Topical Antimicrobials in Burn Wound Care: A Recent History

“It is nearly 100 years since antisepsis came to dominate the treatment of burns. All that has been accomplished, as far as we can see from the data available, has been to offset the good that sound physiological and surgical principles and modern aseptic technique should have afforded.”¹
—Carl A. Moyer, MD, 1954

The topical therapy of burn wounds dates back to the beginnings of civilization. Throughout history, a number of famous philosophers, physicians, and scientists have contributed to the knowledge of burn wound management, including such notables as Hippocrates, Celsus, Pliny the Elder, Galen, Aristotle, Rhases, Clowes, Paré, Hildanus, Marjolin, Dupuytren, and Syme.² A diverse variety of substances have been advocated as effective topical burn treatments including various plants, gums, milks (goat milk, and milk from “a women who has given birth to a son”), tea leaves, roasted angle worms, oak bark extract, honey, cork, bear fat, bran, ashes, vinegar, wine, fat from “very old wild hogs,” calcium chloride soaks, moss “from the skull of a person hung,” red sandalwood, cold water, saline baths, lemon strips soaked in oily dressings, soot, spider webs, linseed oil mixed with lime water, picric acid, medicated paraffin, carbolic acid, cod liver oil, and “portions of a genuine mummy.”^2–4 Such ancient history, while fascinating, has little utility in contemporary practice with the possible exception of providing entertainment on teaching rounds. This article will concentrate instead on the more recent history of topical agents utilized in burn care.
Over the years, the goals of topical burn treatment have changed. At the beginning of the 20th century, it was understood that the systemic derangements seen in burn patients resulted from a release of “toxins” from the burn wound, and the goal of topical therapy was to bind or leach toxins before they could be absorbed.⁴ A secondary goal was to dry out the burn wound or to create a hard coagulum to minimize exudate, drainage, or fluid loss. A number of “escharotics” have been employed, alone or in combination, including 5% or 10% silver nitrate solution, gentian violet,^2,5 “triple” dyes, trinitrophenol, and tannic acid. Davidson at the Henry Ford Hospital first described the use of tannic acid spray in 1925,^2,6 and believed that this modality reduced pain and produced a cleaner wound bed.² In 1935, Bettman added 10% silver nitrate to a 2.5% tannic acid solution, which allowed wound tanning to occur in seconds.⁴ Reports of liver necrosis in patients treated with tannic acid began to appear in the 1930s, although the liver necrosis was often ascribed to the burn injury itself. Additionally, pus tended to accumulate under the coagulum formed by tannic acid application. McClure, also from Henry Ford Hospital, reported in 1944 that tannic acid was a hepatotoxin and the use of this agent was discontinued.²
The next major advance in topical burn management was the development of successful burn resuscitation strategies. As eloquently described by Peterson,³ “the development of efficacious topical agents had to await the understanding of burn shock and the need for resuscitation. Only then did the patient live long enough to fall victim to burn wound sepsis.” At the same time, work by Aldrich, Teplitz, Lindberg and others established that septicemia in burn patients, a major cause of mortality, frequently originated in the burn wound.⁵ Attention now turned to the application of various topical antimicrobials to the burn surface. While the development of mafenide (Sulfamylon®, UDL Laboratories Inc., Rockford, Ill), silver nitrate, silver sulfadiazine, and others revolutionized burn care. This advancement, however, came with a price. Before the concept of aggressive burn excision, burn eschar separated from the wound as a result of bacterial action. Control of burn wound florae slowed this process. Peterson³ noted, “with the introduction of mafenide it took 6 to 8 weeks for the eschar to separate, let alone for the wound to be covered. In one grand move, we more than doubled the time in the hospital for the burn patient.”
The final advance in contemporary burn wound management was the realization that aggressive surgical management should play a primary, rather than a supportive role. In 1947, Cope et al⁷ published a small series of burn patients managed by wound excision and grafting. In 1970, Zora Janzekovic⁸ published her personal experience with more than 1600 patients managed by a new technique called tangential excision and grafting. The next step was the concept of early excision and grafting, although considerable disagreement remains regarding the definition of “early.” Finally, in certain burn centers, excision of all burns within 24 hours of admission is now advocated.
Many partial-thickness burns will heal without grafting if the wound is kept clean and the florae maintained at manageable levels. Topical antimicrobials, therefore, retain a critical role in contemporary burn management. The developmental history of select agents is presented.

