Topical agents in burn and wound care.

With any open wound infection may occur. Many factors such as age and general health status may increase the likelihood of infection, but tbe size and depth of the wound are critical factors in detemining tbe chronicity of any wound. Infection greatly adds to the morbidity associated with open wounds. An infected wound not only heals more slowly, there is also the fisk of systemic infection and even death. Infected wounds also scar more severely and are associated with more prolonged rehabilitation. Topical therapeutic agents have been shown to be effective in the management of open skin wounds. These agents may assist less complicated healing and decrease the conversion of a partial-thickness injury to a full-thickness injury, and thereby reduce woundrelated morbidity. Common topical agents with suggestions for application are discussed in this review, [Ward RS, Saffle JR. Topical agents in bum and wound care. Phys Ther. 1995; 75:526-5381

Key Words: Burns, Topical agents, Wound care. Physical therapists are often involved with direct treatment of open wounds, including the application of topical agents and dressings. The severity of a wound, its location, and its depth and size can affect healing time and generate problems of pain, malaise, and disability. Knowledge of the status of a wound, and its effect on the patient, is useful in making decisions about the application of appropriate tropical agents.[l(ppl45-146)]

Wound treatment protocols vary, and competent wound care requires an understanding of the rationale for numerous treatment techniques that include the application of topical agents. Such treatments often use fixed protocols. The purpose of this article is to provide information on which sound judgment can be rendered in the selection of topical agents in the care of bums and other skin wounds.

Wound Assessment

Depth

Wounds are often described in terms of depth of injury. Bums and some other skin traumas, for example, are classified as superficial first degree), partial-thickness (second degree), or full-thickness (third degree) injuries.[2] Superficial injury involves the epidermis, and such wounds are erythematous and mildly painful.[3] Partial-thickness injury involves some degree of damage to the dermis and may be further classified as superficial partial-thickness or deep partial-thickness injury.[3] Superficial partial-thickness injury, which disrupts the epidermis and the superficial portion of the dermis, is manifested as painful, red, blistered, and moist when the blisters are broken, whereas deep partial-thickness injury involves deeper layers of the dermis and can present as pale or red wounds that can also be painful or relatively anesthetic.[3] Full-thickness injury involves destruction of the entire dermis, which results in a relatively painless wound with a leathery, dry, and often tan or brown texture and appearance.[3]

Depth of injury for skin or pressure ulcers is commonly described by using a staging system.[4] A stage I ulcer (or nonblanching erythema) is characterized by red, unbroken skin in which the erythema at the site does not fade with elimination of pressure. A stage 11 ulcer exhibits disrupted epidermis, often with some invasion into the dermis. Stage III ulcers demonstrate dermal injury. Stage IV ulcers include exposed subcutaneous tissue and may penetrate even deeper.

Size

Bum wounds, and other large wounds, are described according to percentage of body surface area involvement.5 Smaller wounds, such as pressure ulcers, are characterized by measurements that often include the circumference or the distances between the borders of the wound.[4,6] The size of the wound is important partly because, in general, large wounds are at greater risk for infection than smaller wounds. Some topical agents should not be used for extended periods of time over large open wounds because of the risk of toxicity secondary to systemic absorption.[7(pp1165-1166)-11]

Location

Because skin responds to injury by contracting, wounds that are located over joints may lead to limitation of movement and eventual contracture. Topical agents, and a dressing that is minimally restrictive, can be important in allowing motion. Many topical agents also are not recommended for the face because of concerns that the agent may enter the eye or be unintentionally ingested.

Reassessment of the Wound

Documentation of the depth and size of injury is important in measuring the progress of wound healing. Depth, size, and location of injury will also help in making a determination of an appropriate topical agent. Wound evaluation is necessary to make decisions about the efficacy of, or the potential for modifying the choice of, a topical agent. If the chosen topical agent does not appear to be successful, another topical agent may be substituted. Table 1 outlines conditions related to wound care that should invite medical consultation.

[TABULAR DATA 1 OMITTED]

Common Infections

Common bacterial skin infections include gram-positive bacteria (eg, Streptococcus, Staphylococcus aureus) and gram-negative bacteria (eg, Pseudomonas aeruginosa).[12] Candida is a common source of fungal infections in skin wounds.[13] Because the stratum corneum is normally too dry to support microbial growth, infections on the skin rarely occur unless the skin is broken. Topical wound therapy provides treatment against severe infection, and, if infection does occur, another topical agent should be selected. A wound that appears to be regressing (Tab. 1) should be cultured and the infecting agent should be identified, and the wound should be treated with debridement and application of an appropriate topical agent and dressing.

