Symposium on Burns
Topical Therapy William W. Monafo, M.D., F.A.C.S., * and Vatche H. Ayvazian, M.D., F.A.C.S. t
Burns are prone to infection. The larger the injury, the greater is the risk. Age and general debility both probably add significantly to the propensity to infection; protein-calorie malnutrition, which adversely affects the already impaired immunocompetence of the burned patient, almost certainly does. Most of the considerable morbidity and mortality that attends major burn injury is the result-directly or indirectly-of infection of the wounds by bacteria or fungi. Similarly, morbidity in patients with smaller burns is also largely relatable to infection. Topical antimicrobial agents are indicated in all moderate and major burn injuries, and in many so-called "minor" burns as well. The evidence is overwhelming that, properly used, effective topical agents significantly lessen morbidity and mortality. A burn severe enough to warrant hospitalization of the patient who bears it should be treated with a topical antimicrobial agent, as infection will cause whatever early morbidity is to occur. Bacterial infection may deepen a dermal burn and thus delay spontaneous healing or even cause conversion to a full thickness injury. On the other hand, most fresh, small, superficial burns in outpatients are satisfactorily treated with a simple sterile occlusive dressing which will effectively protect the wound from bacterial contamination. This paper will outline the rationale for the use of topical agents in general, set forth broad criteria for their selection, and describe the advantages and disadvantages of currently available agents.
RATIONALE FOR TOPICAL TREATMENT Burns are ischemic wounds. Confluent thrombosis, which involves arterioles, capillaries, venules, and, at times, even larger vessels, is characteristic of full thickness burns. In partial thickness burns, thrombosis is incomplete; the dermal circulation in the deeper, viable segments of *Chairman, Department of Surgery, and Director, Burn Unit, St. John's Mercy Medical Center, St. Louis; Associate Clinical Professor of Surgery, St. Louis University School of Medicine, St. Louis; Clinical Associate Professor of Surgery, University of Missouri, Columbia, Missouri t Associate Chairman, Department of Surgery, and Associate Director, Burn Unit, St. John's Mercy Medical Center, St. Louis, Missouri
Surgical Clinics of North America-Vol. 58, No.6, December 1978
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the dermis is gradually reestablished within a few days, although the dead, superficial portion of the dermis of course remains avascular. Because of the wound ischemia, systemically administered antimicrobial agents are not reliably delivered to the site where they are needed, as diffusion from the wound periphery for a variable but often considerable distance is their only means of access; moreover the wound surface closest to the heat source is at once the most severely injured and ischemic and as well the original site of most burn wound infections. Antimicrobial agents are therefore best used topically to treat burns.
Prophylactic or Therapeutic? Normal skin harbors few pathogenic bacteria. Most burns are sterile initially, although contamination usually by soil or water may occur after the accident as a result of first aid measures or during transport. When the burns are large (greater than 50 per cent of body surface area), dense colonization by pathogenic bacteria can occur within 24 hours in untreated patients. Adequate topical therapy should therefore be instituted as rapidly as possible following injury. Topical wound therapy in patients with large burns is equally as urgent a need as is fluid resuscitation. The topical treatment initially in most instances is prophylactic; if the original treatment fails and significant wound infection occurs, a different agent should be substituted when that diagnosis is made. Infections may vary in severity from light surface colonization of little clinical significance to a rapidly spreading, necrotizing phlegmon that invades previously unburned tissue-the so-called "burn wound sepsis."
CRITERIA FOR ASSESSMENT OF TOPICAL AGENTS Topical burn therapy likely began at man's first adverse encounter with fire. Before there was knowledge of the existence of bacteria, of the immune response, or of the ischemic nature of the wounds, topical medicaments were intuitively applied to burns both to relieve pain and to encourage kind healing. The wildly empiric remedies of the pre-Listerian era-the gamut ran from pigeon dung to turpentine-were of course excusable because they were conceived in ignorance. Fortunately, enough now is known to permit a rational evaluation of agents currently available or newly proposed for the treatment of burns.
In Vitro Antimicrobial Spectrum The agent must have a demonstrable and appropriately broad in vitro range of activity which should include the gram-negative aerobic intestinal bacteria, Pseudomonas aeruginosa, Staphylococcus aureus, and preferably fungi as well. Should it eventuate that viral burn wound infections are more common than it now appears, this consideration will also become relevant.
Clinical Efficacy The agent should possess a clinical record of efficacy; its effect on the microbial flora of burn wounds of varying magnitude should be
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known; in major burns, the mortality attending use of the agent should also have been documented. Unfortunately, recommendations are still made for the use of agents without such appropriate supportive evidence. The assumption, for example, that an antimicrobial agent that is efficacious in eliminating bacteria from normal skin will be of value when applied to major burn wounds (or even minor ones) is unjustified. Absorption and Toxicity Ideally, a topical agent should penetrate the eschar, yet not be appreciably absorbed systemically. It clearly should not have significant local histotoxicity. There should be knowledge of the rate of absorption of a given agent, the blood or tissue levels reached, the routes of excretion, and the most common toxicity to be expected. The reader will recognize from what follows that these criteria are not wholly fulfilled by some of the agents in common use. Open burn wounds may have a potential absorptive surface of 10,000 cm2 or more. Many once popular topical agents have belatedly been abandoned after it was recognized that significant absorption and, as a result, prohibitive systemic toxicity attended their use. Tannic acid was in vogue for more than 20 years before its hepatic toxicity was generally appreciated. More recently, serious systemic toxicity, including renal and pulmonary failure, has resulted from the topical application on burns of the antibiotics neomycin and gentamicin and of the sulfonamide mafenide; the general use of these relatively toxic agents for topical burn therapy should therefore be sharply restricted. These drugs should be used as briefly as possible, and on the smallest possible wound area, usually not as prophylactic agents, but for the treatment of a specific established infection in order to achieve the desired antimicrobial effect without incurring toxicity. Superinfection Superinfection, which, iffrequent, will eventually result in decreased efficacy is a complication of importance that varies appreciably in frequency depending on the agent in question. Superinfection explains why antibiotics are actually harmful when they are used routinely topically for the prophylaxis of burn wound infections. Since antibiotics act at a specific site on the microorganism, the selection pressure they exert is heavy: resistant strains tend to emerge rapidly. This criterion is pertinent as well to topical burn antimicrobials not in the antibiotic class. One of the major advantages, for example, of 0.5 per cent silver nitrate solution is that the emergence of silver-resistant strains has proved to be infrequent, even when the agent is routinely used for long periods. I Other Considerations Some agents cause local pain, others stain skin or linen, some must be used with exposure, others with dressings. Factors such as flexibility of use, cost, availability, patient acceptance, etc. are usually less important than the foregoing ones, but nevertheless must be considered. In many developing areas of the world, cost is actually a primary con-
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sideration: funds for numerous professional personnel, dressings, etc. are not available.
LIMIT ATIONS OF TOPICAL AGENTS Topical agents are an important part of the burn treatment program but they are not substitutes for meticulous local wound care, or for a carefully planned and executed program of management that leads relentlessly toward the ultimate objective of early permanent wound closure, or for proper metabolic and nutritional support of the patient who bears the wound. Thus sub escharotic abscesses must be promptly unroofed; detritus or devitalized tissue, which may favor the proliferation of microorganisms, should be removed or excised; repetitive microbial inoculation of large wounds by contaminated water or other unrecognized sources will likely eventually result in uncontrollable infection; undue delay in attaining permanent wound closure will by itself increase the risk of infection; and a hypermetabolic patient whose nutritional needs have been inadequately provided for may die of sepsis originating on his wounds. In patients with major injury the potential pitfalls are many indeed. It is generally tempting (but not necessarily more accurate) to ascribe treatment failure to lack of efficacy of the topical agent used rather than to tactical or judgmental errors. On the other hand, the successful use of topical agents prevents the bacterial conversion of deep thermal burns to deeper injury and results in the spontaneous healing of wounds that appeared initially clinically to be full thickness. Truly full thickness burn eschars do not slough within a few weeks in a sea of fetid pus, but remain intact and can be excised THE BURN
INFECTION
EQUATION
MICROBIAL
BURN WOUND
VIRULENCE
\
DENSITY
DEPTH
/
I~"--
TOPICAL THERAPY
~~~
"'"
INVASION POTENTIAL
~
INFECTION
NUTRITIONAL
SURFACE
AREA
/
WOUND SEVERITY
OC MICROBIAL BURDEN HOST RESISTANCE
f \
INTEGRITY
PRE-EXISTING DISEASE
(he:;'~c~~.-:~~~i:~~:y..,c)
Figure 1. The burn infection equation is complex. Successful topical therapy minimizes the bacterial density, as indicated, and may prevent additional, infection related necrosis which deepens the wound.