Dakin’s Solution

Berthollet discovered sodium hypochlorite (NaOCl) in France in 1788, and at the time was unsure of its exact chemical composition, but noted that the compound had bleaching and disinfecting properties.⁹ Four years later in Javel, France, Percy produced potassium salt and sold it as a disinfectant called eau de Javel.⁹ In 1820, a similar hypochlorite compound, developed by the pharmacist Labarraque was sold as “Liqueur de Labarraque.” This compound facilitated the embalming of Louis XVIII, whose severely decomposed body was unapproachable until disinfected and deodorized.9 Balard discovered that the chemical composition of Berthollet’s solution was a mixture of sodium chloride and sodium hypochlorite in 1834.9 Sodium and potassium hypochlorite briefly fell into disuse after the discovery of the more stable calcium hypochlorite, which was the disinfectant used by Semmelweis in 1846 to control the endemic puerperal fever at his clinic.⁹ Over the next 50 years, a number of new manufacturing processes simplified the production and increased the purity of various hypochlorite compounds, which found widespread use as disinfectants and deodorants. Commercially available hypochlorite compounds, however, proved too irritating and caustic for general use as antiseptics.⁹ Early on in World War I, French surgeons used eau de Javel and similar compounds with limited success because of the irritation they produced.⁹ In 1915, Dr. Henry D. Dakin from the Herter Laboratory (New York, NY), investigated a number of antiseptic substances, including phenol, salicylic acid, hydrogen peroxide, iodine, mercuric chloride, and sodium hypochlorite. He concluded that hypochlorite had “high germicidal action” and “many other desirable properties,” but that commercial preparations were of variable quality and often contained free alkali or free chlorine, which accounted for the tissue irritation. Dakin described a method of hypochlorite synthesis devoid of irritating contaminants that produced an end-concentration of 0.5% to 0.6% sodium hypochlorite. This solution could be continuously applied to wounds for more than a week without irritation.¹⁰ Dakin reported success with this new solution in 6 months of clinical use “by a number of different observers in different hospitals,” but did not provide further details.¹⁰ At this point, a famous collaboration occurred.
Alexis Carrel, the surgeon who won the 1912 Nobel Prize in Medicine for his work on vascular anastomoses,11 was a French citizen working at the Rockefeller Institute in New York. During a vacation to France in 1914, he was drafted into the French Army.¹¹ Noting that 70% of limb amputations were being performed as a result of infection rather than initial injury,¹² he obtained funding from the Rockefeller Institute to study ways to improve wound treatment methods. The Rockefeller Institute also funded Dr. Dakin as a collaborator, and the two created a system of mechanical cleansing, surgical debridement, and topical application of hypochlorite solution.¹³ The Carrel technique was personnel and resource-intensive. Physicians and nurses were required a minimum 3 weeks of close supervision to ensure proper mastery of the methodology.¹³ The Carrel technique involved proper clearing and cleansing of the wound, followed by the placement of 10-in to 15-in rubber irrigation tubes into the open wounds, which were then loosely packed with gauze.¹⁴ Dakin’s solution was then instilled into the irrigation tubes every 2 hours.13,14 Doctors took smears from the wounds every 2 days for microscopic examination; surgical closure was deferred until the point where “only one bacterium is found in 5 or 10 fields.”¹³ Dakin’s solution was subsequently widely utilized in World War II¹⁵ to treat both war wounds and burns. Along with other topical agents, Dakin’s solution fell out of favor when systemic antibiotics became available,¹⁶ but was reintroduced in the 1980s.¹⁶ In 1991, Heggers et al¹⁶ investigated the bacterial properties of different dilutions of sodium hypochlorite using 10 different species of Gram-positive and Gram-negative bacteria isolated from burn wounds. This group also studied the cytotoxic properties of different hypochlorite dilutions using mouse fibroblasts and a rat model. The studies concluded bacteriocidal effects to all tested pathogens occurred only at concentrations of 0.025% and above. Tissue toxicity was observed at a concentration of 0.25%, but not at 0.025%. On this basis, the authors concluded that a “modified” Dakin’s solution of 0.025% concentration was optimal.¹⁶

Gentamicin Sulfate

Gentamicin sulfate was briefly utilized as 0.1% topical cream burn dressing, intended for antipseudomonal coverage of invasive burn wounds.^17,18 The drug is readily absorbed through the burn wound, and topical use was associated with ototoxicity and nephrotoxicity.¹⁷ Burn resistance and super-infection developed rapidly. This, and the fact that early excision and grafting have largely eliminated invasive burn wound infections, has made topical gentamicin obsolete for routine use in burn patients.