Techniques of Wound Care

Antiseptics

The use, or misuse, of antiseptics that are used to cleanse and prepare wounds for application of a topical agent should be recognized. Antiseptics are used to reduce bacterial contamination by inhibiting the growth of microorganisms, and antiseptics should be applied to intact skin and not used directly on wounds as topical agents.[14] Antiseptics may increase the intensity and duration of inflammation,[15,16] and they have also been shown to be toxic to human keratinocytes[17] and fibroblasts,[18,19] and to retard epithelialization.[20]

Iodine solutions and iodophors are often used as antiseptics. Diluted iodine solutions (iodine solution USP [United States Pharmacopeia] [2% iodine, 2.5% sodium iodide] and iodine tincture USP [2% iodine, 2.5% sodium iodide, 50% alcohol]), though bactericidal, may irritate tissue, stain the skin, and cause sensitization.[21(p784)] Iodine solutions have a broad spectrum and rapid germicidal action. Iodophors (such as povidone-iodine), which are compounds of iodine and carriers or solubilizing agents, are not as problematic as other iodine solutions with regard to irritation, skin staining, and sensitization.[20] As germicidal agents, however, iodophors are not as effective as the sodium-iodine solutions.[22,23]

Hydrogen peroxide is very commonly used as an antiseptic on wounds; however, it has limited bactericidal effectiveness,[20,24] is toxic to fibroblasts,[20] and impairs the microcirculation of wounds.[17] The mechanical cleansing effect of hydrogen peroxide, often attributed to the "fizzing" (which is caused by its decomposition to oxygen and water when it comes in contact with blood tissue fluids), is questionable. Given the concerns about the detrimental effects of hydrogen peroxide on tissue at the wound site, it is not recommended as an antiseptic.[14]

Wound Dressings

Wounds require periodic washing, debridement, and observation. Because the effectiveness of topical agents is time limited,[25(pp137-139)] these agents must be reapplied to enhance their therapeutic effects. Washing the wound and reapplying the topical agent before there is an infection will reduce the risk of infection. After it has been thoroughly cleansed to remove any loose eschar or debris as well as old topical medications (Figure), the wound should be dried to afford better adherence before topical agents are applied to the wound surface. Topical antibiotics are applied to the wound site to the appropriate thickness and covered with a dressing. The dressing is applied to prevent removal of the topical agent by contact with objects and to maintain a moist wound environment. The comfortable, moist covering for the wound that is afforded by topical agents will increase patient acceptance of the dressing application, and the moist environment may also enhance wound healing and decrease the stiffness frequently associated with dry wounds.

A discussion of all of the dressings that are currently available to assist with wound care is beyond the scope of this article. Nevertheless, the proper combination of topical agents with either biologic or synthetic wound coverings can decrease the likelihood of infection and enhance wound healing.

Topical Agents

The term "topical agent" implies the use of an antimicrobial applied to the surface of the wound. The importance of a topical application is particularly apparent in ischemic wounds, in which dependable dispatch of a systemic (ie, bloodstream) antimicrobial to the damaged tissue cannot be assured.[25(pp137-139)] Further, the loss of the stratum comeum decreases the resistance of percutaneous absorption of the chemical agents.

The following section provides information on currently used topical agents, but is not exhaustive. A list of the topical agents is provided in Table 2.

Table 2. Common Topical Agents
Used in Wound Care
Type of
Topical         Proprietary or
Agent           Nonproprietary Name
Ointments       Bacitracin
                Polymyxin B sulfate
                Neomycin
                Polysporin
                Neosporin
                Povidone-iodine 10%
                ointment(a)
Creams          Silver sulfadiazine 1% cream(a)
                Mafenide acetate 0.5% cream(a)
                Nystatin(a)
                Nitrofurazone 0.2%
                compound(a)
                Gentamicin 0.1% cream(a)
Solutions       Acetic acid 0.5% solution
                Sodium hypochlorite (Dakin's)
                solution
                Silver nitrate 0.5% solution(a)
                Chlorhexidine gluconate 0.05%
                solution
(a) Physician's prescription required.

Ointments

Techniques/indications for use.

Ointments are water-in-oil preparations in which the amount of oil exceeds the amount of water in the emulsion.[26] The ointment base of these topical agents is comfortable and soothing, and although these agents can be used successfully on both partial- and full-thickness wounds, they are most commonly applied on partial-thickness injuries. Ointments are typically more occlusive and lubricating than other preparations. Ointments should be applied just thickly enough to cover the wound and to keep the wound moist. A petrolatum gauze is often placed over the ointment-covered wound. The dressing should be changed routinely, because the antibacterial action of the ointments will last for only approximately 12 hours. In addition, the ointments eventually dry and the dressings will then stick to the wound, leading to pain and damage of cells with removal. Because of the lubricating properties of ointments, they may be useful as topical agents for wounds such as exposed tendons.

Though some hypersensitivity reactions (eg, itching, rashes, swelling) have been reported, these incidents are uncommon and mainly occur over areas of normal skin that have been exposed to the agent for an extended period of time.