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and skin grafted, with a reasonable take of the grafts at an appropriate time of election. Exposed granulations appear healthy. Signs of systemic illness, except possibly for fever, which is common and may have a multiplicity of causes in the burned patient, are absent. Nutritional goals can be met regularly because adynamic ileus, the troublesome harbinger of sepsis, is not a recurrent problem. Concomitantly, bacteriological monitoring of the wounds indicates that the flora is relatively homogenous, usually comprising one or two species, and that its density is well below the critical level of lOS per cm2 of wound surface area above which invasive infection becomes a hazard (Fig. 1).
TOPICAL AGENTS The following section discusses those topical agents currently in frequent use, but is not necessarily all-inclusive. The criteria discussed previously should be applied to aid in their selection in a given situation: in vitro and clinical efficacy, toxicity (absorption), superinfection rate, ease and flexibility of use, cost, patient acceptance, and side effects. Since none of the agents is uniformly successful, it may become necessary to substitute a different one on all or part of the wounds at a later stage in treatment. Fortunately, failure with one agent does not preclude success with another. Frequent clinical observations, augmented by properly interpreted bacteriological and other laboratory determinations, facilitate these decisions.
Silver Sulfadiazine Silver sulfadiazine is a poorly soluble compound readily synthesized by reacting silver nitrate with sodium sulfadiazine. It is available commercially, compounded in a "micronized," water-soluble cream base in a concentration of 1 per cent, which provides amounts of the agent well above those necessary in vitro to inhibit the growth of sensitive microorganisms. This concentration was arbitrarily selected because it contains approximately the same amount of silver as does 0.5 percent silver nitrate (30 mEq per liter). The in vitro antimicrobial spectrum of silver sulfadiazine is appropriately wide and includes S. aureus, Enterobacteriaceae, E. coli, and Candida albicans. It is unclear whether the parent silver sulfadiazine molecule itself exerts an antimicrobial effect, or whether its gradual dissociation into silver and sulfadiazine moieties, each of which individually has an effect, is primarily responsible for its activity. Sulfadiazine is a well-known competitive inhibitor of para-aminobenzoic acid. The antimicrobial effect of silver has been variously explained; it likely has multiple sites of action. It has been suggested that silver sulfadiazine acts primarily on bacterial cell walls in which it induces visible ultrastructural changes, and also that bacterial DNA replication may be impaired due to silver (but not sulfadiazine) binding·in that molecule, the sulfadiazine acting merely as a vehicle. Clinically, controlled trials of silver sulfadiazine in both large and small burns have demonstrated that it has highly efficient prophylactic
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value, particularly against gram-negative bacteria. The incidence of sterile cultures is usually in the order of20 per cent in major injuries. Our studies indicate that, used prophylactically, silver sulfadiazine may delay wound colonization by gram-negative bacilli for from 10 to 14 days in extensive injuries, after which the wounds nearly invariably become colonized in moderate density. Treatment failure is frequent, however, when the wound size exceeds 60 per cent of body surface area. The mortality rate attending the use of silver sulfadiazine roughly parallels that observed using 0.5 per cent silver nitrate solution. 6 Silver sulfadiazine has been widely used during the past several years. As already pointed out, an important requirement for the routine use of a topical agent is a stable sensitivity pattern of the principal pathogens to the agent employed. A theoretical disadvantage of silver sulfadiazine is the potential for the emergence of sulfadiazine resistance. This was not reported in the early clinical trials. However, it has lately been suggested that a significant proportion of gram-negative bacilli, particularly Enterobacteriaceae, can become highly resistant to sulfadiazine as a result of its protracted use. This was associated with a reduced prophylactic effectiveness of the agent. Several patterns of antibotic resistance were documented to have occurred as the result of inter-species transfer of resistance plasmids, especially from Enterobacter species, a phenomenon almost certainly due to the selection pressure exerted by the protracted use of silver sulfadiazine. 1 The factors involved in the analysis of such a phenomenon are always complex. Reports of the emergence of resistant strains must always be carefully evaluated epidemiologically, as the repetitive early inoculation of wounds with bacilli resident in drains, hoses, etc. used for hydrotherapy (for example) may overcome the prophylactic effectiveness of any agent and result in an epidemic of "resistant" bacteria. Unchecked, selection pressure exerted by the therapy may in fact eventually result in the emergence of resistant strains and a further decrease in clinical efficacy. Some absorption of sulfadiazine occurs. Blood levels are on the order of 1. 5 to 4 mg per 100 ml, depending on the size of the burn and the interval post injury. Silver absorption is minimal, probably due to local binding at the wound of the insoluble chloride and proteinate salts. Largely because of its poor absorption, significant or persistent toxicity related to silver sulfadiazine is rare, even in extensive burns. This factor has undoubtedly contributed to its popularity. Crystalluria, a well-known toxic effect of sulfonamides, is rare. Transient leukopenia, typically occurrring after the first few days of application, attends the use of silver sulfadiazine in about 5 per cent of patients. 5 In our experience, the leukopenia is ordinarily relative, that is, in the low normal range, but inappropriate to the magnitude of the associated injury, and is rarely absolute. The leukopenia typically spontaneouslyremits despite the continued use of the drug. Since there is no known correlation with septic· episodes, the clinical significance of the leukopenia is moot. Cutaneous sensitivity reactions to silver sulfadiazine occur in 5 per cent or less of patients; they are rarely severe enough to warrant withdrawal of the agent.
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Silver sulfadiazine cream should be liberally applied to the wound, which can then either be left open or covered with a dressing. Exposure of the cream to direct sunlight results in the oxidation of silver to a metallic gray color, but the cream does not stain linen or skin. When silver sulfadiazine is applied to dermal burns, a proteinaceous gel several millimeters thick forms on the surface of the wounds. This "pseudoeschar" can easily be removed in sheets after 72 hours or more.
Cerium Nitrate-Silver Sulfadiazine There is recent evidence that the modification of silver sulfadiazine by the incorporation into it of cerium nitrate strikingly enhances its clinical efficacy. Cerium, one of the lanthanide elements, has a broad in vitro antibacterial and antifungal spectrum. Its potential utility as a topical antimicrobial seemed worthy of investigation in view of the favorable, if imperfect, results observed in the topical treatment of burns during the last decade using silver compounds. Cerium was selected from among the lanthanides, all of which have antimicrobial activity in vitro, because it is readily available, has low toxicity, and is poorly absorbed from open wounds, primarily because of the insolubility ofits phosphate and protein salts. After preliminary animal testing confirmed its safety, cerous nitrate (Ce(N0 3)3· 6H 2 0) was used alone in a clinical trial as a cream incorporated in a water-soluble base. It soon became apparent that gram-negative bacilli were comparatively rarely present on cerium-treated wounds, but that gram-positive bacteria, particularly Staphylococcus aureus, were not as effectively suppressed as when either silver nitrate or silver sulfadiazine had been used. Mortality was essentially the same as with the use of silver nitrate or silver sulfadiazine. These observations led to a clinical trial of simultaneous topical treatment with cerium nitrate-silver sulfadiazine. Commercially available silver sufadiazine cream was modified by stirring into it a concentrated (100 gm per 100 ml) aqueous solution of cerium nitrate so that the final concentration of cerium nitrate was 2.2 per cent (0.05M), whereas that of the silver sulfadiazine was only slightly less than its original 1 per cent. After resultant thin cream was topically applied, the wounds were covered with dressings, except on the face and genitalia. The clinical results during the past two and one half years have been extremely promising. Treatment failures have been few and septic deaths from any cause have occurred only in elderly patients and those with massive (greater than 80 per cent of body surface area) injuries. In vitro experiments indicate that the minimal bactericidal concentration of ionic silver can be reduced approximately threefold by the presence in the medium of ionic cerium in concentration less than that required for a bactericidal effect due to cerium alone. The precise mechanism of action of cerium is not known. Theoretically, the cerium nitratesilver sulfadiazine cream provides four potentially active antimicrobial substances in vivo as ionization proceeds at the wound surface: Ag +, Ce + + +, cerium sulfadiazine (readily synthesized in vitro), and silver sulfadiazine.
