Annals of Burns and Fire Disasters - vol. XIII - n. 4 - December 2000

LOCAL BURN TREATMENT - TOPICAL ANTIMICROBIAL AGENTS

Noronha C., Almeida A.

Burn Unit, St Joseph Hospital, Lisbon. Portugal

SUMMARY. Effective topical antimicrobial agents decrease infection and mortality in burn patients. Silver sulphadiazine continues to be the antimicrobial agent most often used in burn care facilities. Combined topical use of silver sulphadiazine and other antimicrobials may be a possible solution to bacterial resistance in burn wounds. Other agents seem to be useful in isolated clinical situations. None of the available topical antimicrobials, whether alone or in combination. will however prevent colonization of burn wounds. although invasive infections are infrequent.

Only after resuscitation has been initiated and haemodynamic and respiratory stability are being restored should attention be directed to the burn wound itself.
Topical antimicrobial therapy is the single most important component of wound care in hospitalized patients. Following their introduction. topical antimicrobial agents immediately decreased burn patient mortality by 5Vc, when applied effectively.

The eschar forms on both partial- and full-thickness burns. With increasingly thick eschar over deeper burns, the administration of systemically administered antibiotics to eschar is not reliable.
Post-burn. the eschar is virtually sterile, but in the absence of topical antimicrobials it will be colonized in the first 24 h by Gram-positive organisms that are superseded in 3 to 7 days by Gram-negative species (Table I).

* This paper was presented at the First Meeting of the Portuguese Bums Society, held in Lisbon in October 1999.

None of the topical antimicrobials available today, whether alone or in combination, has the characteristics of an ideal prophylactic agent (Table II), but they will elimnate colonization of burn N~ ounds, and invasive infections are infrequent.
We present below a summary of topical agents in current use.

Silver sulphadiazine (Fox et al., 1968)
With an excellent spectrum of activity, low toxicity, and ease of application with minimal pain, silver sulphadiazine is still the most frequently used topical agent.
Mechanism of action. Silver sulphadiazine is thought to act via inhibition of DNA replication and modifications of the cell membrane and cell wall.
Spectram of antimicrobial activity. The drug is bactericidal against species of both Gram-positive and GramneLyative organisms, but resistance has occasionally been reported.
Clinical use. Silver sulphadiazine is used as an adjunct in the prevention and treatment of infection in second- and third-degree burns. However, treatment fails with continued use in large burns (> 50qc TBSA). Concomitant administration of appropriated systemic anti-infective agents may be necessary if infection is present or suspected. The use of silver sulphadiazine is frequently associated with the development of a "pseudo-eschar" within 2 to 4 days, owing to interaction of the drug with proteinaceous exudate in the wound, which can lead to error in the evaluation of burn depth by the inexperienced observer.
Adverse effects. Local skin reactions, such as pain, burning, or itching and hypersensitivity, are occasionally reported. Transient leukopenia occurs in 5 to 15% of patients, but there is no increased incidence of infectious complications. This may be an intrinsic response to burn injury unrelated to the use of silver sulphadiazine. Systemic absorption may produce reactions characteristic of sulphonamides, including crystalluria or methaemoglobinaemia.

Cerium nitrate-silver sulphadiazine (Fox et al., 1977)
The incorporation of cerium nitrate to sulphadiazine results in enhanced clinical efficacy in patients with large burns.
Mechanism of action. Cerium nitrate has antimicrobial activity in vitro and reverses post-burn cell-mediated immunosuppression.
Spectrum of antimicrobial activity. The addition of cerium nitrate to silver sulphadiazine probably gives Grampositive and Gram-negative organisms and fungus superior antimicrobial activity.
Clinical use. The clinical use of cerium nitrate-silver sulphadiazine is identical to that of silver sulphadiazine alone. The drug combination produces an adherent eschar that provides satisfactory wound coverage until tangential excision can be carried out. Clinical trials showed no difference in mortality between silver sulphadiazine used alone and with the addition of cerium nitrate.
Adverse effects. The adverse effects of cerium nitratesilver sulphadiazine are similar to those seen with silver sulphadiazine alone.

Mafenide (Lindberg et al., 1968)
With its excellent antimicrobial activity and the best eschar penetration of any agent, mafenide was dropped from general clinical use because of its severe side effects, especially when applied in large areas.
Mechanism of action. Mafenide appears to act in the bacterial cellular metabolism.
Spectrum of antimicrobial activity. In topical application, mafenide is bacteriostatic against Gram-positive and Gram-negative bacteria. However, it has limited action against S. aureus and fungus. The development of resistant organisms has not been reported.
Clinical use. Mafenide is used as an adjunct in the treatment of bacterial invasion in second- and third-degree burns to prevent septicaemia caused by susceptible organisms. It also efficiently penetrates cartilage, which makes it an excellent choice for use in burned ears and noses.
Adverse effects. Pain or a burning sensation following mafenide application is the most frequently reported adverse effect. Mafenide is a strong carbonic anhydrase inhibitor and its use leads to alkaline diuresis, which can cause acidbase abnormalities. It also inhibits epithelial regeneration.

Silver nitrate solution 0.5 % (Moyer et al., 1965)
Mechanism of action. The effects of silver nitrate may result from silver ions readily combining with sulphydryl, carboxyl, phosphate, amino, and other biologically important chemical groups.
Spectrum of antimicrobial activity. Silver nitrate is a broad-spectrum agent, bacteriostatic at a concentration of 0.5%; development of resistance to the silver ion is distinctly uncommon.
Clinical use. Silver nitrate 0.5%o is effective in prophylactic use in second- and third-degree burns; it does not however penetrate burn eschar, and needs bulky and frequent dressing changes, which limits its use.
Adverse effects. Silver nitrate is prepared with distilled water resulting in an extremely hypotonic solution leading to electrolyte imbalance. Methaemoglobinaemia is another potential complication, owing to the reduction of nitrate to nitrite by bacteria.