Bacitracin. Bacitracin is a polypeptide antibiotic that is generally available in a white petrolatum base (ointment). This ointment is effective against gram-positive cocci and bacilli. The mechanism of action for bacitracin is inhibition of cell-wall synthesis.[21(p779)] The development of bacitrucin-resistant organisms is rare. Bacitracin promotes wound healing indirectly by controlling the level of infection on a wound surface. Bacitracin may also enhance reepithelialization of the wound,[27,28] although bacitracin has been shown either to have no affect on keratinocyte proliferation or to slightly decrease it in vitro.[29] The uncommon incidence of resistant strains is unlikely to increase, because bacitracin acts on the properties of the bacterial plasma membrane and not on molecular synthesis.[30] Bacitracin augments the antimicrobial-action of polymorphonuclear leukocytes (PMNs).[31] Although this antimicrobial action may act to enhance the bactericidal properties of bacitracin, the significance of this to wound healing is not fully understood. Bacitracin has been shown to be safe for topical application in infants and children, as well as adults, with rare occurrence of hypersensitivity reactions (itching, swelling, anaphylaxis), and is unlikely to result in contact dermatitis.[32] A recent survey of bum centers showed that bacitracin was used in 43% of these facilities.[33] When topically applied, the absorption of bacitracin is minimal and systemic toxicity is unusual. Topical nonprescription bacitracin has a concentration of 400 to 500 U/g of ointment. Bacitracin is typically applied one to three times daily. In bum and wound care, bacitracin is often used on superficial partial-thickness wounds and bums to the face.

Polymyxin B sulfate. Polymyxin B is a simple, basic peptide antibiotic that is generally available in an ointment base (white petrolatum). This ointment is effective against gram-negative organisms such as Enterobacter and Escherichia coli and may mildly inhibit most strains of P aeruginosa.[34] Interaction of polymyxin B with phospholipids allows penetration and disruption of bacterial cell walls and therefore affects membrane permeability. The phospholipid content of certain bacterial cell walls may preclude entrance of the drug.[35] The formation of polymyxin B-resistant organisms is infrequent. As with bacitracin, polymyxin B encourages healing by containing surface bacteria. Polymyxin B caused a greater reduction of keratinocyte proliferation in vitro than does bacitracin.[29] According to Hansbrough et al,[31] polymyxin B inhibited the ability of PMNs to destroy ingested microorganisms, which may suppress the ability of the wound to restrain bacterial proliferation. Hypersensitivity reactions (itching, swelling, anaphylaxis) occur infrequently with topical application. The absorption of topically applied polymyxin B is negligible, and systemic toxicity is rare and is often related to use over a large area for an extended period of time. Combinations of either 5,000 or 10,000 U/g of ointment are available in nonprescription form. This ointment is generally applied one to three times per day to superficial partial-thickness injuries and to bums of the face.

Neomycin. Neomycin is available in an ointment base for topical application. This broad-spectrum antibiotic is particularly effective against gram-negative organisms such as E coli, Enterobacter, and Klebstella pneumoniae, but may also inhibit gram-positive organisms such as S aureus.[7(pp1165-1166)] The bactericidal activity appears to result from the inhibition of protein synthesis of bacteria by binding to a ribosomal Subunit.[7(pp1152-1153)] Resistant organisms are more common with neomycin than with polymyxin B or bacitracin. Neomycin influences wound healing by controlling the proliferation of bacteria on the wound surface. It appears that neomycin has no negative affect on keratinocyte proliferation in vitro,[29] but it has demonstrated inhibitory action on PMNs.[31] Hypersensitivity reactions, particularly skin rashes, also occur more frequently with neomycin (occurring in 5%-8% of patients) than with bacitracin or polymyxin B.[7(pp1165-1166),32] Ototoxicity and nephrotoxicity have been reported following application to large area wounds.[7(pp1165-1166)] The common concentration is 3.5 mg of neomycin per gram of ointment. Neomycin may also be prepared in a cream. This ointment is generally applied one to three times per day to superficial partial-thickness wounds.

Polysporin or Neosporin. Polysporin is a combination of polymyxin B sulfate and bacitracin in an ointment base. Neosporin is a blend of neomycin, bacitracin, and polymyxin B sulfate, also in an ointment. The combination of these agents produces no untoward interactions, side effects, or hypersensitivities different than those mentioned for the individual drugs. The combination, however, has advantages and disadvantages. For example, hypersensitivity may be more Common with the use of Neosporin than Polysporin because of the presence of neomycin in the ointment. Although the mixtures of antimicrobials in these ointments may be used to provide a broader spectrum antibiotic, no data exist that establish the superiority of the combination of ointments over any of the individual agents discussed previously.

Povidone-iodine. The ointment form of povidone-iodine can be used as a topical agent. The bactericidal spectrum of povidone-iodine includes gram-positive and gram-negative bacteria in vitro, Candida, and fungi. The mechanism of action appears to relate to the capability of iodine to oxidize microbial protoplasm. Information about the development of resistant organisms could not be found. Povidone-iodine fosters healing by restricting the number of infective organisms on a wound. The value of the antimicrobial effects of this topical agent must be weighed against reports of delayed wound healing.[36,37] Povidone-iodine at clinical concentrations has been shown to be toxic to human fibroblasts and keratinocytes in vitro.[38,39] Polymorphonuclear leukocytes are inhibited by this topical agent.[31] Povidone-iodine is not a commonly utilized topical agent for bum care in the United States.33 Contact dermatitis has been reported with prolonged exposure of the ointment to uninjured skin,[40] and metabolic acidosis has also been described with extended exposure to this topical agent,[8-10] although these reports do not establish povidone-iodine as the absolute cause of the acidosis.[41] Povidone-iodine has also been reported to be inactivated by wound exudate.[42,43] This topical agent may "harden" wound eschar rather than

soften it, thus increasing the difficulty and discomfort of wound debridement. This topical agent should not be during pregnancy, on a newborn, on small children, or on patients with suspected or known thyroid disease.[41] Povidone-iodine ointment should be applied one or two times daily. The ointment may also temporarily stain skin or linens. Povidone-iodine may be best suited, but may not be the first choice, for use on full-thickness tissue injuries.

