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Article 273
An Overview of the Topical
Antimicrobial Agents Used in the
Treatment of Burn Wounds
Cherylann McNulty, Gail L. Rodgers, Joel E. Mortensen
Burn victims are susceptible to a wide array of in- strate a slow spontaneous rate of healing. 3) Deep fectious complications. Overall, care in burn centers (full thickness or third degree) burns destroy both epi- with dedicated specialists in all aspects of burn care dermis and dermis. They have a dry pearly white or has led to advances in the medical and surgical man- charred surface which may be depressed from the agement of burn victims leading to decrease in infec- surrounding skin. They are often less painful or in- tious complications. Medical improvements include: sensitive to stimuli (although the surrounding areas advances in resuscitation and intensive care specifi- of lesser degree burns may be painful). They demon- cally management of fluids and shock, recognition of strate no spontaneous healing. To prevent scarring the role of early enteral feeding, use of topical antimi- and contractures skin grafting is necessary.
crobials and adherence to strict infection control prac-tices. Surgical advances include: early debridement Skin Defense Mechanisms
and excision of the wound and improved grafting The skin has many natural protective defense techniques and materials. Despite these remarkable mechanisms which deter invasion of microorganisms.
advances, burn wound infection (BWI) continues to These mechanisms include: a dry skin surface which be an important source of morbidity and mortality in limits bacterial survival and proliferation, continual burn patients. Although the Microbiology Laboratory skin desquamation, a nutritionally poor composition is rarely called upon to help in selection of topical an- (acidic pH and fatty acids) which inhibit bacterial timicrobial agents, we need to understand how these multiplication and the presence of non pathogenic agents are similar to, and different from, the kinds of normal flora which inhibits the growth of potentially antimicrobial agents more commonly tested and re- ported so that we can contribute to the care of thesecritically ill patients, when needed. This review is de- The Burn Wound
signed to familiarize Laboratory Technologist/Scien- Burn injury disrupts the skin’s natural protective tists with some of the more common antimicrobial barrier, which serves to protect the body from invad- agents used in the topical care of burn patients and to ing environmental bacteria. The skin’s surface flora introduce the basic medical concepts needed to un- changes after burn injury, resulting in the eventual derstand how these agents are used by clinicians.
overgrowth of pathogenic organisms. Until a com-plete epithelization occurs, the burn patient is suscep- Classification of Burns
tible to bacterial invasion and infection. Burns are classified according to the degree of Burn wounds are targets for bacterial colonization dermal damage and the ability of the skin to epithe- and subsequent tissue invasion. The burn wounds pro- lialize. Partial thickness wounds consist of superficial vide an excellent medium to cultivate bacteria due to and deeper thermal burns which have a remnant of their warm surface temperature, moist environment dermal appendage and are therefore capable of re ep- and availability of nutrients. The microorganisms that ithelialization. In full thickness wounds, no dermal colonize the burn wound may originate from the pa- appendages are left and the skin is incapable of re tient’s normal flora or from the environment.
During the first hours post burn, wounds are gen- Partial thickness wounds may be further subdivid- erally sterile or are at the stage of superficial bacteri- ed into 3 categories: 1) superficial (partial thickness al colonization. The first organisms to colonize the or first degree) burns involve the epidermis and part wound are staphylococci. By the fourth to fifth day of the superficial dermis. Common features include post burn, extensive bacterial involvement of the Philadelphia, PA; Gail L. Rodgers, MD, a red surface which blanches upon pressure, dis- wound itself is evident and Gram-negative organisms charge, and pain with temperature changes and pres- are present. By the end of the first week, the damaged sure stimuli. Healing is spontaneous and rapid. 2) skin is thoroughly permeated by the increased num- Deep dermal (partial thickness or second degree) ber of organisms and more virulent organisms begin burns destroy both epidermis and the superficial der- active invasion of the unburned tissue. The avascular PhD, Cincinnati‘Children’s Hospital, mis showing a dark red surface with moderate dis- nature of the burn predisposes the burn site to bacter- charge. They are less sensitive to stimuli and demon- ial invasion by impeding effective delivery of the bod- 74 April 2004 • Continuing Education Topics & Issues