0.5% Silver Nitrate

Five and 10% silver nitrate solution was used as a caustic and escharotic for burn care in the early 20th century, but was largely abandoned by the time of World War II because infections tended to become trapped under the hard eschar produced.^2,3 In 1965, Moyer et al¹ described the use of a dilute (0.5%) silver nitrate solution. In an attempt to control heat and water loss through burned skin, Moyer and colleagues kept burn patients immersed in a 600-L stainless steel tub, continuously bathed in Locke’s solution, a mixture of sodium, potassium, calcium and magnesium chlorides; bicarbonate; and phosphate. This treatment controlled heat and electrolyte loss, decreased pain, increased range of motion, and facilitated eschar separation. Unfortunately, the bacterial density of the fluid after 1 h was 1 x 10⁶ despite the use of microfilters in series with an ultraviolet liquid sterilizer; wound infection developed rapidly. Attention then turned to topical materials that would reduce heat and water flux. This methodology failed because of bacterial growth. Realizing that control of pathogenic bacteria in the burn wound was the key to the topical control of vaporizational heat loss, the team established criteria for an appropriate burn antiseptic and searched for suitable candidates. Silver salts met all criteria in that they were nontoxic; water soluble; non-antigenic; did not interfere with epithelialization; easily procurable; had a long duration of action; and did not promote bacterial resistance. The prior successful use of 0.5% silver nitrate solution over stasis ulcers, ischemic ulcers, necrotizing fasciitis, and skin grafts by one of the authors of this study probably influenced this choice. The original article described several case studies, a dressing methodology, and a suggestion that black floors and walls up to 5 ft high would be esthetically proper for a burn unit utilizing silver solutions. During 7 months of use, in more than 1300 burn wound cultures, no new emergence of bacterial resistance was noted.¹ Nearly 45 years after the publication of this study, 0.5% silver nitrate remains a first-line topical agent in many burn centers. For many years, 0.5% silver nitrate has also enjoyed a niche use as a topical agent for patients with toxic epidermal necrolysis (TEN). Because sulfa drugs are a common initiating factor in TEN, avoidance of mafenide and silver sulfadiazine in this setting is prudent. The use of silver nitrate solutions for TEN has been largely supplanted by Biobrane® (Smith & Nephew, Largo, Fla), and silver-containing dressing materials such as Acticoat® (Smith & Nephew, Largo, Fla) and Silverlon® (Argentum Medical, Willowbrook, Ill).

