium hypochlorite
solution, buffered with boric acid, as the agent of choice. He
described the antimicrobial properties of the solution and as-
serted that clinicians had found it non-irritating to tissues [11].
Carrel tested the solution as one component of what we would
nowadays call a ‘‘bundle’’ of care, which included a three-
week training program for physicians and nurses, wide incision
and debridement of wounds, implantation of tubes into the
wound to permit the instillation of the solution, frequent
(every two to four hours) infusion of the solution, bacterio-
logic analysis of wound contents, and delayed wound closure
to correspond with resolution of infection [12,13]. Devel-
opment, documentation, and popularization of the method
was accelerated by Carrel’s relationship with leading Bel-
gian surgeon Antoine Depage, at whose hospital at Com-
piègne Carrel oversaw an 80-bed ‘‘experimental clinic’’
[14]. Carrel’s method was, however, subject to numerous
pitfalls requiring precision in its implementation, and was
logistically and technically demanding [15,16].
Antimicrobial Agents
The role of antisepsis in wound care began to be eclipsed
during the inter-war years by the development of antibacterial
drugs. Paul Ehrlich (1854–1915), the pioneering immunolo-
gist and biochemist, had discovered dyes that preferentially
stained tissues such as axons in living organisms and other
dyes that identified the different categories of granulocytes
(neutrophils, basophils, and eosinophils). Perhaps the same
concept could be used to target micro-organisms? Methy-
lene blue was only somewhat effective against malaria, and
trypan red against Trypanosoma equinum. Ehrlich et al.
[17] then turned to arsenicals, synthesizing and testing
approximately 1,000 compounds. Their compound 606,
arsphenamine (salvarsan), was found to be effective against
Treponema pallidum in a rabbit model of syphilis, the first
synthetic antibiotic.
Gerhard Domagk (1895–1964], a German pathologist
and bacteriologist, built on Ehrlich’s work, exploring the
antibacterial properties of various dyes at IG Farbenindus-
trie. He noted that, ‘‘For coccal infections, there have been
no reasonable effective chemotherapeutants known.’’ He
found that a red crystalline powder related to the azo dyes
and synthesized by others in 1932, Prontosil (4¢-sulfanamid-
2,4-diaminoazobenzene; Bayer AG, Leverkusen, Germany),
was curative when given subcutaneously or orally in a lethal
mouse model of intra-peritoneal streptococcal infection. (In-
terestingly, this drug was effective only in vivo but not
in vitro; this is because it is what we now call a pro-drug and is
metabolized to sulfanilamide.) Also, Prontosil had differential
efficacy against different organisms; it was effective against
Streptococcus, somewhat against Staphylococcus, and not at
all against Pneumococcus. He referred to this selectivity as
‘‘elektive Wirkung’’ [18].
After performing murine studies of streptococcal perito-
nitis similar to those done by Domagk [19], English physician
Leonard Colebrook (1883–1967), a student of Almroth
Wright, conducted an uncontrolled clinical trial of Prontosil
in puerperal sepsis in 1936. The use of Prontosil resulted in a
decrease in the death rate in this disease from 16.6%-31.6%
in previous years to 4.7% [20]. This stunning advance her-
alded the beginning of the age of antibiotic agents.
Another inter-war development was growing interest in
improving the care of thermal injuries, but application of the
recent advances in microbiology and debridement was de-
layed by competing theories on burn pathophysiology. The
toxemia theory held that the eschar released a toxin into the
circulation. The identity and effects of this toxin were ill-
defined, which did not deter Davidson [21] from writing in
1925 that the concept was ‘‘most strongly supported.’’ Al-
though some authors described the ‘‘early and complete re-
moval of the burned tissue,’’ Davidson [21] proposed the use
of tannic acid to precipitate proteins and other ‘‘poisonous
materials’’ in the burn wound. This became a standard first
aid treatment for burns through the middle of World War II.
On the other hand, Aldrich claimed that tannic acid merely
delayed the onset of infection [22]. He, and others, performed
bacteriologic studies of burn wounds, demonstrating that
 TOPICAL ANTIMICROBIAL AGENTS 3

wound cultures became positive for streptococci beginning at

approximately the eighteenth hour post-burn [23,24]. Aldrich
[22] used a dye-based topical antimicrobial, gentian violet, to
prevent streptococcal infection. Later, he added acriviolet
and brilliant green to address gram-negative bacteria, thus
constituting ‘‘triple dye’’ therapy. He concluded ‘‘that the
conception of a burn as an infected surgical lesion is correct,
and that it is infection rather than the absorption of a split
protein which causes death’’ [23].