ies own defenses and preventing systemic antibiotics tion, non toxic, able to enhance wound healing and not impede it, long lasting, inexpensive and easy to Organisms which are frequently isolated from store. Unfortunately, the ideal topical agent does not burn wounds include Staphylococcus aureus, exist. Most important in choosing an agent is its ac- Pseudomonas aeruginosa, Enterobacteriaceae tivity against pathogens in the patient and in the burn (Klebsiella, Enterobacter, Providencia, Serratia, and unit. This is usually based on known susceptibilities Proteus spp.) and Candida spp. In 1987, Winkler of the topical agent because susceptibility testing of demonstrated that Gram-positive organisms account- individual isolates is rarely performed outside of the ed for 62.5% of bacterial isolates from 122 patients research setting. Therefore it may be useful in pa- with burns > 40% total body surface area (TBSA); tients at highest risk of infection (>30% TBSA) to S. aureus was the most frequent isolate. Subsequent- perform routine surveillance cultures to know what ly, Laursen described 253 patients admitted to the their colonizing organisms are and base topical thera- Copenhagen Burn Center. S. aureus was the most py on these results. Although skin surface cultures are frequently isolated organism. Infection by Gram-neg- more widely used due to the ease of performance, ative bacteria tended to be found later in the course culture of burn wound biopsies provides the most re- of hospitalization in this series. Predominant organ- liable information as to the bacterial species and den- isms may vary by institutions due to differences in sity. Isolation of pathogenic organisms on surface cul- resident microflora and antibiotic utilization. tures does not establish a diagnosis of infection but Microbial factors involved in colonization and in- identifies colonizing organisms that if in high density vasion include: bacterial adhesion and attachment (>100,000org/gram of tissue) may invade underlying properties, the production of exotoxins, endotoxins, unburned, viable tissue causing burn wound infec- permeability factors and enzymes. Consequences of tion. Frequent clinical observation is needed for as- bacterial invasion include: impairment or delay of the sessing the therapeutic response in burn wound ther- healing process, destruction of viable epithelial cells apy. Use of an active topical agent decreases the which may convert partial thickness wounds to full organism density to prevent possible invasion. Once a thickness wounds, decreased graft survival, develop- burn wound infection is established, topical therapy ment of generalized symptoms or systemic inflam- plays an adjunctive role since management includes matory response secondary to production of bacterial surgical debridement and excision and systemic an- toxins and invasion of deeper tissue leading to local Acquired Resistance
Goal of Topical Antimicrobial
Acquired resistance to topical antimicrobials has Treatment
been documented, particularly for topical gentamicin The burn eschar is the affected full thickness (possibly reflecting the routine use of susceptibility burned tissue which consists of coagulative necrosis testing of gentamicin vs. other topical agents), al- of the epidermis, dermal and subcutaneous fat necro- though resistance to silver containing antimicrobials sis as well as vascular thrombosis involving the arte- in S. aureus, Providencia stuartii, and Enterococcus rioles capillaries and venules. The denatured proteins spp. has been reported. Resistant organisms may pose and cellular debris along with the relative avasculari- a problem particularly in a setting where the patient ty of the eschar provides an ideal environment for numbers are large and isolation facilities are inade- proliferating microorganisms. Although topical an- quate. As a general rule, antimicrobials that are to be timicrobial agents do not sterilize the burn wound, used systemically should not be used topically due to their goal is to limit bacterial proliferation below the the rapid emergence of resistance and possible trans- threshold required to invade underlying viable tissue mission of these organisms in the burn unit. and cause burn wound infection. This converts a“dirty” open wound to a “clean” closed one. Since Summary of Specific Agents
systemically administered antimicrobial agents lack Bacitracin (Generic) is available as water soluble
adequate access to the damaged eschar, topical agents solutions and suspensions in petroleum bases. The are thought to be useful in providing therapeutic lev- mechanism of action is the interruption of cell wall els on the wound surface where microbial numbers synthesis. Bacitracin spectrum of activity is primarily against Gram-positive organisms with limited effec-tiveness against Gram-negative organisms and no an- Choosing Topical Agents
tifungal activity. Bacitracin has limited eschar-pene- Topical antimicrobial agents are often chosen trating ability. It is used for outpatient burns and based on physician preference and experience. The shallow partial thickness burns, in particular on the optimal topical agent should be: a broad spectrum face. A white petroleum base allows for soothing and agent and include activity against organisms endemic comfortable application that makes it useful for small to the burn unit, easy to apply, painless upon applica- burns. It is also used on grafted wounds and donor tion, able to penetrate eschar, lack systemic absorp- sites. Due to bacitracin’s limited eschar penetrating Continuing Education Topics & Issues • April 2004 75
ability, it should not be used on deep burns. Adverse gal activity. Early enthusiasm for its prophylactic use effects to topical application and. are very rare; but in- was tempered by its systemic toxicity and by the pain clude hypersensitivity reactions and fungal over- which results from its application. The drug is so rapidly absorbed that wound concentrations aremarkedly reduced within several hours, so that it is Cerium Nitrate Silver Sulfadiazine (Flammac-