Mafenide Acetate

Both the distant¹⁹ and recent²⁰ history of mafenide have been well described, and the original article by Jelenko et al19 in 1966, belongs in the collection of every burn care provider. Mafenide hydrochloride was first synthesized in the United States in 1938 and was described in the Journal of the American Chemical Society in 1940.²¹ The drug proved ineffective as an oral antibiotic and further development was deferred.
During World War II, German military physicians became interested in antimicrobial agents that could delay the development of gas gangrene and other infections while evacuating injured soldiers from the battlefield.¹⁹ A number of drugs that were previously found to be orally ineffective were re-examined for possible use as topical agents. Of these, the only effective topical antibiotic for wounds containing either blood or pus was mafenide, which was also known in Germany as marfanil.
In August 1941, the Germans started issuing topical mafenide as a mixture of marfinal and protalba (sulfanilamide) to troops on the Eastern Front. This therapy was so effective that by 1943 it was issued on all fronts. In June 1943, British troops captured supplies of mafenide from the Germans in Tunisia, and brought the drug home for analysis. The effective topical antimicrobial properties of mafenide were confirmed. The United States Army later took possession of medical equipment captured in Tunisia, but was slow to recognize the potential of this drug and the captured supply of mafenide remained undisturbed in an Aberdeen Proving Ground (Maryland) warehouse for many years.
Aqueous mafenide for topical use in wounds was re-discovered by Janice Mendelson, MD, FACS in the late 1950s. Dr. Mendelson was an Army surgeon with a research interest in blast injury. She had the same goal as her German predecessors: a topical antibiotic that could be applied to war-related injuries to delay infection until evacuation could be accomplished. She developed a war wound model in anesthetized goats that produced a blast injury complete with open fractures and devitalized tissue. Unless prompt surgical debridement was carried out, this model was 100% lethal at 3 days post-injury secondary to clostridial infection. The model did not require the addition of bacteria because Clostridia perfringens and Pseudomonas aeruginosa are normal flora found in the goat species she utilized. Mendelson tested this model against a number of topical antibiotics.²² She found that topical 10% or 20% aqueous mafenide solution would prolong survival sufficiently to permit delayed debridement, and that some animals survived without debridement when topical aqueous mafenide was used. Topical mafenide spray was “the only therapy of the numerous ones tested over several years, which permitted recovery of any of the animals without amputation.”²³
Mendelson noted the effective anti-pseudomonal properties of mafenide in her goat model and passed this information along to the US Army Surgical Research Unit (Army Burn Center) at Brooke Army Medical Center (Fort Sam Houston, Tex). Starting in 1962, the burn center team tested aqueous mafenide in animal models and confirmed its efficacy against Pseudomonas. Human trials began in 1964, and the mortality rate from burn injuries at the institute immediately dropped, corresponding to better control of burn wound sepsis.
The origins of 10% mafenide cream are somewhat less scientific than the powder form or aqueous solution. An un-named pharmacist at Brooke Army Medical Center was reportedly queried regarding the proper formulation of the newly arrived drug, and promptly replied that it should be mixed up as a water-soluble 10% cream (personal communication, Janice Mendelson, MD, FACS, April 2006). The original formulation of mafenide as hydrochloride salt was also changed to acetate to avoid the hyperchloremic metabolic acidosis associated with the former.²³ A 5% mafenide aqueous solution was developed as an adjunct to wound debridement and as a dressing over autografts; it went into clinical use at the Army Burn Center in 1971. Lacking US Food and Drug Administration (FDA) approval, 5% mafenide acetate solution was utilized on research protocol as an Investigational New Drug at the Army Burn Center from 1971 until 1998, and at least 13 other burn centers in the United States during this period. At other centers, a dilute aqueous solution was mixed from the commercially available 10% cream. Five percent aqueous mafenide acetate was FDA approved as an orphan drug in 1998.
In the 1960s, mafenide powder made its way into the US Special Operations community as a war-wound treatment, was carried on NASA spacecraft, and was carried in the emergency medical supplies that accompanied President Richard Nixon when he first visited China.²⁰ Mendelson became re-acquainted with the drug during her tour in Vietnam, where she was tasked with setting up a burn center in a civilian hospital in Saigon. The hospital did not have gloves, laundry facilities, or dressings. Mendelson began spraying 10% aqueous mafenide over body wounds and 5% aqueous mafenide solution to the face with the rationale that a 5% mafenide ophthalmic preparation had been previously marketed, suggesting that this concentration would be safe for the eyes. The patients were instructed to actively range extremities as they were being sprayed, providing physical therapy. A 16-mm movie was produced to show subsequent surgeons how to provide patient care at the burn center, was converted to VHS format and made commercially available several years ago. Mendelson²⁴ published her experiences at the Saigon hospital in 1997. Despite the availability of newer agents, mafenide acetate remains a useful drug in the burn center armentarium, and has been utilized off-label in the management of blast injuries, contaminated open fractures, and necrotizing fasciitis.^20,25