Creams

Techniques/indications for use. An assortment of antibacterial agents are available in cream bases. Creams are oil-in-water emulsions in which the amount of water exceeds the amount of oil, and the term "creams" is most commonly used for water-miscible products.[44(p2839),45] Each of the agents is potent and useful for the appropriate wound and infective organisms. Creams are usually easy to apply, are often soothing to the patient, and are useful on varying depths of wound (Figure). Following removal of old dressings, creams from previous treatments are washed off and the wound is lightly debrided. The cream is then applied to the gently dried wound. A cream should be applied so that the wound cannot be visualized through it.[25(137-139)] A dry gauze wrap should then be placed over the treated wound. Regular dressing changes are encouraged to avoid the drying of the topical agent and because the creams are effective against organisms for only 8 to 12 hours. The following topical agents are commonly available in cream form.

Silver sulfadiazine 1% cream. Silver sulfadiazine is a topical sulfonamide compound of silver nitrate and sodium sulfadiazine introduced by Fox[46] and prepared in a 1% water miscible cream. Silver sulfadiazine is effective against a wide range of flora, particularly gram-negative bacteria (eg, E coli, Enterobacter, Klebsiella species, P aeruginosa), but including gram-positive bacteria (eg, S aureus) and Candida albicans.[42,47] The formation of resistant organisms and superinfection to silver sulfadiazine is rare.[42] Superinfection occurs when a new organism, which is resistant to the current treatment, infects the wound. Bactericidal effects are likely due to modification of the cell membrane and alteration of the cell wall. This topical agent promoters healing because of its bactericidal properties. There is evidence that silver sulfadiazine is toxic to human keratinocytes and fibroblasts in vitro.[39,48,19] The rate of reepithelialization in a porcine wound model, however, was enhanced when the wound was treated with silver sulfadiazine.[28,50] Silver sulfadiazine also appears to inhibit the effect of PMNs in killing microorganisms as well as local lymphocyte function,[31,51] although whether this has an influence on wound healing is yet unknown.

Silver sulfadiazine is currently the most extensively used topical agent for burn care in the United States.[33] Although trunsient leukopenia has been reported after the first few days of use,[52-54] the leukopenia is typically not severe,[52] remits even with continued use of the drug,[52] occurs in only 5% to 15% of patients,[53] and is not correlated with septic episodes.[47,54] Allergies to the sulfa in the cream are unusual, and very mild cutaneous sensitivity (typically a rash) occurs in less than 5% of patients and seldom requires discontinuance of topical therapy.[42] Because of the possibility of kernicterus (associated with sulfonamide therapy), silver sulfadiazine should be avoided during pregnancy, on premature infants, or on infants younger than 2 months of age.[55] The cream itself causes no pain. This cream is easy to apply, comfortable and soothing for patients, and is readily removed with washing. Though the silver may oxidize to a gray color, this cream does not stain skin or linen. Silver sulfadiazine should be applied one to two times daily. This agent is indicated for use with deep partial-thickness and full-thickness injuries. Its use on superficial partial-thickness injuries may be indicated if the wound is large and the patient is at risk for systemic sepsis or for comfort and ease of dressing a smaller wound. Some retardation of healing time is likely to be expected.

Mafenide acetate 0.5% cream (Sulfamylon). Mafenide acetate 0.5% cream (mafenide) is a methylated topical sulfonamide compound. Mafenide was introduced prior to silver sulfadiazine and was widely used for the treatment of burns.[56] Until silver sulfadiazine was marketed, mafenide was the most widely used topical agent for bums. This drug has a wide range of antibacterial activity against most gram-negative and gram-positive pathogens (its activity may be limited against some S aureus).[42-57] The formation of resistant organisms is rare, but superinfection with Candida may occasionally develop.[58] The mechanism of mafenide is not fully understood. Mafenide assists with wound healing by providing control of superficial infection. This topical agent has been shown to inhibit human keratinocytes and fibroblasts in vitro.[39,48,49] McCauley et al[59] suggest that the use of mafenide may be more inhibitory to reepithelialization than silver sulfadiazine. Mafenide suppresses PMN and lymphocyte activity.[31,51]