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Table 1. The Results of Gauze Capillarity Wound Surface Cultures in 300 Patients Whose Wounds Were Treated with Cerium Nitrate-Silver Su~fadiazine (Wound Bacterial Density Exceeded 10 4 per cm 2 in Only Four Per Cent of These Cultures) NO. OF
NO. OF
NO. OF
NO. OF
QUANTITATIVE WOUND
STERILE
CULTURES YIELDING
PATIENTS
SURFACE CULTURES
CULTURES
GRAM-NEGATIVE STRAINS
300
7126
4023 (57%)
1007 (14%)
Blood cerium levels in patients with major burns treated for many weeks with the cerium nitrate-silver sulfadiazine are less than 10 ILg per 100 m!. Two of 300 patients treated with the agent have evidenced transient methemoglobinemia due to bacterial reduction of nitrate and subsequent absorption, but no other toxicity attributable to cerium has been demonstrated. Bacteriological surveillance of the wounds using the quantitative gauze capillarity surface culture technique has been intensive (Table 1). The incidence of sterile wound cultures has been relatively high, even in patients with extensive injuries; the wound flora is generally comparatively sparse in density. Moreover, the recovery rate of gram-negative bacilli has remained relatively low, on the order of 15 per cent. The mortality data show that the observed death rate is approximately 50 per cent less than that expected, using as a baseline the age-adjusted statistical tabulations of the National Burn Information Exchange or those of Bull and Fisher. Table 2 indicates the observed versus the expected mortalities in this series of patients. Importantly, the apparent reduction in mortality is present in large injuries of from 50 to 80 per cent of body surface area as well as in smaller ones. 4 In summary, the initial results with cerium nitrate-silver sulfadiazine indicate that this agent provides more efficient prophylaxis against gram-negative bacteria than has previously been possible. Not surprisingly, a reduction in mortality of approximately 50 per cent has Table 2. Mortality Observed with Cerium Nitrate-Silver Sulfadiazine Topical Wound Treatment NO. OF BSA (PER CENT)
1 to 20 to 40 to 60 to 80 to
19 39 59 79 100
TOTAL
NO. OF
DEATHS
NO. OF
PATIENTS
OBSERVED
PREDICTED DEATHS
190 53 28 15 14 300
2 2 8 3 11 26
6.5* to 5.4t 9.4 to 10.7 14.5 to 14.7 11.9 to 12.0 13.6 to 14.0 56 to 58
*From Feller, 1., et al.: Baseline results of therapy for burned patients. J.A.M.A., 236:1943-1947, 1976. tFrom Bull, J. P.: Revised analysis of mortality due to burns. Lancet, 2: 1133-1134, 1971.
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resulted. Except for occasional methemoglobinemia, significant toxicity has not been observed. Unless hitherto unrecognized toxicity of this agent is demonstrated, and unless the emergence of resistant strains later proves to be a frequent occurrence, it should prove to be an effective and safe topical prophylactic agent for extensive bums. Silver Nitrate Solution (0.5 Per Cent) One half per cent silver nitrate solution has a long history as a clinically useful antiseptic. It was reintroduced as a topical agent for the treatment of major bums in 1965. Ionic silver has a potent in vitro antimicrobial effect. Its spectrum includes the common bacterial and fungal bum wound pathogens. The emergence of silver-resistant organisms is uncommon, probably because silver inhibits growth by several mechanisms, rather than acting at a single site on the bacterium. Properly used, silver nitrate is an effective prophylactic agent, although its efficacy decreases appreciably when wound size exceeds 50 to 60 per cent of body surface area. Data from several clinics indicate that its routine use prevents death from infection in most instances in otherwise good risk patients with injuries of up to 40 to 50 per cent of body surface area; treatment failure is common however when bum size exceeds 60 per cent of body surface area. No reports of decreasing clinical efficacy with its protracted use have appeared. The bacterial flora of wounds treated with silver nitrate is principally gram-negative. The overall proportion of sterile wound cultures is about 20 per cent, but most wounds larger than 30 per cent of body surface area eventually become colonized. Silver nitrate may delay colonization for only a few days when wound size exceeds 70 per cent of body surface area. Staphylococcus aureus is recoverable from 30 to 50 per cent of wounds, but its density is generally low and staphylococcal bacteremia is uncommon. Fungal superinfections are rare unless concomitant administration of systemic antibiotics is intense and prolonged. Minimal absorption of silver occurs through open wounds because of the insolubility of its chloride and other biologically important salts that precipitate on the wound. Plasma silver levels are low, rarely exceeding 200 JLg per 100 ml. Moreover, most absorbed silver is excreted through the liver and kidney, the remainder being incorporated by reticuloendothelial cells where it causes no known abnormalities. Argyria does not occur with the topical use of silver nitrate, but care should be taken in patients with facial bums to avoid persistent wetting of the conjunctiva with silver nitrate solution, as permanent discoloration of the conjunctiva (argyrosis) can result. Silver is essentially nonallergenic. Distilled or deionized water must be used as a solvent for silver nitrate solution (29.4 mEq of Ag per liter) to avoid the precipitation of the silver by chloride and other anions. When this hypotonic solution is kept in contact with open wounds, leaching of plasma sodium, potassium, and other electrolytes regularly occurs; 350 mEq or more of sodium per square meter of wound surface area can be lost daily into the dressings. Oral or intravenous supplementation with as much as 20 to 30 gm of sodium
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chloride daily is therefore routinely necessary in patients with extensive injuries; plasma and urine sodium and potassium content must be carefully monitored in order to accurately gauge the necessary replacement therapy. Troublesome diarrhea can occur from the large enteral salt supplements. Many gram-negative bacteria can reduce nitrate to nitrite. Absorption of nitrite through the wound occasionally results in methemoglobinemia. This diagnosis should be made if the skin or wounds acquire a slate-gray or cyanotic color and the blood is brown despite a normal partial pressure of oxygen. Laboratory confirmation of the diagnosis by determination of the percentage of methemoglobin in the blood should be done. Withdrawal of the nitrate is the only treatment necessary in mild or moderate cases. Intravenous administration of reducing agents such as methylene blue or ascorbic acid may be necessary in severe cases; they usually quickly lower the methemoglobin concentration. TECHNIQUE. Since there is little absorption of silver through the eschar, the surface must be scrupulously tended before each application of the dressing. Thick cotton dressings saturated with silver nitrate solution are then applied; they must be wetted at two hour intervals in order to ensure a constant source of silver ions at the wound surface. Dressings are changed once or twice daily. Concentrations of silver nitrate much above 1 to 2 per cent are caustic; undue drying of the dressing as water evaporates from it should be avoided for this reason also. The wet dressing tends to minimize evaporational water loss and its attendant caloric requirement. 8 Silver nitrate does not cause appreciable pain on open wounds, but it stains brown or black everything that it touches; troublesome crusts of silver salts tend to accumulate on uninjured or newly healed skin, from which their removal is tedious. Stain-resistant floor and wall coverings are available but add to cost. In summary, silver nitrate dressings are effective and safe, but the necessity for continuously wet dressings adds appreciably to the cost of the method. Resistant bacterial strains do not frequently emerge. Mineral leaching by the hypotonic solution necessitates careful monitoring of blood electrolytes; hyponatremia can occur rapidly, particularly in infants with extensive burns. Methemoglobinemia is a rare toxic effect that is readily treated by withdrawal of the agent. Silver nitrate is an excellent prophylactic agent, but should not be used for the treatment of true invasive burn wound sepsis.
Mafenide (Paraaminomethylbenzene Sulfonamide Acetate) This drug is available commercially as a 10 per cent preparation in a water-miscible hydroscopic cream base. It was routinely used as a prophylactic agent for burns of all severity in many centers during the past 10 years, but accumulated experience suggests that its use should be restricted to the treatment of invasive burn wound sepsis caused by organisms sensitive to the drug. Mafenide has a large spectrum ofin vitro activity against the common gram-negative burn wound pathogens, including Pseudomonas
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aeruginosa. It also possesses a gram-positive spectrum, which includes the Clostridia, although it has little antifungal activity. Mafenide is not significantly bound by protein or inactivated by wound exudates. Clinically, the initial clinical experience attending its routine use was favorable. Mortality rates were significantly decreased in burns of up to approximately 60 per cent of body surface area, and deaths from burn wound sepsis, especially those caused by Pseudomonas aeruginosa, were infrequent. The mortality attending its routine use was equivalent to that observed with 0.5 per cent silver nitrate or silver sulfadiazine. However, by the early 1970's, reports of superinfection, especially by antibioticresistant Providencia stuartii, began to appear. 2 Fungal superinfection also was recognized to occur with some frequency. Evidently, selection pressure is significant when the drug is routinely used. In addition, it has become apparent that deaths from pulmonary failure related to the toxicity of the drug also are comparatively common. The eventual result in centers where it is routinely used has been a reversion of the mortality rates to that which existed prior to its introduction. Mafenide is readily absorbed from burn wounds. Actually, absorption is so rapid that therapeutic wound concentrations cannot be maintained unless the agent is reapplied at 12 hour intervals. Once applied, the drug is deaminated to its acidic paracarboxy metabolite, which is excreted primarily by the kidneys; mafenide is a strong carbonic anhydrase inhibitor; its application to large wounds promptly results in the alkalinization of the urine. This combination of acid-loading and impairment of renal bicarbonate conservation predictably leads to metabolic acidosis, which is compensated for by hyperventilation. Tachypnea, with a sustained increase in minute ventilation (up to 50 liters per minute) is a result. Static compliance of the lung falls. This compensatory respiratory response regularly attends the use oftopical mafenide. Respiratory failure or pneumonia ultimately results in significant numbers of patients unless the drug is discontinued. Mafenide causes pain on application probably because of its high osmolarity. Another of its undesirable effects that has been demonstrated experimentally is inhibition of spontaneous epithelial regeneration. Despite its numerous and significant disadvantages, mafenide can be used successfully to control invasive burn wound infections, especially when they are relatively localized. The agent should be used for as brief a period as possible and withdrawn promptly when there is evidence of significant systemic toxicity. Careful monitoring of acid base balance and pulmonary function are essential. Its use in patients with preexisting respiratory insufficiency due, for example, to inhalation injury, should be particularly carefully monitored.