Nitrofurazone
Mechanism of action. It appears that the drug acts by inhibiting bacterial enzymes involved in carbohydrate metabolism. Organic matter inhibits the antibacterial action of nitrofurazone.
Spectrum of antimicrobial activity. Nitrofurazone has a wide spectrum of activity against Gram-positive and Gram-negative bacteria. It is not however particularly active against most strains of P. aeruginosa and does not inhibit fungi or viruses. S. aureus and E. coli can develop resistance to nitrofurazone.
Clinical use. Nitrofurazone is used topically as adjunctive therapy in patients with second- and third-degree burns. With good eschar penetration, it can be used in the treatment of invasive burn wound infections with sensitive agents. The drug presents some advantages for the ambulatory patient. Tissue granulation begins sooner and crusts separate more rapidly,
Adverse effects. Allergic contact dermatitis is the most frequently reported adverse effect, occurring in approximately 1 % of patients treated. The polyethylene glycols present in nitrofurazone ointment (but not in cream) can be absorbed through denuded skin and may cause renal impairment.

Chlorhexidine
Mechanism of action. Ch torhexidine acts by destruction of the bacterial cellular wall and precipitation of cellular content.
Spectrum of antimicrobial activity. Chlorhexidine has a broad spectrum of antimicrobial action, but some Pseudomonas and Proteus species develop resistance.
Clinical use. Several preparations of chlorhexidine have been used clinically in moderate burn injuries and are the subject of continuing investigations. The addition of 1 % chlorhexidine digluconate to 1 % silver sulphadiazine increases the agent's antibacterial effectiveness.
Adverse effects. The most frequent adverse effects of chlorhexidine digluconate are local pain and ototoxicity.

Povidone iodine
Mechanism of action. Povidone iodine acts by destroying microbial protein and DNA.
Spectrum of antimicrobial activity. This drug has excellent in vitro antimicrobial activity but is inactivated by wound exudate.
Clinical use. Povidone iodine has not been proved useful as a topical antimicrobial treatment for burn patients.
Adverse effects. Systemic absorption of iodine, with resulting renal and thyroid dysfunction.
Table III presents a summary of the antibacterial activity of the above drugs.

Norfloxacin
Because of its broad spectrum of antimicrobial action, norfloxacin and its silver salt were formulated in a topical cream base. However, they warrant further development as topical anti-infective agents for use in treating burn patients.

Mupirocin
Methicillin-resistant S. aureus (MRSA) strains have become increasingly prevalent as nosocomial pathogens, especially in burn wounds. Both in vitro and in vivo mupirocin has proved to be highly effective in the treatment of MRSA infections. The safety and efficacy of mupirocin ointment in burns exceeding 20% TBSA need to be established. The use of intranasal mupirocin ointment appears to reduce the risk of infection among patients during MSRA-related outbreaks.

Sodium hypochloride
The use of sodium hypochloride as a topical agent was abandoned as a topical agent because of its basic pH, which causes pain and has a low antimicrobial effect. This problem may be solved by using hypochloride buffered to

Many other antimicrobial agents are used in the local therapy of the burn patient. The clinical usefulness of some of these requires further study. The following are some of the most cited in literature:

Gentamicin
Gentamicin cream should be reserved for treating patients with wounds infected by gentamicin-sensitive P. aeruginosa and patients allergic to sulpha drugs, because of the appearance of gentamicin-resistant strains.

Bacitracin
Most clinical use of bacitracin is in the prophylaxis of Gram-positive bacteria infection in open areas. The addition of neomycin and polymyxin B expands the antimicrobial action to Gram-negative bacteria.
A physiological pH. A freshly prepared 0.1% NaOCl solution decontaminates skin colonized with S. aureus, C. albicans, and P. aeruginosa within 10, 20, and 30 min, respectively. There is no report of microbial resistance to hypoehloride. More studies need to be done before clinical use is possible. Hypochloride has the additional advantages of reducing oedema and of having no effect on granulation and epithelialization.

The incidence of invasive infection and overall mortality was significantly reduced after the introduction into clinical practice of topical burn wound antimicrobial agents. The drug of choice for prophylaxis in most burn patients is silver sulphadiazine. The addition of cerium nitrate appears to enhance bacterial control in large burns, and the addition of other drugs such as chlorhexidine and norfloxacine seems reduce the emergence of bacterial resistance.
In selected clinical situations mafenide, nitrofurazone and tnupiruein may be useful. New agents and new combinations of existing agents are to be seen in the literature, but their clinical efficacy has to be confirmed.

RESUME. Les agents topiques effìcaces réduisent 1'infection et la mortalité dans les patients brnlés. La sulphadìazine arQentée continue à étre 1'agent antimicrobien utilisé le plus fréquemment dans les centre des brGlures. L'emploi topique de la sulphadiazine areenteé associée à d'autres agents antimicrobiens pourrait ztre une solution pour la résistance bactérienne dans les brQlures. D'autres agents semblent étre utiles dans certaines situations cliniques isolées. Cependant. aucun des agents topiques antimicrobiens disponibles, soft seuls ou en association, nest capace de prévenir la colonisation des lesions dues aw brîtlures, méme si les infections invasives ne sont pas fréquentes.

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