Although mafenide is available in many bum centers in the United States, it is used with much less frequency than silver sulfadiazine.[33] The drug is readily absorbed into the eschar and may therefore be a useful alternative to silver sulfadiazine for an invasive wound infection.[42] The chance of sulfa allergy is higher with mafenide acetate than it is with silver sulfadiazine. Rashes may be seen in about 50% of patients receiving mafenide treatment.[42] In addition, secondary tachypnea and hyperventilation may result as a consequence of a drug-induced metabolic acidosis (secondary to inhibition of carbonic anhydrase).[60] Metabolic acidosis induces the respiratory compensation, and elevated minute ventilation has been reported to extend to 50 L/min.[42] When mafenide is being used, respiratory status, blood gases, and pH levels should be monitored regularly. Moncrief[11] reported that toxicity may increase in correlation with the duration of treatment and size of area treated. The drug is considerably painful upon application.[61] Because of the risk of toxicity and the associated pain, the agent is indicated for full-thickness tissue injury, either on small wounds or for as short a time as possible on large wounds. Further, the topical agent should not be applied more often than every 12 hours because of the absorption of the drug.

Mafenide acetate may also be made into a solution from powder (5% concentration) for use in "wet-to-moist" dressings. Its bactericidal activity is comparable to that of the mafenide cream and causes less pain on application.[11,57,62] The risk of toxicity-related acidosis may also be decreased with the use of the 5% mafenide solution.[62]

Nystatin. Nystatin is an effective fungicide against Candida. Candida albicans develops little resistance to the drug, but other strains of Candida may develop resistance.[63] Increased cell-wall permeability is thought to be the mechanism for nystatin's fungicidal action. If a fungal infection is present on the wound surface, nystatin may aid healing by containing the contagion. No reports could be found describing the effect of nystatin on human keratinocytes or fibroblasts. Dermal hypersensitivity reactions are rare even with extended use, and the cream does not stain skin or linen, Nystatin cream should be applied one to three times each day on wounds with fungal invasion.

Though often used in cream form, nystatin is also available as ointment. Nystatin can also be mixed into solution from its powder form for use in "wet-to-moist" dressings. It may also seem reasonable to combine nystatin in solution with other agents such as bacitracin, polymyxin B sulfate, neomycin, or mafenide acetate to increase the spectrum of activity of the solution. Though reasonably intimated, mixtures may not guarantee an increase in antibacterial efficacy. Kucan and Smoot[63] reported that adding nystatin powder (5,000,000 U/L) to 5% mafenide solution did not adequately control fungal growth in studied bum wounds. Any of these solutions must be prescribed by a physician and mixed by a pharmacist.

Nitrofurazone 0.2% compound Nitrofurazone demonstrates a broad antibacterial spectrum, including being effective against S aureus, Enterobacter, and E coli, but it is less effective against P aeruginosa than silver sulfadiazine or mafenide acetate and has no significant fungicidal activity. The formation of resistant organisms is rare, but bacteria may develop a mild resistance with prolonged use. The mechanism of action appears to be by inhibition of bacterial enzymes. Wound healing is likely augmented by the control of surface infection. Nitrofurazone has been shown to have a detrimental effect on the growth and migration of keratinocytes in culture.[39] Nitrofurazone is not frequently used in bum centers in the United States.[33] The cream causes no pain following application. The development of usual symptoms of contact dermatitis (rash, local edema, and pruritus), though rare, have been reported. This topical agent should be applied once daily and is indicated more for use on full-thickness injuries.

Nitrofurazone may also be mixed in solution for application with "wet-to-dry" dressings. Information about the bactericidal effects, wound healing, and hypersensitivity reactions of the cream applies equally to the solution.

Gentamicin 0.1% cream. This drug is very effective against gram-negative organisms such as Enterobacter, Klebsiella, and P aeruginosa.[7(pp1161-1163)] The mechanism of action of this agent appears to be inhibition of protein synthesis and messenger ribonucleic acid translation.[7(pp1161-1163)] Resistant organisms can be expected, and this resistance certainly limits the use of this medication. Gentamicin may not be excessively toxic to keratinocytes,[29] but has been shown to inhibit the activity of PMNs.[31] Skin hypersensitivity has been reported with gentamicin. Ototoxicity and nephrotoxicity can occur, particularly when the drug is used in large volumes or for an extended period of time.[7(pp1161-1163)] Gentamicin should be applied to small wounds or larger full-thickness injuries once a day.[7(pp1161-1163)] Because of the development of resistant bacterial strains and the risk of toxicity, it is suggested that this topical agent be used only when treatment with other topical medications has been unsuccessful, that it not be used prophylactically, and that it be discontinued when the wound colonization is controlled.