Povidone-Iodine Povidone-iodine is a complex of polyvinylpyrrolidone and iodine with a long record of clinical efficacy as an antiseptic for use on normal skin and mucous membranes. It is commercially available for topical use compounded in a water-miscible cream base in which the iodine content
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is 1 per cent. The brown cream is strongly acidic (pH 2.43). Povidoneiodine has an appropriately wide in vitro antimicrobial spectrum. Although it has been recommended for use in moderate and major burns, clinical data documenting its efficacy in suppressing the wound flora in such patients are scant. Similarly, the mortality that attends its use in patients with major burns has not been adequately documented. There is evidence that protein binding of iodine in the open wounds may result in a diminished in vivo antimicrobial effect. Open wounds covered with the brown cream quickly lose that color, evidently the result of absorption. In confirmation of this clinical observation, blood iodine content has been shown to be extraordinarily high. The blood or tissue levels of the polyvinylpyrrolidone moiety of the agent are still unknown. Lethal metabolic acidosis attributed to povidone-iodine renal toxicity has been reported; one of the patients had a relatively small burn of 35 per cent of body surface area. 7 In short, more information is needed concerning the absorption, safety, and efficacy of povidone-iodine before its use in extensive burns can be recommended.
Gentamicin Sulfate Gentamicin is a bactericidal aminoglycoside antibiotic. It is available for topical use as a 0.1 per cent cream or ointment. SysteInically administered, gentaInicin is an agent of proved efficacy in the treatment of gramnegative infections, especially those caused by pseudomonads. Applied topically to open wounds, the drug is readily absorbed; ototoxicity or nephrotoxicity can result. Gentamicin may be useful for brief periods, applied to the smallest possible areas of invasive infection, in which case blood levels of the drug should be carefully monitored. Superinfection with resistant bacterial strains will quickly occur with its protracted topical use. MONITORING EFFICACY OF TOPICAL THERAPY Periodic bacteriological cultures should be used to monitor the efficacy of the topical therapy employed. Culture results, properly interpreted, may be helpful in predicting treatment failure several days before overt clinical evidence of such failure is present. In large injuries, a sampling problem obviously exists no matter what culture method is employed. Swab cultures of burn wounds may adequately sample the wound flora; falsely sterile cultures are comparatively frequent. Additionally, luxuriant overgrowth of some strains may mask the presence of additional ones. Swab cultures give no quantitative information. The gauze capillary surface culture technique is simple, reproducible, and relatively inexpensive, but assesses the surface flora only and is obviously unsatisfactory for the assessment of intraescharotic, subescharotic, or truly invasive infections. In the latter instance, a portion of the wound is best biopsied under sterile conditions and the tissue cultured,
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Table 3. Methods for Bacteriological Assessment of the Burn Wound* METHOD
ADVANTAGE
DISADVANTAGE
Gauze capillarity surface culture Wound biopsy culture (with histologic examination)
Noninvasive, simple, reproducible, quantitative Quantitative, samples crosssection of wound
Samples surface flora only
Swab culture
Simplest, noninvasive, painless
Rapid slide technique for quantitation of bacteria in specimens
Quantitates specimen bacterial density within a few hours
Most expensive, invasive, unsuitable for frequent multiple cultures False negatives, no quantitation, speciation may be incomplete None if rapid quantitation desirable
*Modified from Edlich, R. E., Rodeheaver, G. T., Spengler, M., et al.: Practical bacteriologic monitoring of the bum victim. Clin. Plast. Surg., 4:561-569, 1977.
preferably quantitatively, as well as examined histologically after appropriate staining techniques that permit visual identification of bacteria (Table 3). Routine anaerobic culturing of burn wounds is unnecessary, except in special situations such as high-voltage electrical injury or exceptionally deep thermal burns in which appreciable volumes of devitalized muscle exist. Clostridial and other anaerobic soft tissue infections may occur in this circumstance. Wound cultures should be obtained at least once weekly from either the deepest area of burn or that which clinically has at least satisfactory appearance. In patients with extensive burns, several sites should be cultured at more frequent intervals. The culture results must be interpreted in light of the clinical situation, as they can be misleading if they are not. If the cultures repeatedly indicate that the bacterial density is inordinately high and the clinical situation is consistent with the presence of significant wound sepsis, another topical agent should be substituted. There is considerable evidence that surface densities of greater than 10° per cm 2 (or tissue densities greater than 10" per gm) correlate positively with the invasion of adjacent tissue irrespective of the microbial strain involved. The selection ofthe alternative topical agent should be based on· whether unacceptably dense surface colonization has occurred or whether invasion of adjacent tissue is occurring; in the latter instance an agent known to be absorbed through the wound should be selected and the administration of systemic antibiotics initiated.
SYSTEMIC ANTIBIOTICS Septic episodes and opportunistic superinfections with antibiotic resistant organisms are both a constant hazard during the long convalescence from a major burn. The empiric administration of systemic antibiotics to these generally febrile patients is a continuing temptation. Antibiot-
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ics must of course often be administered and can be of significant benefit; however their use should be restricted to the treatment of specific concomitant infections. Antibiotics are best not regularly used adjunctively with topical agents to treat the resident wound bacterial flora, except for the specific clinical indication (preferably confirmed by bum wound biopsy and culture) that uncontrolled invasive infection is occurring. Beta hemolytic streptococcal burn wound infection, which may be fulminating, tends to occur primarily during the first week post injury. The prophylactic administration of penicillin systemically is highly effective in preventing this infection. Penicillin is usually given routinely during the first post injury week or more for this purpose. Bacteremia is known to result from surgical manipulation of contaminated wounds, including burns. We think it reasonable to administer one dose of an appropriate systemic antibiotic prophylactically several hours prior to scheduled excisional or skin grafting procedures and one additional dose in the immediate postoperative period. Although there are no data specifically confirming the efficacy of this approach in burned patients, a similar practice has been shown to decrease the operative infection rate in other types of trauma and contaminated surgical wounds. Tracheobronchial or pulmonary infections are commonly a reason for the administration of systemic antibiotics. They should be given in full dose for 10 to 14 days according to in vitro sensitivity tests, with monitoring of the peak and trough blood antibiotic levels.
OVERVIEW Topical antimicrobial agents can prevent or minimize infection in bum wounds and should therefore be used in all patients at significant risk, either because of age, associated illness, general debility that is judged to increase the probability of their incurring wound sepsis, or because of the severity of the burn injury itself. All topical agents currently available have shortcomings; some of them have considerable toxicity. It is essential that topical treatment failure be promptly recognized and an appropriate alternative agent substituted if the best possible results are to be achieved. Systemic antibiotics should be used sparingly, but are often necessary to treat pulmonary or other concomitant infections, especially in patients with major injuries. The overall treatment program should minimize the chances of wound microbial contamination. Appropriate metabolic and nutritional supportive treatment is essential.
REFERENCES J. L.: Drug resistance in relation touse of silver sulphadiazine cream in a burns unit. Clin. Pathology, 30: 160-164, 1977. 2. Curreri, P. W., Bruck, H. M., Lindberg, R. B., et al.: Providencia stuartii sepsis: A new challenge in the treatment of thermal injury. Ann. Surg., 177:133, 1973. 1. Bridges, K., and Lowbury, E.
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3. Edlich, R. F., Rodeheaver, G. T., Spengler, M., et al.: Practical bacteriologic monitoring of the burn victim. Clin. Plas. Surg., 4:561-569, 1977. 4. Fox, C. L., Monafo, W. W., Ayvazian, V. R., et al.: Topical chemotherapy for burns using cerium salts and silver sulfadiazine. Surg. Gynecol. Obstet., 144:668-672, 1977. 5. Kiker, R. G., Carvajal, J. F., Mlcak, R. P., et al.: A controlled study of the effects of silver sulfadiazine on white blood cell counts in burned children. J. Trauma, 17: 835-836, 1977. 6. Moncrief, J. A.: Topical antibacterial therapy of the burn wound. Clin. Plast. Surg., 1 :563576, 1974. 7. Pietsch, J., and Meakins, J. L.: Complications of povidone-iodine absorption in topically treated burn patients. Lancet, 280-282, 1976. 8. Shuck, J. M., Moncrief, J. A., and Monafo, W. W.: The management of burns. I. General considerations and the Sulfamylon method. II. The silver nitrate method. Curro Probl. Surg., February, 1969. Department of Surgery St. John's Mercy Medical Center 615 S. New Ballas Road St. Louis, Missouri 63141
Topical Therapy William W. Monafo, M.D., F.A.C.S., * and Vatche H. Ayvazian, M.D., F.A.C.S. t
Burns are prone to infection. The larger the injury, the greater is the risk. Age and general debility both probably add significantly to the propensity to infection; protein-calorie malnutrition, which adversely affects the already impaired immunocompetence of the burned patient, almost certainly does. Most of the considerable morbidity and mortality that attends major burn injury is the result-directly or indirectly-of infection of the wounds by bacteria or fungi. Similarly, morbidity in patients with smaller burns is also largely relatable to infection. Topical antimicrobial agents are indicated in all moderate and major burn injuries, and in many so-called "minor" burns as well. The evidence is overwhelming that, properly used, effective topical agents significantly lessen morbidity and mortality. A burn severe enough to warrant hospitalization of the patient who bears it should be treated with a topical antimicrobial agent, as infection will cause whatever early morbidity is to occur. Bacterial infection may deepen a dermal burn and thus delay spontaneous healing or even cause conversion to a full thickness injury. On the other hand, most fresh, small, superficial burns in outpatients are satisfactorily treated with a simple sterile occlusive dressing which will effectively protect the wound from bacterial contamination. This paper will outline the rationale for the use of topical agents in general, set forth broad criteria for their selection, and describe the advantages and disadvantages of currently available agents.