usually applied twice daily. Pulmonary complications erium). Since the mid-1970s, silver sulfadiazine mod- are frequent with the continuous use of mafenide in ified by the addition of the lanthanide salt cerium ni- large burns. The risk of systemic toxicity increases in trate has been used in the control and treatment of proportion to the wound area being treated and the burn wounds. The ‘rare earth’ elements, one of which duration of treatment. A maculopapular rash occurs is the relatively non-toxic cerium, all have antimicro- in about 5% of patients, but this reaction is usually bial activity in vitro. The antimicrobial spectrum of controlled with antihistamines and may not require cerium nitrate-silver sulfadiazine in vitro is similar to discontinuing the drug. Although the use of mafenide that of silver sulfadiazine or silver nitrate. Some in- as a prophylactic topical agent has decreased in re- vestigators have suggested that the efficacy of the cent years, its excellent eschar penetration makes it cerium nitrate-silver sulfadiazine combination might useful for the short-term control of invasive infec- be due in part to an effect on immune function. The tions. In some centers, toxicity is minimized or avoid- cell-mediated immune response appears to be pre- ed in patients with large burns by alternating the top- served in burned mice treated with cerium nitrate alone or in combination with silver sulfadiazine.
sulfadiazine. Careful monitoring of pulmonary func- Methemoglobinemia, due to the absorption of re- tion and acid-base balance is essential in patients with duced nitrate from the combination cream, has been only rarely seen. Cerium nitrate-silver sulfadiazinecream is not associated with electrolyte disturbances.
Mupirocin (Bactroban). Mupirocin was formerly
Absorption of cerium has been documented in pa- known as pseudomonic acid and is a metabolic end tients with large burns treated continuously with it for product of Pseudomonas fluorescens. Mupirocin’s mechanism of action is inhibition of protein synthesisby irreversibly binding to bacterial isoleucyl tRNA.
Gentamicin (Garamycin, Gentamar, et al). Gen-
At low concentrations mupirocin is reported as bac- tamicin is usually applied as a 0.1% in a water misci- teriostatic, but at higher concentrations the drug is re- ble ointment. Its mechanism of action is it binds irre- ported to be progressively bacteriocidal. Its spectrum versibly to the 30s ribosome and inhibits protein of activity is mainly Gram-positive organisms.
synthesis. Gentamicin is a bacteriocidal, aminogly- Mupirocin is also effective against multiply resistant coside with activity against Gram-negative organisms isolates of S. aureus, although some oxacillin-resis- including Pseudomonas sp., although Pseudomonas tant S. aureus may be resistant. Other Gram-positive sp. can develop resistance. The drug is readily ab- bacteria including Corynebacterium spp. and Micro- sorbed when applied topically which can result in sig- coccus luteus are less susceptible, as are anaerobic nificant blood levels and systemic toxicity including Gram-positive bacteria such as Peptostreptococcus ototoxicity and nephrotoxicity. Other adverse affects spp., Clostridium spp. and Propionibacterium spp. In include overgrowth of non-susceptible organisms general the majority of Gram-negative bacilli are less such as fungus and Pseudomonas sp. Due to the rapid susceptible. Strains of E. coli, Klebsiella pneumoniae, emergence of resistance of Gram-negatives and its Enterobacter spp., Proteus mirabilis, and Proteus vul- marked toxicity when applied topically it should not garis were inhibited by 64 to 128 µg/ml, but strains of Morganella morganii, P. aeruginosa, and Serratiamarcescens were sensitive only to concentrations Mafenide Acetate (Sulfamylon). Mafenide (a-
ranging from 1,600 to 6,400 µg/ml. Adverse reactions amino-p-toluene sulfonamide monoacetate) was in- include burning, and stinging itching, rash and con- troduced as a topical burn treatment in the mid-1960s.
It is available in a water-soluble cream base at 5%concentration. Sulfonamides mechanism of action is Nitrofurazone (Furacin). A water-soluble cream
that they are competitive inhibitors of p-aminoben- base containing 0.2% nitrofurazone is available. The zoate into dihydropteroic acid, the immediate precur- mechanism of action is that it inhibits several bacter- sor of folic acid. Mafenide acetate is bacteriocidal ial enzymes involved in carbohydrate metabolism. It only in higher concentrations than are obtained with is bacteriocidal. Its spectrum of activity includes a va- topical therapy. It has excellent antibacterial activity riety of different Gram-positive and Gram-negative against most Gram-positive species, including organisms, including S. aureus, Escherichia coli, En- clostridia, but has limited activity against some terobacter cloacae and Proteus spp., but does not staphylococci, particularly oxacillin-resistant strains.
have significant activity against P. aeruginosa or It has a broad spectrum of activity against most fungi. Nitrofurazone has good penetration into burn Gram-negative burn pathogens, but minimal antifun- eschar and can be used with a variety of dressings.