Solutions

Techniques/indications for use. Topical agents in solution are useful if the choice of dressing is "wet-to-moist." [44(p2838)] The drug of choice is generally added in its powder form to distilled water or physiologic saline. Solutions are a useful form for topical agents, especially when applied to wounds with cavities or fissures, because they can easily be cleansed by rinsing.[44(p2838)] The wound should be thoroughly rinsed following removal of old dressings to ensure removal of previously applied agents. The wound may then be gently debrided, and a gauze that has been soaked in the solution of choice is then placed on the wound. If the gauze is being placed in a deep wound, care must be taken to not disrupt healing tissue by overaggressive insertion of the dressing. All exposed parts of the wound should be covered by the soaked gauze.[44(p2838)] This type of dressing is often held in place by an elastic wrap because the occlusiveness of the wrap helps prevent leakage of the solution. Gauze soaked with the solution form of a topical agent is easily applied and removed from most wounds unless the gauze is allowed to dry out, at which time it can be damaging because of the associated removal of newly forming tissue.[44(p2838)] The solutions should be applied often enough to keep the dressing from drying.

Topical agents in solution generally provide safe and effective treatment of infected wounds, but the requirement that dressings not be allowed to dry out undoubtedly increases the cost of the technique. These solutions are necessarily unstable, and therefore they must be mixed fresh. Topical solutions must be prescribed by a physician and should be mixed by a pharmacist to ensure appropriate concentrations and antiseptic preparation. The following topical solutions are frequently used in the treatment of cutaneous wounds.

Acetic acid 0.5%. Acetic acid at this concentration is bactericidal to many gram-negative and gram-positive microorganisms but is especially effective against P aeruginosa.[64-65] Solutions of 0.250/o acetic acid have also been reported, but they appear to be less effective in reducing microorganisms on wounds.[38] This weak acid penetrates the cell wall and disrupts the cell membrane to establish its bactericidal effects. Any wound-healing assistance provided by this solution would be in curbing growth of inhibitory infective organisms on the surface. Acetic acid has demonstrated toxicity to fibroblasts in culture.[38] Reduced epithelial cell proliferation in culture[29] and delayed healing of cultured epithelial autografts have been reported at 0.25% strength.[66] It may be that 0.5% concentrations are more toxic to regenerating epithelium, but this has not been reported. Gruber et al[67] described no adverse effect on reepithelialization of donor sites when comparing 0.25% acetic acid with saline. Acetic acid has been shown to reduce PMN function.[31] Skin irritation may occur if acetic acid is used at, or higher than, the 0.5% concentration. Acidosis may result from protracted use over large surface-area wounds. This solution should be applied frequently enough to keep the wound moist, and it should be rinsed off thoroughly between applications. This topical agent in solution is a good choice for small infected wounds.

Sodium hypochiorite (Dakin's solution). This sodium hypochlorite (0.5% or 0.25% NaOCl) solution is considered a general bactericidal (eg, Stapbylococci and Streptococci), fungicidal, and virucidal agent. Concentrations as low as 0.025% have also demonstrated bactericidal effects.[68] The bactericidal effects are the suggested rationale for aiding wound healing. Sodium hypochlorite at 0.25%, however, has displayed toxicity to fibroblasts[38,39,68,69] and keratinocytes[29,39] in culture. Polymorphonuclear leukocyte viability is also inhibited by this topical agent.[31,69] Sodium hypochlorite solutions of 0.5% would be expected to demonstrate at least these same levels of toxicity. Tissue toxicity was not observed at concentrations of 0.025%.[68] Delays in epithelialization and neovascularization might be expected.[29,39] Sodium hypochlorite dissolves blood clots and may also delay clotting. Bleeding may ensue, and the wound should be carefully monitored when using this solution. Acidosis may result following continuous use over large-area wounds. This solution may also cause pain. A diluted sodium hypochlorite solution is frequently used to irrigate wounds. In any dilution, the solution should be thoroughly rinsed of the site between dressings, as prolonged exposure can lead to skin irritation. The soaked dressing should be changed often enough to avoid drying of the dressing. As with acetic acid, this sodium hypochlorite might be considered as an alternative for treating small, infected wounds. Because of its level of tissue toxicity at typical concentrations, this solution may not be a suitable choice for treatment of partial-thickness injuries that are sparsely colonized. Less concentrated solutions such as 0.025% should be considered for clinical use.[68]

Silver nitrate 0.5%. Silver nitrate in solution provides bactericidal activity against a wide range of bacterial flora, but is probably more effective against gram-positive bacteria (eg, S aureus). Silver nitrate solution has demonstrated invulnerability to resistant organisms.[70] Wound healing may be enhanced by control of local infection with this topical agent. There are conflicting reports about the toxicity of silver nitrate solution to epithelium.[39,71] The solution is extremely hypotonic, and electrolytes (eg, sodium and potassium) leach into the dressing. This leaching can lead to electrolyte imbalances, especially with prolonged use over large-area wounds. Use of silver nitrate on large wounds requires monitoring of electrolytes.[72] Bacterial reduction of nitrate to nitrate may lead to methemoglobinemia with use of this topical agent.[73] This potential complication, though rare, should be suspected if skin around the wound appears gray or cyanotic, and the diagnosis can be confirmed with blood methemoglobinemia measurement.[42] No reports of hypersensitivity reactions in the skin have occurred with the use of silver nitrate solution. Because of potential toxicity, silver nitrate has been suggested to be more effective on smaller surface-area wounds.[47] Although silver nitrate is a reasonable choice as a topical agent for smaller wounds, frequent soaking of the dressings (about every 2 hours) is required for the agent to remain effective and application of the solution may be slightly painful. Further, the solution stains skin, wounds, dressings, linen, and clothing a dark brown or black. The agent does not penetrate eschar readily and therefore should not be the first choice for treatment of established infections.[42]