RATIONALE FOR TOPICAL TREATMENT Burns are ischemic wounds. Confluent thrombosis, which involves arterioles, capillaries, venules, and, at times, even larger vessels, is characteristic of full thickness burns. In partial thickness burns, thrombosis is incomplete; the dermal circulation in the deeper, viable segments of *Chairman, Department of Surgery, and Director, Burn Unit, St. John's Mercy Medical Center, St. Louis; Associate Clinical Professor of Surgery, St. Louis University School of Medicine, St. Louis; Clinical Associate Professor of Surgery, University of Missouri, Columbia, Missouri t Associate Chairman, Department of Surgery, and Associate Director, Burn Unit, St. John's Mercy Medical Center, St. Louis, Missouri
Surgical Clinics of North America-Vol. 58, No.6, December 1978
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AYVAZIAN
the dermis is gradually reestablished within a few days, although the dead, superficial portion of the dermis of course remains avascular. Because of the wound ischemia, systemically administered antimicrobial agents are not reliably delivered to the site where they are needed, as diffusion from the wound periphery for a variable but often considerable distance is their only means of access; moreover the wound surface closest to the heat source is at once the most severely injured and ischemic and as well the original site of most burn wound infections. Antimicrobial agents are therefore best used topically to treat burns.
Prophylactic or Therapeutic? Normal skin harbors few pathogenic bacteria. Most burns are sterile initially, although contamination usually by soil or water may occur after the accident as a result of first aid measures or during transport. When the burns are large (greater than 50 per cent of body surface area), dense colonization by pathogenic bacteria can occur within 24 hours in untreated patients. Adequate topical therapy should therefore be instituted as rapidly as possible following injury. Topical wound therapy in patients with large burns is equally as urgent a need as is fluid resuscitation. The topical treatment initially in most instances is prophylactic; if the original treatment fails and significant wound infection occurs, a different agent should be substituted when that diagnosis is made. Infections may vary in severity from light surface colonization of little clinical significance to a rapidly spreading, necrotizing phlegmon that invades previously unburned tissue-the so-called "burn wound sepsis."
CRITERIA FOR ASSESSMENT OF TOPICAL AGENTS Topical burn therapy likely began at man's first adverse encounter with fire. Before there was knowledge of the existence of bacteria, of the immune response, or of the ischemic nature of the wounds, topical medicaments were intuitively applied to burns both to relieve pain and to encourage kind healing. The wildly empiric remedies of the pre-Listerian era-the gamut ran from pigeon dung to turpentine-were of course excusable because they were conceived in ignorance. Fortunately, enough now is known to permit a rational evaluation of agents currently available or newly proposed for the treatment of burns.
In Vitro Antimicrobial Spectrum The agent must have a demonstrable and appropriately broad in vitro range of activity which should include the gram-negative aerobic intestinal bacteria, Pseudomonas aeruginosa, Staphylococcus aureus, and preferably fungi as well. Should it eventuate that viral burn wound infections are more common than it now appears, this consideration will also become relevant.
Clinical Efficacy The agent should possess a clinical record of efficacy; its effect on the microbial flora of burn wounds of varying magnitude should be
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known; in major burns, the mortality attending use of the agent should also have been documented. Unfortunately, recommendations are still made for the use of agents without such appropriate supportive evidence. The assumption, for example, that an antimicrobial agent that is efficacious in eliminating bacteria from normal skin will be of value when applied to major burn wounds (or even minor ones) is unjustified. Absorption and Toxicity Ideally, a topical agent should penetrate the eschar, yet not be appreciably absorbed systemically. It clearly should not have significant local histotoxicity. There should be knowledge of the rate of absorption of a given agent, the blood or tissue levels reached, the routes of excretion, and the most common toxicity to be expected. The reader will recognize from what follows that these criteria are not wholly fulfilled by some of the agents in common use. Open burn wounds may have a potential absorptive surface of 10,000 cm2 or more. Many once popular topical agents have belatedly been abandoned after it was recognized that significant absorption and, as a result, prohibitive systemic toxicity attended their use. Tannic acid was in vogue for more than 20 years before its hepatic toxicity was generally appreciated. More recently, serious systemic toxicity, including renal and pulmonary failure, has resulted from the topical application on burns of the antibiotics neomycin and gentamicin and of the sulfonamide mafenide; the general use of these relatively toxic agents for topical burn therapy should therefore be sharply restricted. These drugs should be used as briefly as possible, and on the smallest possible wound area, usually not as prophylactic agents, but for the treatment of a specific established infection in order to achieve the desired antimicrobial effect without incurring toxicity. Superinfection Superinfection, which, iffrequent, will eventually result in decreased efficacy is a complication of importance that varies appreciably in frequency depending on the agent in question. Superinfection explains why antibiotics are actually harmful when they are used routinely topically for the prophylaxis of burn wound infections. Since antibiotics act at a specific site on the microorganism, the selection pressure they exert is heavy: resistant strains tend to emerge rapidly. This criterion is pertinent as well to topical burn antimicrobials not in the antibiotic class. One of the major advantages, for example, of 0.5 per cent silver nitrate solution is that the emergence of silver-resistant strains has proved to be infrequent, even when the agent is routinely used for long periods. I Other Considerations Some agents cause local pain, others stain skin or linen, some must be used with exposure, others with dressings. Factors such as flexibility of use, cost, availability, patient acceptance, etc. are usually less important than the foregoing ones, but nevertheless must be considered. In many developing areas of the world, cost is actually a primary con-
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AYVAZIAN
sideration: funds for numerous professional personnel, dressings, etc. are not available.
LIMIT ATIONS OF TOPICAL AGENTS Topical agents are an important part of the burn treatment program but they are not substitutes for meticulous local wound care, or for a carefully planned and executed program of management that leads relentlessly toward the ultimate objective of early permanent wound closure, or for proper metabolic and nutritional support of the patient who bears the wound. Thus sub escharotic abscesses must be promptly unroofed; detritus or devitalized tissue, which may favor the proliferation of microorganisms, should be removed or excised; repetitive microbial inoculation of large wounds by contaminated water or other unrecognized sources will likely eventually result in uncontrollable infection; undue delay in attaining permanent wound closure will by itself increase the risk of infection; and a hypermetabolic patient whose nutritional needs have been inadequately provided for may die of sepsis originating on his wounds. In patients with major injury the potential pitfalls are many indeed. It is generally tempting (but not necessarily more accurate) to ascribe treatment failure to lack of efficacy of the topical agent used rather than to tactical or judgmental errors. On the other hand, the successful use of topical agents prevents the bacterial conversion of deep thermal burns to deeper injury and results in the spontaneous healing of wounds that appeared initially clinically to be full thickness. Truly full thickness burn eschars do not slough within a few weeks in a sea of fetid pus, but remain intact and can be excised THE BURN
INFECTION
EQUATION
MICROBIAL
BURN WOUND
VIRULENCE
\
DENSITY
DEPTH
/
I~"--
TOPICAL THERAPY
~~~
"'"
INVASION POTENTIAL
~
INFECTION
NUTRITIONAL
SURFACE
AREA
/
WOUND SEVERITY
OC MICROBIAL BURDEN HOST RESISTANCE
f \
INTEGRITY
PRE-EXISTING DISEASE
(he:;'~c~~.-:~~~i:~~:y..,c)
Figure 1. The burn infection equation is complex. Successful topical therapy minimizes the bacterial density, as indicated, and may prevent additional, infection related necrosis which deepens the wound.