76 April 2004 • Continuing Education Topics & Issues
Hypersensitivity reactions in the patient are rare. The competitive inhibitor of para aminobenzoic acid. adverse effects such as burning sensation, irritation, Silver has been reported to act on the bacterial cell etc. are mainly due to the polyethylene glycol which membranes. Silver binding may also impair bacterial DNA replication. Although bacteriostatic, it has invitro activity against a wide range of microbial Povidone Iodine (Betadine). Povidone iodine is
pathogens including S. aureus, E. coli, Klebsiella spp.
often used to treat minor burns. It is a water soluble P. aeruginosa, Proteus spp., other Enterobacteriaceae complex formed by the interaction of iodine with the and C albicans. The advantages of silver sulfadiazine polymer polyvinyl pyrrolidone. On contact with the include a broad spectrum of activity, low toxicity, skin, it releases iodine slowly from the complex pro- ease of application and minimal pain with applica- viding a mild antimicrobial effect. Although not com- tion. Penetration of silver sulfadiazine into the skin pletely understood, it seems most likely that iodine eschar is intermediate. Adverse effects usually asso- acts by oxidizing the sulfhydryl group of the amino ciated with sulfonamide are rare. The most common acid cysteine. The spectrum of action of free iodine is adverse effect with use is transient leukopenia, and very wide and includes both gram-positive and gram- on rare occasion a maculopapular rash. The use of sil- negative organisms, including staphylococci and ver sulfadiazine may also cause a “pseudoeschar” to Pseudomonas spp., along with protozoal cysts, virus- develop within 2 4 days due to interaction of the drug es, mycobacteria. Acquired resistance has been re- with proteinaceous exudate in the wound. Although ported for Pseudomonas alcaligenes and Alcaligenes clinical trials suggest that silver sulfadiazine reduces faecalis. The adverse effects include pain, discomfort wound bacterial numbers and delays colonization and secondary effects on thyroid function secondary with gram-negative bacteria, treatment failures still to systemic absorption, alterations in renal function, occur with some frequency in large burns. The agent which may include renal failure and/or serious elec- is usually applied on a daily or twice daily basis.
trolyte alterations mainly in severely burned children.
When it is used on superficial second degree burns, a Therefore, when using povidone careful monitoring yellow-gray barrier may form after several days. of the patient for electrolyte imbalances is necessary.
References
Silver Nitrate (Generic). 0.5% silver nitrate solu-
Carvagal, Hugo F., Parks, Donald H., Burns in Children. Pedi- tion was introduced as an effective topical burn thera- atric Burn Management. Year Book Medical Publishers, Inc, py in the mid-1960s. This began the present era of topical therapy with silver compounds. The antibac- Herruzo-Cabrera, R., Garcia-Torres, V. Rey-Calero, l Vizcaino- Alcaide, M.l. (1992). Evaluation of the penetration strength, bac- terial action of silver nitrate is unknown but is proba- terial efficacy and spectrum of action of several antimicrobial bly dependent on free silver ions. It is bacteriostatic at creams against isolated microorganisms in a burn centre. Burns lower concentrations (0.5%) and bacteriocidal at higher concentrations (10%). As a topical agent sil- Laursen, H., Kjaeldgaard, P., Thomsen, M., Rosdahl, U.T.
(1988). Mikrobiologiskefund hos brandsar patienter, Ugeskriftfor ver nitrate is effective against most strains of Laeger (Copenhagen) 150:1786-1789.
S. aureus and Staphylococcus epidermidis and also Leyden J.J. (1987). Mupirocin: A new topical antibiotic. Sem- has activity against P. aeruginosa. It has less activity inars in Dermatology. 6(1 ):48-54.
against other Gram-negative species such as Enter- Maple, P.A.C., Hamilton-Miller, J.M.T., Brumfitt, W. (1992).
obacter and Klebsiella spp. It does not penetrate the Comparison of the in-vitro activities of the topical antimicrobialsazalic acid, nitrofurazone, silver sulfadiazine, and mupirocin skin eschar to any significant degree because silver against Methicillin Resistant Staphylococcus aureus. J Antimicrob chloride and other silver salts are highly insoluble and precipitate on the wound surface. Adverse effects Moafo, W.W., West, M.A. (1990). Current Treatment Recom- seen with silver nitrate are electrolyte imbalances sec- mendations for Topical Burn Therapy. Drugs 40(3):364-373.