When the United Kingdom began experiencing large
numbers of burned aviators during the Battle of Britain in
1940, Archibald McIndoe assumed the care of these casual-
ties at the Queen Victoria Hospital in East Grinstead [25].
Among his numerous contributions to the nascent field of
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burns was condemnation of tannic acid treatment. Not only

did it fail to prevent infection, but also ‘‘the hard inelastic
crust’’ led to ‘‘totally crippled hands and severe facial de-
formities with loss of vision’’ [26].
During 1940–1941, the U.S. government stood up two
organizations to support medical preparations for war: the
Advisory Committees to the Surgeon Generals of the Na-
tional Research Council (NRC) and the Committee on
Medical Research. The NRC’s Subcommittee on Surgical
Infections funded eight U.S. civilian hospitals to establish
wound study units. The original project called for a multi-
center controlled study of sulfa drugs for the prevention of
infection in burn and non-burn wounds. These plans changed
after the attack on Pearl Harbor of December 1941 [27].
Approximately 60% of the more than 500 casualties at the
naval hospital had burns, and their treatment varied widely.
Despite McIndoe’s rejection of tannic acid, it was liberally
used there. For example, Flit guns (normally used to deliver
insecticide) were used to spray tannic acid onto wounds
(Fig. 1). Gentian violet or triple dye, with or without silver
nitrate, was also used. In some cases, sulfanilamide powder
was mixed in with these substances. Sulfa drugs were also
given orally if infection was suspected [28].
I.S. Ravdin and Perrin H. Long visited Pearl Harbor after
the attack to report back to the NRC on the medical response.
They derived an overly optimistic impression of the ‘‘in-
calculable value of sulfonamide therapy,’’ both oral and
topical [29]. As a result, they recommended that, ‘‘You
cannot withhold from these patients the benefit of the sul-
fonamide drugs,’’ and the use of the controls in the eight-
center civilian study became optional. The results of that
study ultimately were less sanguine and found no clear ad-
vantage to sulfa drugs. Referring to staphylococci and gram-
negative organisms in the burn wounds, Frank Meleney
concluded: ‘‘Something must be sought which will be ef-
fective at halting the growth of these organisms in the
presence of the dead and damaged tissue of burns’’ [27].
Furthermore, the wound study units found that ‘‘tanned
burns showed a high incidence of infection,’’ leading to a
recommendation in October 1942 that procurement of tannic
acid be discontinued [30].
The limitations of tannic acid and of sulfa drugs gave
impetus to the development of penicillin. Alexander Fleming
discovered penicillin in 1929, tested it in vitro, and suggested
that it could serve as an ‘‘efficient antiseptic’’ when applied
topically onto or injected into infected wounds [31]. Eleven
years later, the Oxford team of Chain and Florey [32] and
others succeeded in producing enough penicillin to permit
FIG. 1. Use of a Flit gun to apply a topical agent to a burn
patient following the attack at Pearl Harbor, 1941. (Source:
Getty Images.)
in vivo studies of efficacy in murine models, and clinical use
in a handful of patients [33]. With this evidence in hand,
Florey traveled to the United States in 1941 to gain support
for mass production and clinical trials. One such clinical
study was ready to go under the leadership of Champ Lyons
at the Massachusetts General Hospital (MGH) at the time
of the Cocoanut Grove Nightclub fire in November 1942
[30,34]. Topical treatment of these patients at the MGH
consisted of boric ointment strips and sterile gauze under a
pressure dressing. Intravenous sulfadiazine was given pro-
phylactically, and penicillin as a treatment to 13 patients with
clinical signs of infection, albeit at doses subsequently rec-
ognized as subtherapeutic [34].
As penicillin production ramped up, it was first studied in
U.S. combat casualties by Lyons (now an active duty Army
officer) at Bushnell General Hospital, Brigham City, Utah,
and then at Halloran General Hospital, Staten Island, New
York [35]. It was then distributed to British and U.S. hos-
pitals in the Mediterranean theater. Lyons reported from
that theater in 1944 that the proper role of antibiotic agents
was as an adjunct to, not as a substitute for, surgical man-
agement. Furthermore, he rejected the listerian concept
of topical antisepsis: ‘‘Experience in wound management
justifies the abandonment of local use of any chemical agent
in a wound’’ [36]. Despite that caveat, the extraordinary
collaboration among military, commercial, academic, and
government entities that delivered this new drug to the
battlefield is certainly one of the most important achieve-
ments of the war, and prepared the way for further post-war
antibiotic development [37].