Triple antibiotic solution. Bacitracin (50,000 U), polymyxin B (200,000 U), and neomycin (40 mg) can be combined in 1 L of saline to produce a triple antibiotic (TAB) solution to use as a "wet-to-moist" dressing for infected wounds of several types.[25(p174)] This solution shows at least a moderate level of activity against a variety of gram-negative and gram-positive organisms, with activity against P aeruginosa being poor.[74] No data on resistant organisms were available. The components of the solution, when in ointment form, showed limited toxicity to keratinocytes.[39] Nystatin, in powder form, may be added to the solution if there is a combined bacterial/fungal infection. This TAB solution may be indicated for fresh, poorly colonized wounds such as new skin grafts or donor sites because of its potentially low level of tissue toxicity.

Chlorhexidine gluconate solution. Chlorhexidine gluconate solution (0.05% in distilled water) affords antibacterial activity against gram-positive bacteria, including P aeruginosa and Klebsiella, and against gram-positive bacteria such as S aureus and E coli.[74] Local infection control may assist wound healing. No data could be found that discussed the tissue toxicity of this solution, and systemic toxicity appears to be rare.[42,75] This solution rarely causes skin reactions; however, with prolonged, repeated use, contact dermatitis may develop.[76,77] The apparent low toxicity and high bactericidal properties of this solution indicate that it may be a useful option as a topical therapeutic solution for different depths and sizes of injury. The solution should be used often enough to keep the wound moist.

Moisturizers

Although moisturizers are not typically discussed in the context of "topical agents," a brief discussion is warranted, particularly as it relates to sensitivity reactions and to antipruritic agents. Dryness, flakiness, and pruritus are typical in freshly epithelialized wounds and result from the loss of production of skin oils. Superficial wounds and true partial-thickness wounds will eventually recover the ability to produce skin oils; however, deeper wounds will not. Topical moisturizers, used as needed (often more frequently than twice a day), will relieve most complaints of flakiness and itching. Hypoallergenic moisturizers that are not alcohol based, and contain no perfumes, are preferred. Patients may develop sensitivity reactions to moisturizers that contain perfumes.[78] These reactions often occur as skin rashes or increased pruritus. if such a reaction occurs, the use of that moisturizer should be discontinued, the rash should be allowed to clear, and the patient should then explore other moisturizers to find one that will not produce an irritation. If the rash persists following a change of topical agent, a medical consultation should be obtained.

There are some mild antipruritic creams that may be acquired without prescription, and these creams should be applied as infrequently as will allow for control of itching. There are also several choices of topical corticosteroids that are used as anti-inflammatory and antipruritic agents. These corticosteroids, which require physician prescription, should be applied as prescribed and seldom require prolonged use. Adverse reactions of burning, itching, erythema, and skin and papular rashes have been reported, and topical corticosteroids should be discontinued if any of these symptoms occur. Systemic effects of topical corticosteroids are considered reversible.

Other Considerations

General contraindications. Any known sensitivities, or the development of sensitivities to the pharmaceutical components of each of these preparations in ointment, cream, or solution, should be considered a standing contraindication for a particular topical agent.

Resistant strains. Although resistant strains of organisms may develop against some of the topical agents discussed, this has not created a major barrier to treatment of wound infection by the available choices of agents provided in this review. Methicillin-resistant Staphylococcus aureus (MRSA) is a reasonably common gram-positive species of bacteria that can cause a number of infections, including bacteremias, pneumonias, and soft tissue and bone infections. Because most cases are nosocomial, infection control and isolation precautions should be a part of any wound care measures along with the use of topical agents. In the case of MRSA, silver sulfadiazine, mafenide acetate, and nitrofurazone (as well as mupirocin, a topical agent not described in this article) may be effective in treating this resistant strain.[79-81] Smoot et al[81] report that in their bum unit mafenide acetate has limited activity against MRSA. This may be the result of their frequent use of this agent, which may have produced an MRSA resistance in their particular center.[81] If there is a topical agent of choice in a clinic and a resistance to a particular organism develops, the resistance may be clinic specific and other topical agents should be used in attempts to subdue the resistant pathogen.

Other. Incorrect medication can result in delayed healing, discomfort, increased scarring, progression of the infection, or toxicity. For example, delayed healing may lead to proliferation of fibroblasts and an increase in scarring. A large-area wound treated with the same topical agent for several clays also has a potential for systemic toxicity.[7(pp1165-116)-11] A therapist who is aware of recurring wounds or infections should refer the patient to a physician.

Patients should be taught the appropriate application of topical agents and dressings, as well as the signs of infection. Patients should also understand that such drugs are never to be taken internally.