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TOPICAL THERAPY
and skin grafted, with a reasonable take of the grafts at an appropriate time of election. Exposed granulations appear healthy. Signs of systemic illness, except possibly for fever, which is common and may have a multiplicity of causes in the burned patient, are absent. Nutritional goals can be met regularly because adynamic ileus, the troublesome harbinger of sepsis, is not a recurrent problem. Concomitantly, bacteriological monitoring of the wounds indicates that the flora is relatively homogenous, usually comprising one or two species, and that its density is well below the critical level of lOS per cm2 of wound surface area above which invasive infection becomes a hazard (Fig. 1).
TOPICAL AGENTS The following section discusses those topical agents currently in frequent use, but is not necessarily all-inclusive. The criteria discussed previously should be applied to aid in their selection in a given situation: in vitro and clinical efficacy, toxicity (absorption), superinfection rate, ease and flexibility of use, cost, patient acceptance, and side effects. Since none of the agents is uniformly successful, it may become necessary to substitute a different one on all or part of the wounds at a later stage in treatment. Fortunately, failure with one agent does not preclude success with another. Frequent clinical observations, augmented by properly interpreted bacteriological and other laboratory determinations, facilitate these decisions.
Silver Sulfadiazine Silver sulfadiazine is a poorly soluble compound readily synthesized by reacting silver nitrate with sodium sulfadiazine. It is available commercially, compounded in a "micronized," water-soluble cream base in a concentration of 1 per cent, which provides amounts of the agent well above those necessary in vitro to inhibit the growth of sensitive microorganisms. This concentration was arbitrarily selected because it contains approximately the same amount of silver as does 0.5 percent silver nitrate (30 mEq per liter). The in vitro antimicrobial spectrum of silver sulfadiazine is appropriately wide and includes S. aureus, Enterobacteriaceae, E. coli, and Candida albicans. It is unclear whether the parent silver sulfadiazine molecule itself exerts an antimicrobial effect, or whether its gradual dissociation into silver and sulfadiazine moieties, each of which individually has an effect, is primarily responsible for its activity. Sulfadiazine is a well-known competitive inhibitor of para-aminobenzoic acid. The antimicrobial effect of silver has been variously explained; it likely has multiple sites of action. It has been suggested that silver sulfadiazine acts primarily on bacterial cell walls in which it induces visible ultrastructural changes, and also that bacterial DNA replication may be impaired due to silver (but not sulfadiazine) binding·in that molecule, the sulfadiazine acting merely as a vehicle. Clinically, controlled trials of silver sulfadiazine in both large and small burns have demonstrated that it has highly efficient prophylactic
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AYVAZIAN
value, particularly against gram-negative bacteria. The incidence of sterile cultures is usually in the order of20 per cent in major injuries. Our studies indicate that, used prophylactically, silver sulfadiazine may delay wound colonization by gram-negative bacilli for from 10 to 14 days in extensive injuries, after which the wounds nearly invariably become colonized in moderate density. Treatment failure is frequent, however, when the wound size exceeds 60 per cent of body surface area. The mortality rate attending the use of silver sulfadiazine roughly parallels that observed using 0.5 per cent silver nitrate solution. 6 Silver sulfadiazine has been widely used during the past several years. As already pointed out, an important requirement for the routine use of a topical agent is a stable sensitivity pattern of the principal pathogens to the agent employed. A theoretical disadvantage of silver sulfadiazine is the potential for the emergence of sulfadiazine resistance. This was not reported in the early clinical trials. However, it has lately been suggested that a significant proportion of gram-negative bacilli, particularly Enterobacteriaceae, can become highly resistant to sulfadiazine as a result of its protracted use. This was associated with a reduced prophylactic effectiveness of the agent. Several patterns of antibotic resistance were documented to have occurred as the result of inter-species transfer of resistance plasmids, especially from Enterobacter species, a phenomenon almost certainly due to the selection pressure exerted by the protracted use of silver sulfadiazine. 1 The factors involved in the analysis of such a phenomenon are always complex. Reports of the emergence of resistant strains must always be carefully evaluated epidemiologically, as the repetitive early inoculation of wounds with bacilli resident in drains, hoses, etc. used for hydrotherapy (for example) may overcome the prophylactic effectiveness of any agent and result in an epidemic of "resistant" bacteria. Unchecked, selection pressure exerted by the therapy may in fact eventually result in the emergence of resistant strains and a further decrease in clinical efficacy. Some absorption of sulfadiazine occurs. Blood levels are on the order of 1. 5 to 4 mg per 100 ml, depending on the size of the burn and the interval post injury. Silver absorption is minimal, probably due to local binding at the wound of the insoluble chloride and proteinate salts. Largely because of its poor absorption, significant or persistent toxicity related to silver sulfadiazine is rare, even in extensive burns. This factor has undoubtedly contributed to its popularity. Crystalluria, a well-known toxic effect of sulfonamides, is rare. Transient leukopenia, typically occurrring after the first few days of application, attends the use of silver sulfadiazine in about 5 per cent of patients. 5 In our experience, the leukopenia is ordinarily relative, that is, in the low normal range, but inappropriate to the magnitude of the associated injury, and is rarely absolute. The leukopenia typically spontaneouslyremits despite the continued use of the drug. Since there is no known correlation with septic· episodes, the clinical significance of the leukopenia is moot. Cutaneous sensitivity reactions to silver sulfadiazine occur in 5 per cent or less of patients; they are rarely severe enough to warrant withdrawal of the agent.
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Silver sulfadiazine cream should be liberally applied to the wound, which can then either be left open or covered with a dressing. Exposure of the cream to direct sunlight results in the oxidation of silver to a metallic gray color, but the cream does not stain linen or skin. When silver sulfadiazine is applied to dermal burns, a proteinaceous gel several millimeters thick forms on the surface of the wounds. This "pseudoeschar" can easily be removed in sheets after 72 hours or more.
Cerium Nitrate-Silver Sulfadiazine There is recent evidence that the modification of silver sulfadiazine by the incorporation into it of cerium nitrate strikingly enhances its clinical efficacy. Cerium, one of the lanthanide elements, has a broad in vitro antibacterial and antifungal spectrum. Its potential utility as a topical antimicrobial seemed worthy of investigation in view of the favorable, if imperfect, results observed in the topical treatment of burns during the last decade using silver compounds. Cerium was selected from among the lanthanides, all of which have antimicrobial activity in vitro, because it is readily available, has low toxicity, and is poorly absorbed from open wounds, primarily because of the insolubility ofits phosphate and protein salts. After preliminary animal testing confirmed its safety, cerous nitrate (Ce(N0 3)3· 6H 2 0) was used alone in a clinical trial as a cream incorporated in a water-soluble base. It soon became apparent that gram-negative bacilli were comparatively rarely present on cerium-treated wounds, but that gram-positive bacteria, particularly Staphylococcus aureus, were not as effectively suppressed as when either silver nitrate or silver sulfadiazine had been used. Mortality was essentially the same as with the use of silver nitrate or silver sulfadiazine. These observations led to a clinical trial of simultaneous topical treatment with cerium nitrate-silver sulfadiazine. Commercially available silver sufadiazine cream was modified by stirring into it a concentrated (100 gm per 100 ml) aqueous solution of cerium nitrate so that the final concentration of cerium nitrate was 2.2 per cent (0.05M), whereas that of the silver sulfadiazine was only slightly less than its original 1 per cent. After resultant thin cream was topically applied, the wounds were covered with dressings, except on the face and genitalia. The clinical results during the past two and one half years have been extremely promising. Treatment failures have been few and septic deaths from any cause have occurred only in elderly patients and those with massive (greater than 80 per cent of body surface area) injuries. In vitro experiments indicate that the minimal bactericidal concentration of ionic silver can be reduced approximately threefold by the presence in the medium of ionic cerium in concentration less than that required for a bactericidal effect due to cerium alone. The precise mechanism of action of cerium is not known. Theoretically, the cerium nitratesilver sulfadiazine cream provides four potentially active antimicrobial substances in vivo as ionization proceeds at the wound surface: Ag +, Ce + + +, cerium sulfadiazine (readily synthesized in vitro), and silver sulfadiazine.