 4 CANCIO
Topical Antimicrobial Agents
The exposure method
In January 1947, Edwin Pulaski moved from the Halloran
General Hospital (where early clinical studies of penicillin
had been conducted during World War II) to Brooke General
Hospital, Fort Sam Houston, Texas, to establish a new sur-
gical research unit (SRU; later the U.S. Army Institute of
Surgical Research [ISR]). This unit’s mission was ‘‘evalua-
tion and interpretation of new antibiotics, chemotherapeutic
agents and surgical technics’’ [38]. Patients admitted to this
unit included not only those with burns, but also those with a
variety of infected wounds. After 1949, the unit focused in-
creasingly on burns in anticipation of possible nuclear war.
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Pulaski traveled to Birmingham, United Kingdom, to learn
about topical treatment with penicillin cream from Colebrook,
but ultimately adopted the ‘‘exposure method’’ from A.B.
Wallace at Edinburgh, who claimed that allowing burns to dry
out prevented infection and enhanced healing [39–42]. Results
of the exposure technique at the SRU were less encouraging.
Careful documentation of clinical and microbiologic data in
burn patients at the SRU showed that during 1953–1963, there
was a continued high prevalence of bacteremia as the cause of
death, and a gradual shift in the causative organism from Sta-
phylococcus aureus to Pseudomonas. Control of Staphylo-
coccus aureus was attributed to the successful use of penicillin
derivatives. On the other hand, intravenous antibiotic agents
were ineffective at controlling Pseudomonas wound infection
or bacteremia. Furthermore, 90% of ‘‘burn wound sepsis’’
cases in 1963 had burn wound cultures positive for large
amounts of Pseudomonas.
Two divergent approaches were proposed to address this
problem. On the one hand, SRU surgeons noted that half of
septicemic patients during 1950–1954 had been treated with
the exposure method, and half with occlusive dressings.
Thus, the method of topical treatment did not seem to mat-
ter—particularly in larger burns. This ‘‘focuses attention on
the need for wound closure at the earliest possible time.’’ But
the ‘‘heroic’’ decision to ‘‘excise eschars boldly in stages
during the immediate post-burn period is difficult to make.’’
On the other hand, they developed a model of invasive
Pseudomonas aeruginosa burn wound infection in rats, in
which they proved the wound origin of fatal post-burn sep-
ticemia [43]. The failure of systemic antibiotics to prevent or
treat these infections was explained by the avascular nature of
the eschar [44].
Mafenide
An answer to this problem was suggested by Janice Men-
delson, an Army surgeon doing research on blast injury in
goats. Fortuitously, a supply of mafenide hydrochloride (Sul-
famylon or marfanil; p-aminomethylbenzenesulfonamide)
seized from the Germans during World War II was discovered
in an Army warehouse in Maryland [45]. This antibiotic had
been synthesized in the United States but abandoned because of
a report of low efficacy against streptococci [46]. (The murine
model used to test efficacy was intra-peritoneal injection of
Streptococcus pyogenes, followed by oral treatment [47].)
However, it was shown to have better activity against Clos-
tridium perfringens [48]; the Germans issued it to their troops
for topical and oral use on the Eastern Front in 1941, and more
widely in 1943, mainly in order to prevent gas gangrene [49].
Mendelson and Lindsay [50] demonstrated its efficacy when
applied topically (by spray) in a goat model of undebrided blast
injury complicated by a (naturally occurring) Clostridium
perfringens infection and related these findings to the SRU
group. At the SRU, Robert Lindberg and Arthur D. Mason, Jr.
(1928–2013) applied Sulfamylon in the form of a cream in the
rat burn wound infection model. When applied either imme-
diately or at 24 hours post-burn, the treatment produced a 100%
survival rate. Even as late as 72 hours post-burn, there was a
mortality effect [44]. This dramatic finding motivated imme-
diate translation to burn patients in January 1964 (Fig. 2) [2].
The results were similarly dramatic: a reduction in burn wound
sepsis as the cause of death from 59% (during 1962–1963) to
10% (during 1964–1966) [2].
Despite its structural similarity to sulfanilamide, mafe-
nide’s mechanism of action is different. Unlike sulfa drugs,
mafenide does not act on bacteria to inhibit the folate pre-
cursor, para-aminobenzoic acid (PABA). Furthermore,
PABA does not inactivate mafenide, which is important be-
cause PABA may be present in large quantities in wounds.