Bacitracin

Bacitracin is a mixture of cyclic polypeptides produced by the Tracy-1 strain of Bacillus subtilis bacteria. This strain was first cultured in the 1940s from damaged tissue and street dirt debrided from an open fracture sustained by a 7-year-old girl named Margaret Tracy.^26,27 The name bacitracin is a combination of Bacillus and Tracy. The antibiotic was jointly developed by Balbina A. Johnson, a bacteriologist, and Frank L. Meleney, a surgeon known for his work with synergistic bacterial gangrene.²⁸ The discovery of this new antibiotic was published in 1945.²⁹ The authors noted that the new antibiotic was neutral, nontoxic, water soluble, and useful chiefly against Gram-positive organisms, but also had activity against gonococcus and meningiococcus.²⁹ Subsequent work revealed substantial effectiveness against Treponema pallida and suggested it had a synergistic action with penicillin for this pathogen.²⁷ Intravenous injection of bacitracin was associated with albuminuria and nephrotoxicity,26,27 and the drug soon found a niche as a topical antibiotic. Further research revealed that the ideal topical preparation in terms of effectiveness and stability was the addition of bacitracin powder to a water-free petrolatum base (r29). In the first 5 years following the discovery of bacitracin, 200 surgical infections were treated with 87% “favorable results.”²⁶ In 1952, Meleney³⁰ published results of 160 cases treated with bacitracin and noted a 78% success rate in a number of different infections, three-quarters of which had previously failed other antibiotic therapy. “Especially good” results were reported for the local or systemic use of bacitracin in neurosurgical infections, where it was felt that bacitracin might be considered the drug of choice.³⁰ Initial reports suggested that allergy to bacitracin was uncommon.^26,27 More recently, the widespread use of bacitracin as an over-the-counter remedy and as a component of certain cosmetics has resulted in the emergence of bacitracin as a leading allergen.²⁶ Despite lack of efficacy against common Gram-negative burn pathogens, bacitracin remains popular in burn care, particularly on partial-thickness face burns. Whether this beneficial effect is due to the antibiotic itself or simply to the bland petrolatum base remains controversial.

Silver Sulfadiazine and Variants

The near-simultaneous introduction of mafenide acetate and silver nitrate in the mid 1960s ushered in a new era of burn care where control of burn wound florae was now possible. Unfortunately, mafenide caused pain on application and silver nitrate stained everything it contacted. Both agents were associated with fluid and electrolyte disturbances. Charles L. Fox Jr, MD at Columbia University in New York had previously researched the use of soluble sodium sulfonamides for wounds and burns during World War II³¹ and knew that sodium sulfadiazine had previously been combined with tannic acid as a topical burn therapy. In an effort to obtain the “advantages of locally applied agents without their attendant disadvantages,”³² Fox developed an insoluble salt by mixing silver nitrate with the weakly acidic sulfadiazine, creating a new topical burn agent useful against a broad spectrum of pathogens that did not have the major side effects of either mafenide or silver nitrate.^3,32 His initial report in 1968³² detailed the results of studies of scalded mice inoculated with cultures of Pseudomonas aeruginosa “isolated from patients.” The application of either mafenide or silver nitrate decreased mortality from 90% to approximately 50%. In contrast, the daily application of silver sulfadiazine decreased mortality to between 5% and 20%. This report also mentioned an ongoing clinical trial of 16 patients with burns, where the initial impression was “this compound, which is painless and does not darken tissue or withdraw electrolytes, may be of value in burn wounds and other local infections.”³² A follow-up report in 1969 documented human experience with 24 patients with burns treated at Columbia Presbyterian and Bellevue Medical Centers in New York, and 33 patients treated at the Can Tho Provincial Hospital, Republic of Vietnam.³³ Ollstein et al³⁴ compared 100 consecutive burn admissions treated either with topical mafenide acetate or with silver sulfadiazine and noted a 12% mortality rate in both groups. As with any antibiotics, widespread use soon raised concerns of bacterial resistance. To delay the formation of bacterial resistance, or to improve the antimicrobial spectrum, silver sulfadiazine has been alternated with nitrofurazone³⁵ or with mafenide acetate in some burn centers. Alternation of silver sulfadiazine with other agents tends to decrease the incidence of side effects reported when any of these agents are used alone.³⁵
Several variants on the silver-sulfadiazine combination have been evaluated. Fox et al³⁶ studied a zinc-sulfadiazine combination to see if the added zinc would speed wound epithelialization or broaden coverage against Staphylococcus aureus. The zinc-sulfadiazine compound proved as effective as silver sulfadiazine in controlling infection and healing in humans, and produced lower colony counts of S aureus in a rat model. A second advantage is that zinc is 24 times less expensive than silver.³⁶

Conclusion

Burn wound management continues to evolve. It is interesting to note that the newer dressings becoming popular in the early 21st century are evolutions of techniques from the 20th century: silver continues to be utilized in topical pastes, gels, pads, and stretch bandages, and cerium and other additives continue to extend the useful life of Silvadene™ (Monarch Pharmaceuticals, Inc., Bristol, Tenn). The opening quote of this article, however, still serves as a useful reminder that topical agents are simply adjuncts and do not replace the need for meticulous wound care, timely and thorough debridement, and skilled surgical management.