Topical Agents and Wound Healing

Any human tissue requires oxygen to remain viable. The importance of blood supply to the skin can be easily illustrated with the example of a pressure ulcer. Though there are other contributing factors to the formation of pressure ulcers, it is clear that local ischemia caused by pressure-induced constriction of capillaries leads to death of the involved skin. Capillary regrowth and associated wound remodeling are hampered by decreased oxygenation.[82-84] Additionally, infection is enhanced by an ischemic environment because bacteria require little oxygen compared with the associated cells.[85] Further, by consuming oxygen, bacteria decrease the amount of oxygen available to the tissue.[86] Inadequate wound healing with concurrent inflammation and increased scarring is another consequence of bacterial proliferation and related tissue hypoxia.[87] A diabetic ulcer is a classic example of a poorly perfused wound that demonstrates substandard wound healing along with chronic inflammation.[88] Bum wounds are ischemic as a result of the thrombosis caused by the injury. Full-thickness bums display this thrombosis through all layers of affected skin, whereas partial-thickness bums demonstrate incomplete thrombosis.[47] Topical agents are used to fight wound infection related to decreased tissue vascularity.

Controlling infection in open wounds will enhance wound healing. Topical agents reduce the number of germs but do not obliterate them. Improved wound healing decreases the pain and scarring that contribute to wound-related physical impairment.

By removing bacteria and necrotic debris, debridement and cleansing are important components of any wound care program to prevent infection.[1(pp150-156)] Necrotic tissue present on a wound surface promotes infection by providing nutrients for bacteria. Besides fighting superficial infection, most topical agents will help soften wound eschar, which will assist with debridement of tissue. Removing previously applied creams and ointments from the wound allows for repeated assessment of the wound.

Superficial and partial-thickness wounds heal by regeneration of epithelium from existing basal cells at the wound surface.[89] Some mild contraction may be associated with the healing of superficial wounds, but seldom is there scarring. In contrast, deep wounds usually heal by a combination of reepithelialization and contraction.[89] Contraction serves to decrease the area of the wound. Wounds are then reepithelialized from the margins. Scarring and contraction of scar tissue are typically consequent problems to the healing of deep partial-thickness and full-thickness wounds.

The rate of reepithelialization may be enhanced by the application of bacitracin,[27,28] and polymyxin B and Neosporin in an ointment or TAB solution appear to either have no, or only a slight, inhibitory effect on keratinocyte proliferation.[29] In contrast, povidone-iodine,[38,39] silver sulfadiazine,[39,48,49] mafenide acetate,[39,48,49,59] nitrofurazone,[39] acetic acid,[29] and sodium hypochlorite[29,39] Will likely inhibit reepithelialization.[47-90] A bland ointment (bacitracin, polymyxin B sulfate, neomycin, and their combinations) and possibly silver sulfadiazine are often the topical agents of choice for reepithelializing wounds. Bland ointments are also generally less expensive than the sulfa-based topical agents and therefore might be a more cost-effective choice for treatment of small, uncomplicated wounds. Wound contraction is a natural process in which wounds heal by decreasing their size.[91] When a wound is located over or near a joint surface, however, excessive contraction may contribute to loss of joint motion. Further, when the wound encompasses a large surface area, contraction cannot successfully close the wound. Little is known about the effects of topical agents on the rate or amount of wound contraction. Bacitracin and silver sulfadiazine have been shown to retard wound contraction in a pig model,[28] but the direct clinical application of these findings is not yet understood. Additionally, the appropriate choices of topical treatment may speed wound coverage, thereby decreasing the risk of scarring and associated scar contracture. A hypertrophic scar, which results from a poorly treated wound or is the predictable result of a healed full-thickness wound, will continue to contract for several months, even following wound healing.

Conclusion

Because of the availability of several effective topical agents, wound care protocols may vary and still meet with success. Observation of the wound, along with the appropriate selection of a topical therapeutic agent, can improve the healing of wounds and lead to decreased patient morbidity. The physical therapist should be aware of the advantages and disadvantages of varying topical wound care agents. Collaboration with the physician in determining infective organisms at a wound site will assist with making acceptable decisions about the topical agents of choice. Future studies of importance to this clinical area should include controlled comparative clinical studies on the effects of various topical agents on different types of wounds, the interaction of various dressings with topical agents, the potential use of drug enhancers for these topical agents, the effect of different topical agents on wound and scar contraction, the rate of healing and its effect on scar formation, and the cost effectiveness of varying wound treatments.

Acknowledgment

We thank Dr Jody Neuman, Assistant Professor (Clinical), College of Pharmacy, University of Utah Health Sciences Center, for her review of the manuscript.

[ILLUSTRATION OMITTED]

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RS Ward, PhD, PT, is Staff Member, Intermountain Burn Center, and Assistant Professor and Co- Director, Division of Physical Therapy, University of Utah Health Sciences Center, Annex 1130, Salt Lake City, UT 84112 (USA). Address all correspondence to Dr Ward.

JR Saffle, MD, FACS, is Director, Intermountain Burn Center, and Associate Professor, Department of Surgery, University of Utah Health Sciences Center, 50 N Medical Dr, Salt Lake City, UT 84132.