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Table 1. The Results of Gauze Capillarity Wound Surface Cultures in 300 Patients Whose Wounds Were Treated with Cerium Nitrate-Silver Su~fadiazine (Wound Bacterial Density Exceeded 10 4 per cm 2 in Only Four Per Cent of These Cultures) NO. OF
NO. OF
NO. OF
NO. OF
QUANTITATIVE WOUND
STERILE
CULTURES YIELDING
PATIENTS
SURFACE CULTURES
CULTURES
GRAM-NEGATIVE STRAINS
300
7126
4023 (57%)
1007 (14%)
Blood cerium levels in patients with major burns treated for many weeks with the cerium nitrate-silver sulfadiazine are less than 10 ILg per 100 m!. Two of 300 patients treated with the agent have evidenced transient methemoglobinemia due to bacterial reduction of nitrate and subsequent absorption, but no other toxicity attributable to cerium has been demonstrated. Bacteriological surveillance of the wounds using the quantitative gauze capillarity surface culture technique has been intensive (Table 1). The incidence of sterile wound cultures has been relatively high, even in patients with extensive injuries; the wound flora is generally comparatively sparse in density. Moreover, the recovery rate of gram-negative bacilli has remained relatively low, on the order of 15 per cent. The mortality data show that the observed death rate is approximately 50 per cent less than that expected, using as a baseline the age-adjusted statistical tabulations of the National Burn Information Exchange or those of Bull and Fisher. Table 2 indicates the observed versus the expected mortalities in this series of patients. Importantly, the apparent reduction in mortality is present in large injuries of from 50 to 80 per cent of body surface area as well as in smaller ones. 4 In summary, the initial results with cerium nitrate-silver sulfadiazine indicate that this agent provides more efficient prophylaxis against gram-negative bacteria than has previously been possible. Not surprisingly, a reduction in mortality of approximately 50 per cent has Table 2. Mortality Observed with Cerium Nitrate-Silver Sulfadiazine Topical Wound Treatment NO. OF BSA (PER CENT)
1 to 20 to 40 to 60 to 80 to
19 39 59 79 100
TOTAL
NO. OF
DEATHS
NO. OF
PATIENTS
OBSERVED
PREDICTED DEATHS
190 53 28 15 14 300
2 2 8 3 11 26
6.5* to 5.4t 9.4 to 10.7 14.5 to 14.7 11.9 to 12.0 13.6 to 14.0 56 to 58
*From Feller, 1., et al.: Baseline results of therapy for burned patients. J.A.M.A., 236:1943-1947, 1976. tFrom Bull, J. P.: Revised analysis of mortality due to burns. Lancet, 2: 1133-1134, 1971.
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resulted. Except for occasional methemoglobinemia, significant toxicity has not been observed. Unless hitherto unrecognized toxicity of this agent is demonstrated, and unless the emergence of resistant strains later proves to be a frequent occurrence, it should prove to be an effective and safe topical prophylactic agent for extensive bums. Silver Nitrate Solution (0.5 Per Cent) One half per cent silver nitrate solution has a long history as a clinically useful antiseptic. It was reintroduced as a topical agent for the treatment of major bums in 1965. Ionic silver has a potent in vitro antimicrobial effect. Its spectrum includes the common bacterial and fungal bum wound pathogens. The emergence of silver-resistant organisms is uncommon, probably because silver inhibits growth by several mechanisms, rather than acting at a single site on the bacterium. Properly used, silver nitrate is an effective prophylactic agent, although its efficacy decreases appreciably when wound size exceeds 50 to 60 per cent of body surface area. Data from several clinics indicate that its routine use prevents death from infection in most instances in otherwise good risk patients with injuries of up to 40 to 50 per cent of body surface area; treatment failure is common however when bum size exceeds 60 per cent of body surface area. No reports of decreasing clinical efficacy with its protracted use have appeared. The bacterial flora of wounds treated with silver nitrate is principally gram-negative. The overall proportion of sterile wound cultures is about 20 per cent, but most wounds larger than 30 per cent of body surface area eventually become colonized. Silver nitrate may delay colonization for only a few days when wound size exceeds 70 per cent of body surface area. Staphylococcus aureus is recoverable from 30 to 50 per cent of wounds, but its density is generally low and staphylococcal bacteremia is uncommon. Fungal superinfections are rare unless concomitant administration of systemic antibiotics is intense and prolonged. Minimal absorption of silver occurs through open wounds because of the insolubility of its chloride and other biologically important salts that precipitate on the wound. Plasma silver levels are low, rarely exceeding 200 JLg per 100 ml. Moreover, most absorbed silver is excreted through the liver and kidney, the remainder being incorporated by reticuloendothelial cells where it causes no known abnormalities. Argyria does not occur with the topical use of silver nitrate, but care should be taken in patients with facial bums to avoid persistent wetting of the conjunctiva with silver nitrate solution, as permanent discoloration of the conjunctiva (argyrosis) can result. Silver is essentially nonallergenic. Distilled or deionized water must be used as a solvent for silver nitrate solution (29.4 mEq of Ag per liter) to avoid the precipitation of the silver by chloride and other anions. When this hypotonic solution is kept in contact with open wounds, leaching of plasma sodium, potassium, and other electrolytes regularly occurs; 350 mEq or more of sodium per square meter of wound surface area can be lost daily into the dressings. Oral or intravenous supplementation with as much as 20 to 30 gm of sodium
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chloride daily is therefore routinely necessary in patients with extensive injuries; plasma and urine sodium and potassium content must be carefully monitored in order to accurately gauge the necessary replacement therapy. Troublesome diarrhea can occur from the large enteral salt supplements. Many gram-negative bacteria can reduce nitrate to nitrite. Absorption of nitrite through the wound occasionally results in methemoglobinemia. This diagnosis should be made if the skin or wounds acquire a slate-gray or cyanotic color and the blood is brown despite a normal partial pressure of oxygen. Laboratory confirmation of the diagnosis by determination of the percentage of methemoglobin in the blood should be done. Withdrawal of the nitrate is the only treatment necessary in mild or moderate cases. Intravenous administration of reducing agents such as methylene blue or ascorbic acid may be necessary in severe cases; they usually quickly lower the methemoglobin concentration. TECHNIQUE. Since there is little absorption of silver through the eschar, the surface must be scrupulously tended before each application of the dressing. Thick cotton dressings saturated with silver nitrate solution are then applied; they must be wetted at two hour intervals in order to ensure a constant source of silver ions at the wound surface. Dressings are changed once or twice daily. Concentrations of silver nitrate much above 1 to 2 per cent are caustic; undue drying of the dressing as water evaporates from it should be avoided for this reason also. The wet dressing tends to minimize evaporational water loss and its attendant caloric requirement. 8 Silver nitrate does not cause appreciable pain on open wounds, but it stains brown or black everything that it touches; troublesome crusts of silver salts tend to accumulate on uninjured or newly healed skin, from which their removal is tedious. Stain-resistant floor and wall coverings are available but add to cost. In summary, silver nitrate dressings are effective and safe, but the necessity for continuously wet dressings adds appreciably to the cost of the method. Resistant bacterial strains do not frequently emerge. Mineral leaching by the hypotonic solution necessitates careful monitoring of blood electrolytes; hyponatremia can occur rapidly, particularly in infants with extensive burns. Methemoglobinemia is a rare toxic effect that is readily treated by withdrawal of the agent. Silver nitrate is an excellent prophylactic agent, but should not be used for the treatment of true invasive burn wound sepsis.
Mafenide (Paraaminomethylbenzene Sulfonamide Acetate) This drug is available commercially as a 10 per cent preparation in a water-miscible hydroscopic cream base. It was routinely used as a prophylactic agent for burns of all severity in many centers during the past 10 years, but accumulated experience suggests that its use should be restricted to the treatment of invasive burn wound sepsis caused by organisms sensitive to the drug. Mafenide has a large spectrum ofin vitro activity against the common gram-negative burn wound pathogens, including Pseudomonas
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aeruginosa. It also possesses a gram-positive spectrum, which includes the Clostridia, although it has little antifungal activity. Mafenide is not significantly bound by protein or inactivated by wound exudates. Clinically, the initial clinical experience attending its routine use was favorable. Mortality rates were significantly decreased in burns of up to approximately 60 per cent of body surface area, and deaths from burn wound sepsis, especially those caused by Pseudomonas aeruginosa, were infrequent. The mortality attending its routine use was equivalent to that observed with 0.5 per cent silver nitrate or silver sulfadiazine. However, by the early 1970's, reports of superinfection, especially by antibioticresistant Providencia stuartii, began to appear. 2 Fungal superinfection also was recognized to occur with some frequency. Evidently, selection pressure is significant when the drug is routinely used. In addition, it has become apparent that deaths from pulmonary failure related to the toxicity of the drug also are comparatively common. The eventual result in centers where it is routinely used has been a reversion of the mortality rates to that which existed prior to its introduction. Mafenide is readily absorbed from burn wounds. Actually, absorption is so rapid that therapeutic wound concentrations cannot be maintained unless the agent is reapplied at 12 hour intervals. Once applied, the drug is deaminated to its acidic paracarboxy metabolite, which is excreted primarily by the kidneys; mafenide is a strong carbonic anhydrase inhibitor; its application to large wounds promptly results in the alkalinization of the urine. This combination of acid-loading and impairment of renal bicarbonate conservation predictably leads to metabolic acidosis, which is compensated for by hyperventilation. Tachypnea, with a sustained increase in minute ventilation (up to 50 liters per minute) is a result. Static compliance of the lung falls. This compensatory respiratory response regularly attends the use oftopical mafenide. Respiratory failure or pneumonia ultimately results in significant numbers of patients unless the drug is discontinued. Mafenide causes pain on application probably because of its high osmolarity. Another of its undesirable effects that has been demonstrated experimentally is inhibition of spontaneous epithelial regeneration. Despite its numerous and significant disadvantages, mafenide can be used successfully to control invasive burn wound infections, especially when they are relatively localized. The agent should be used for as brief a period as possible and withdrawn promptly when there is evidence of significant systemic toxicity. Careful monitoring of acid base balance and pulmonary function are essential. Its use in patients with preexisting respiratory insufficiency due, for example, to inhalation injury, should be particularly carefully monitored.