Richard, R.L., Staley, M.l, Davis, F.A., Burn Care and Reha- ondary to hypotonicity. Methemoglobin is a rare bilitation. Principles and Practices. (1994). F.A. Davis Company, complication. Application is relatively painless how- ever the dressing must be changed every 2 3 hours to Rodger,G.L, Mortensen, J.E., Fisher, M.C., Long, S.S. (1998).
prevent development of histotoxic concentrations.
In Vitro Susceptibility Testing of Topical Antimicrobial Agents The agent itself is inexpensive, but clinical use is as- Used in Pediatric Burn Patients: Comparison of Two Methods. J Burn Care Rehabil18(5):406-41O.
sociated with significant dressing changes and nurs- Settle, John A. Principles and Practice of Burns Management. ing time costs. Another major disadvantage of silver Churchill Livingstone Publishers, New York. (1996). pp177-185.
nitrate is that it stains everything brownish black.
T.E., Taddino, P.D. Thomson, et al. (1990). A survey of wound monitoring and topical antimicrobial therapy practices in the treat-ment of burn injury. J Burn Care Rehabil. 11 :423-7.
Silver Sulfadiazine (Silvadene, SSD, Ther-
Vu, H., McCoy, L.F., Carino, E., Washington, J., Dang, T., Vil- mazene). Silver sulfadiazine is the most frequently larreal, C., Rosenblatt, J., Maness, C., Goodheart, R., Heggers, J.P.
used topical prophylactic agent. Silver sulfadiazine is (2002). Burn Wound Infection Susceptibilities to topical agents: a white, highly insoluble compound which is synthe- the Nathan’s agar well diffusion technique. P & T 27(8): 390-396.
sized from silver nitrate and sodium sulfadiazine. It is Winkler, M.B., Erbs, G., Muller, F.E., Konig, W. (1987). Epi- demiologische Studien Zm Mikrobiellen Kolonisation Von Schw- available in 1% concentration in a water-soluble erverbrannten patienten. Zentralblatt fur Bakteriologic, Mikrobio- cream base. Sulfadiazine acts independently and is a logic Und Hygiene [B] 184:304-320.
Continuing Education Topics & Issues • April 2004 77
Article 273
Questions for STEP Participants
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In the following, choose the one best answer for each question.
1 The first organisms to colonize a burn wound
6 Mupirocin action is mainly against:
A. Pseudomonas aeruginosa
A. Staphylococci
B. Escherichia coli
B. Gram-negative bacilli
C. Gram-negative bacilli
C. Environmental organisms such as
D. Staphylococcus aureus
D. Gram-positive bacilli
7 Mafenide acetate mechanism of action is:
A. the inhibition of enzymes involved in
2 The mechanism of action of the sulfadiazine
B. inhibition of protein synthesis at the
A. inhibition of cell wall synthesis
B. inhibition of protein synthesis at the
C. inhibition of para-amino benzoic acid
C. inhibition of para-amino benzoic acid
D. bacteriocidal binding to mRNA.
D. bacteriocidal binding to mRNA.
8 Gentamicin is a bacteriocidal agent of the
3 The antibacterial action of silver nitrate is
A. aminoglycosides
B. penicillins
A. the release of nitric acid, a mild
C. cephalosporins
D. amino pepsidase
B. Inhibition of cell wall synthesis
C. the rapid penetration of silver nitrate
In addition to its antimicrobial activity, D. the release and subsequent action of free
A. thyroid function.
B. cell mediated immunity.
4 An important side effect of the use of povi-
C. kidney function.
D. electrolyte balance.
A. the selection of multiply resistant
The mechanism of action of bacitracin is: B. the development of a yellow-gray
A. inhibition of cell wall synthesis
B. inhibition of protein synthesis at the
C. electrolyte imbalance.
D. negative effects on thyroid function.
C. inhibition of para-amino benzoic acid
5 The mechanism of action of nitrofurazone is:
D. bacteriocidal binding to mRNA.
A. the inhibition of enzymes involved in
B. inhibition of protein synthesis at the
C. inhibition of para-amino benzoic acid
D. bacteriocidal binding to mRNA.
78 April 2004 • Continuing Education Topics & Issues

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