Unlike silver preparations, it readily diffuses through the
avascular eschar, or through avascular tissues such as carti-
lage [51]. The latter property makes it ideal for prevention of
chondritis in patients with ear burns. On the other hand, this
means that it needs to be re-applied twice daily to maintain an
effective concentration in the wound [51]. Once absorbed
systemically, it is metabolized rapidly to an inactive metab-
olite, p-carboxybenzenesulphonamide, a compound with
no antibacterial activity [52]. However, this metabolite is a
carbonic anhydrase inhibitor. Thus, some patients with ex-
tensive burns receiving twice-daily Sulfamylon cream treat-
ment may develop metabolic acidosis and compensatory
respiratory alkalosis [53].
Silver compounds and dressings
While SRU researchers were evaluating mafenide in the
early 1960s, Carl Moyer and colleagues performed studies of
silver nitrate (AgNO3) aqueous solution for topical burn
wound treatment. Silver nitrate had been used at concen-
trations of 5%–10% as a tanning agent and had been
FIG. 2. Col. John Moncrief watches Maj. Basil A. Pruitt,
Jr. apply Sulfamylon burn cream to a patient, 1969. (Source:
U.S. Army Institute of Surgical Research.)
 TOPICAL ANTIMICROBIAL AGENTS
discarded. Here, however, a 0.5% solution was used. This
was based on personal experience by one of the authors with
this solution in the treatment of problem wounds such as
necrotizing fasciitis. They observed that a 0.5% solution, but
not a 1% solution, was safe from the standpoint of not im-
peding epithelialization. They presented a case series, dem-
onstrating a reduction in wound colonization with pathogens
like Pseudomonoas aeruginosa and Staphylococcus aureus.
The primary indication of efficacy was a reduction in mor-
tality, from a predicted 41% to an observed 14% [54].
Moyer et al. [54] emphasized the importance of using a
thick gauze dressing and of keeping the dressing moist con-
tinuously. That is, as the water evaporates from the dressing,
the concentration of AgNO3 remaining at the wound surface
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was thought to increase past the safe level. The cause of death
while receiving AgNO3 was related to electrolyte abnor-
malities. As a hypotonic solution, silver nitrate ‘‘leeches’’
electrolytes across the wound surface. This can cause life-
threatening levels of hyponatremia, hypokalemia, and hy-
pocalcemia, mandating frequent laboratory determinations
(at least every six hours). Also, use of this solution can cause
hypothermia caused by evaporation [54]. The primary limi-
tation of AgNO3 is its inability, unlike mafenide, to penetrate
the eschar. However, this limitation does not apply in the
treatment of superficial injuries, or of non-burn desquamating
skin diseases such as toxic epidermal necrolysis syndrome;
the latter is the primary indication for its use at the U.S. Army
Burn Center at this time.
The technical challenges associated with the use of silver
nitrate led Fox to develop silver sulfadiazine (SSD), a com-
plex of silver nitrate and the antibiotic sulfadiazine. When
mixed with chloride-containing fluids on the surface of a burn
wound, this complex releases the silver cation. In scalded
mice with otherwise lethal Pseudomonas aeruginosa wound
infections, SSD appeared to reduce mortality compared to
both silver nitrate and mafenide [55]. The primary mechanism
of action of SSD relates to the silver, rather than to the sul-
fadiazine. In contrast to silver nitrate solution, release of silver
from the silver sulfadiazine complex is slow and steady [56].
Sometimes, SSD is associated with leukopenia, which re-
solves within a few days despite continuation of therapy [57].
The first silver textiles used as dressings in the modern era
were made from nylon and were originally intended to serve
as flexible electric shields or radar reflectors [58]. Deitch et al.
[59] demonstrated in vitro efficacy of silver nylon against
Pseudomonas aeruginosa, Stapylococcus aureus, and Can-
dida albicans. Chu and McManus [58] at the ISR embarked
on a multiyear study of silver nylon dressings in rat models.
Interestingly, they demonstrated greater efficacy when the
dressing was connected, as an anode, to a weak direct current
source, causing increased release of silver cations onto the
wound. Under these conditions, silver nylon was as effective
as SSD [60]. Today, silver nylon is used extensively in burn
care, especially in superficial burns and in clean, deeper burns
of limited extent [61]. A variety of other silver dressings have
been developed, to include those made with nanocrystalline
silver (Acticoat, Smith+Nephew, Fort Worth, TX) [62], soft
silicone combined with foam (Mepilex Ag, Molnlycke,
Gothenburg, Sweden) [63], moisture-retentive spun fibers of
sodium carboxymethyl-cellulose (Aquacel Ag, ConvaTec,
Oklahoma City, OK) [64], and ceramic silver (Milliken As-
sist, Milliken, Spartanburg, SC).