Povidone-Iodine Povidone-iodine is a complex of polyvinylpyrrolidone and iodine with a long record of clinical efficacy as an antiseptic for use on normal skin and mucous membranes. It is commercially available for topical use compounded in a water-miscible cream base in which the iodine content
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AYVAZIAN
is 1 per cent. The brown cream is strongly acidic (pH 2.43). Povidoneiodine has an appropriately wide in vitro antimicrobial spectrum. Although it has been recommended for use in moderate and major burns, clinical data documenting its efficacy in suppressing the wound flora in such patients are scant. Similarly, the mortality that attends its use in patients with major burns has not been adequately documented. There is evidence that protein binding of iodine in the open wounds may result in a diminished in vivo antimicrobial effect. Open wounds covered with the brown cream quickly lose that color, evidently the result of absorption. In confirmation of this clinical observation, blood iodine content has been shown to be extraordinarily high. The blood or tissue levels of the polyvinylpyrrolidone moiety of the agent are still unknown. Lethal metabolic acidosis attributed to povidone-iodine renal toxicity has been reported; one of the patients had a relatively small burn of 35 per cent of body surface area. 7 In short, more information is needed concerning the absorption, safety, and efficacy of povidone-iodine before its use in extensive burns can be recommended.
Gentamicin Sulfate Gentamicin is a bactericidal aminoglycoside antibiotic. It is available for topical use as a 0.1 per cent cream or ointment. SysteInically administered, gentaInicin is an agent of proved efficacy in the treatment of gramnegative infections, especially those caused by pseudomonads. Applied topically to open wounds, the drug is readily absorbed; ototoxicity or nephrotoxicity can result. Gentamicin may be useful for brief periods, applied to the smallest possible areas of invasive infection, in which case blood levels of the drug should be carefully monitored. Superinfection with resistant bacterial strains will quickly occur with its protracted topical use. MONITORING EFFICACY OF TOPICAL THERAPY Periodic bacteriological cultures should be used to monitor the efficacy of the topical therapy employed. Culture results, properly interpreted, may be helpful in predicting treatment failure several days before overt clinical evidence of such failure is present. In large injuries, a sampling problem obviously exists no matter what culture method is employed. Swab cultures of burn wounds may adequately sample the wound flora; falsely sterile cultures are comparatively frequent. Additionally, luxuriant overgrowth of some strains may mask the presence of additional ones. Swab cultures give no quantitative information. The gauze capillary surface culture technique is simple, reproducible, and relatively inexpensive, but assesses the surface flora only and is obviously unsatisfactory for the assessment of intraescharotic, subescharotic, or truly invasive infections. In the latter instance, a portion of the wound is best biopsied under sterile conditions and the tissue cultured,
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Table 3. Methods for Bacteriological Assessment of the Burn Wound* METHOD
ADVANTAGE
DISADVANTAGE
Gauze capillarity surface culture Wound biopsy culture (with histologic examination)
Noninvasive, simple, reproducible, quantitative Quantitative, samples crosssection of wound
Samples surface flora only
Swab culture
Simplest, noninvasive, painless
Rapid slide technique for quantitation of bacteria in specimens
Quantitates specimen bacterial density within a few hours
Most expensive, invasive, unsuitable for frequent multiple cultures False negatives, no quantitation, speciation may be incomplete None if rapid quantitation desirable
*Modified from Edlich, R. E., Rodeheaver, G. T., Spengler, M., et al.: Practical bacteriologic monitoring of the bum victim. Clin. Plast. Surg., 4:561-569, 1977.
preferably quantitatively, as well as examined histologically after appropriate staining techniques that permit visual identification of bacteria (Table 3). Routine anaerobic culturing of burn wounds is unnecessary, except in special situations such as high-voltage electrical injury or exceptionally deep thermal burns in which appreciable volumes of devitalized muscle exist. Clostridial and other anaerobic soft tissue infections may occur in this circumstance. Wound cultures should be obtained at least once weekly from either the deepest area of burn or that which clinically has at least satisfactory appearance. In patients with extensive burns, several sites should be cultured at more frequent intervals. The culture results must be interpreted in light of the clinical situation, as they can be misleading if they are not. If the cultures repeatedly indicate that the bacterial density is inordinately high and the clinical situation is consistent with the presence of significant wound sepsis, another topical agent should be substituted. There is considerable evidence that surface densities of greater than 10° per cm 2 (or tissue densities greater than 10" per gm) correlate positively with the invasion of adjacent tissue irrespective of the microbial strain involved. The selection ofthe alternative topical agent should be based on· whether unacceptably dense surface colonization has occurred or whether invasion of adjacent tissue is occurring; in the latter instance an agent known to be absorbed through the wound should be selected and the administration of systemic antibiotics initiated.
SYSTEMIC ANTIBIOTICS Septic episodes and opportunistic superinfections with antibiotic resistant organisms are both a constant hazard during the long convalescence from a major burn. The empiric administration of systemic antibiotics to these generally febrile patients is a continuing temptation. Antibiot-
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H. AYVAZIAN
ics must of course often be administered and can be of significant benefit; however their use should be restricted to the treatment of specific concomitant infections. Antibiotics are best not regularly used adjunctively with topical agents to treat the resident wound bacterial flora, except for the specific clinical indication (preferably confirmed by bum wound biopsy and culture) that uncontrolled invasive infection is occurring. Beta hemolytic streptococcal burn wound infection, which may be fulminating, tends to occur primarily during the first week post injury. The prophylactic administration of penicillin systemically is highly effective in preventing this infection. Penicillin is usually given routinely during the first post injury week or more for this purpose. Bacteremia is known to result from surgical manipulation of contaminated wounds, including burns. We think it reasonable to administer one dose of an appropriate systemic antibiotic prophylactically several hours prior to scheduled excisional or skin grafting procedures and one additional dose in the immediate postoperative period. Although there are no data specifically confirming the efficacy of this approach in burned patients, a similar practice has been shown to decrease the operative infection rate in other types of trauma and contaminated surgical wounds. Tracheobronchial or pulmonary infections are commonly a reason for the administration of systemic antibiotics. They should be given in full dose for 10 to 14 days according to in vitro sensitivity tests, with monitoring of the peak and trough blood antibiotic levels.
OVERVIEW Topical antimicrobial agents can prevent or minimize infection in bum wounds and should therefore be used in all patients at significant risk, either because of age, associated illness, general debility that is judged to increase the probability of their incurring wound sepsis, or because of the severity of the burn injury itself. All topical agents currently available have shortcomings; some of them have considerable toxicity. It is essential that topical treatment failure be promptly recognized and an appropriate alternative agent substituted if the best possible results are to be achieved. Systemic antibiotics should be used sparingly, but are often necessary to treat pulmonary or other concomitant infections, especially in patients with major injuries. The overall treatment program should minimize the chances of wound microbial contamination. Appropriate metabolic and nutritional supportive treatment is essential.
REFERENCES J. L.: Drug resistance in relation touse of silver sulphadiazine cream in a burns unit. Clin. Pathology, 30: 160-164, 1977. 2. Curreri, P. W., Bruck, H. M., Lindberg, R. B., et al.: Providencia stuartii sepsis: A new challenge in the treatment of thermal injury. Ann. Surg., 177:133, 1973. 1. Bridges, K., and Lowbury, E.
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3. Edlich, R. F., Rodeheaver, G. T., Spengler, M., et al.: Practical bacteriologic monitoring of the burn victim. Clin. Plas. Surg., 4:561-569, 1977. 4. Fox, C. L., Monafo, W. W., Ayvazian, V. R., et al.: Topical chemotherapy for burns using cerium salts and silver sulfadiazine. Surg. Gynecol. Obstet., 144:668-672, 1977. 5. Kiker, R. G., Carvajal, J. F., Mlcak, R. P., et al.: A controlled study of the effects of silver sulfadiazine on white blood cell counts in burned children. J. Trauma, 17: 835-836, 1977. 6. Moncrief, J. A.: Topical antibacterial therapy of the burn wound. Clin. Plast. Surg., 1 :563576, 1974. 7. Pietsch, J., and Meakins, J. L.: Complications of povidone-iodine absorption in topically treated burn patients. Lancet, 280-282, 1976. 8. Shuck, J. M., Moncrief, J. A., and Monafo, W. W.: The management of burns. I. General considerations and the Sulfamylon method. II. The silver nitrate method. Curro Probl. Surg., February, 1969. Department of Surgery St. John's Mercy Medical Center 615 S. New Ballas Road St. Louis, Missouri 63141