5
The mechanism of action of silver is ‘‘oligodynamic,’’
meaning that small amounts (parts per million) of silver are
required for efficacy. Elemental silver is biologically inert;
only the cation (Ag+) is antimicrobial. Proposed mechanisms
of action include: (1) blocking the microbial electron transport
chain; (2) rupturing the cell membrane or wall; (3) binding to
and damaging bacterial DNA (vulnerable because of its lo-
cation in the cytoplasm); and (4) destroying the cell by silver
free radicals. Antimicrobial resistance to silver is uncommon,
thus, the mechanism of action is likely multifactorial, such
that evolution of multiple resistance strategies would be re-
quired. A disadvantage of silver therapy is the fact that silver
cations can be precipitated on the wound surface by anions
such as chloride. This means that the effective concentration
in vivo is many times higher than that in aqueous solutions. It
also means that silver, unlike mafenide, does not penetrate
deeply into a wound. Systemic silver toxicity (argyria) is
extremely rare in burn care [65]. An advantage of silver over
mafenide is that the former has some antifungal activity,
particularly against yeasts, whereas the latter has none.
Cerium
In 1977, Monafo, who with Moyer had described the use of
silver nitrate, treated patients with a combination of cerium
nitrate and SSD. Cerium is a rare-earth metal of low toxicity.
Monafo originally stated that cerium is an antimicrobial, al-
though subsequent studies have not substantiated that claim
[66]. Rather, cerium nitrate results in a firm eschar that pro-
tects against bacterial ingress [67]. The eschar is tightly ad-
herent without a tendency to spontaneously separate from the
burn wound for at least six weeks [68,69]. Cerium also ap-
pears to exert a beneficial effect on host immune function. In
animal studies, cerium nitrate treatments decrease local and
systemic inflammation [70,71], limit burn wound progression
[72], and restore the helper-to-suppressor T-cell ratio [73,74].
Moreover, cerium nitrate plus silver sulfadiazine treatment—
but not mafenide, silver nitrate, or silver sulfadiazine alone—
mitigates cell-mediated immunity suppression in a mouse
model [75].
It is not clear why cerium nitrate has these immune benefits.
Martin Allgöwer (1917–2007), a Swiss surgeon best known as
the co-inventor of the AO system for internal fixation of frac-
tures, proposed (in a manner reminiscent of the toxemia theory),
that burn wounds release lipid-protein complexes (‘‘pernicious
effectors’’) that cause immunosuppression and systemic illness.
Allgöwer and colleagues stated that cerium nitrate binds to these
complexes and mitigates these effects. Other authors demon-
strated superficial connective tissue calcification [69], which
may result from cerium displacing calcium from pyrophosphate
to allow calcium to deposit, analogous to the pyrophosphate-
calcium interaction within cancellous or cortical bone [67].
At the ISR, Kai Leung and colleagues have shown in the
Walker-Mason full-thickness scald-burn model that cerium
nitrate solution (40 mM) treatment, as compared to a control
solution, reduces circulating levels of pro-inflammatory
damage-associated molecular patterns (DAMPs) such as
high-mobility group box protein 1 (HMGB1), hyaluronan,
and xanthine oxidase (XDH) on post-burn day one. On post-
burn day seven, circulating DAMP levels were on average
halved by cerium nitrate treatment, as were levels of cytokines
interleukin (IL)-1b and IL-10 and chemokines GRO-KC and
 6 CANCIO
MIP-1a in wound tissue [70]. At present, cerium nitrate with
SSD is available in several countries as Flammacerium (Derma
UK Limited, Newcastle upon Tyne, UK), and has received
orphan drug status in the United States (it is not yet Food and
Drug Administration-approved).
Honey
Recently, there has been growing interest in the antimicrobial
properties of honey. Honey has been used since ancient times as
a topical antimicrobial and has been proposed as an alterna-
tive under austere or battlefield conditions [76]. Medical-grade
honey is now available throughout the world. The mechanism of
action of honey as an antimicrobial is multifactorial. Honey is
hyperosmolar and has a low pH. Most honeys, because of the
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action of glucose oxidase, produce hydrogen peroxide when
diluted with water. Some honeys contain specific antibacterial
agents. For example, manuka honey (from the flowers of the
Leptospermum tree of New Zealand) contains methylglyoxal, an
alpha-oxoaldehyde that reacts with DNA, RNA, and proteins.
This variety of honey has a broad range of antibacterial activity,
low mammalian toxicity [77], and (to date) low likelihood of
inducing resistance [78]. Honey also shows promise as an an-
tifungal agent [79]. A recent Cochrane Review found that the
studies of honey for burns treatment are of low or very low
quality. The studies are also difficult to interpret because the
comparator treatment is often one that is not widely used [80].
Despite the limitations of these studies, we now commonly use
medical honey and honey dressings, particularly in the care of
problem wounds.
Clinical Experience and Conclusions
A review of burn patient data from 1950–1999 permitted
analysis of the effects of topical mafenide and SSD on sur-
vival at the ISR Burn Center (Fig. 3) [81]. The introduction of
mafenide into burn care in 1964 resulted in a decrease in age-
and burn-size-adjusted mortality risk. This was followed by
an increase in mortality in the latter half of the 1960s, as
resistant strains of Providencia stuartii and Enterobacter
FIG. 3. Age- and burn-size adjusted log-odds of mortality
following thermal injury at the U.S. Army Institute of Sur-
gical Research (U.S. Army Burn Center), 1950–1999
(Source Reference [81].)
cloacae appeared, and sepsis became more common [82]. In
1973, SSD was introduced, and improved control of sepsis
and mortality were gradually achieved. Briefly, SSD was
used as the sole antimicrobial agent; later, it was alternated
every 12 hours with mafenide (a practice called alternating
agents). Throughout this period, typical burn treatment was
as follows. Daily hydrotherapy and topical antimicrobial care
were performed until the burns either healed or the eschar
separated. Then, cadaver allografts were applied, and finally
autografting was performed. Starting in 1978 and following
the pioneering work on the tangential excision by Janzekovic
[83], excision of extensive burns was introduced. A new burn
unit was built, and better isolation procedures were instituted
in 1983 [84], resulting in further improvements in mortality.
The role and relative importance of topical antimicrobial
agents in burn care has since evolved. Today, patients
with smaller burns are readily treated with silver dressings
or with synthetic bilaminar skin substitutes (Biobrane,
Smith+Nephew; Permeaderm, Milliken). The latter have
been shown to hasten healing in comparison with SSD [85].
Total-body excision of patients with large burns is com-
pleted as soon as possible from a physiological standpoint,
often within days of injury [86]. Usually, these wounds are
immediately closed with autograft, or where insufficient donor
sites are available, a combination of widely meshed autograft
covered with an allograft overlay. Under these conditions,
topical antimicrobial treatment is a temporizing intervention.
The major problem becomes the care of the post-operative
wound while it heals, and the prevention or early detection and
treatment of post-operative infections. In this regard, fungal
wound infections remain a particular menace which indepen-
dently increase post-burn mortality [87], and for which no
good preventative measures exist.
On the other hand, some patients are not candidates for
early excision and grafting. These include those with con-
comitant medical diseases or advanced age. Other patients
may live in countries where modern surgical techniques are
not readily available. In a mass-casualty or military setting,
rapid excision may be logistically impossible. In the military
setting, we continue to recommend the use of alternating
agents (mafenide and SSD) for the treatment of unexcised
wounds [88]. Furthermore, Flammacerium or other cerium-
based treatments may be applicable as well. In conclusion,
effective management of the burn wound, to include pre-
vention of infection and successful wound closure, remain
the keys to survival in burn patients [89].
Acknowledgments
The author gratefully thanks Mr. Glen E. Gueller, Records
and Knowledge Manager (retired), and Ms. Susan Reyna,
Library Assistant, both of the Information Management Di-
vision, U.S. Army Institute of Surgical Research.
Funding Information
The author reports no funding for this work.
Author Disclosure Statement
The opinions or assertions contained herein are the private
views of the author, and are not to be construed as official or
as reflecting the views of the Department of the Army or the
Department of Defense.
 TOPICAL ANTIMICROBIAL AGENTS
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Address correspondence to:
Dr. Leopoldo C. Cancio
U.S. Army Burn Center
U.S. Army Institute of Surgical Research
3698 Chambers Pass
JBSA Fort Sam Houston, TX 78234-6315
USA
E-mail: Leopoldo.c.cancio.civ@mail.mil