Topical Sulfamylon cream inhibits DNA and protein synthesis in the skin donor site wound.

BACKGROUND: Whereas Sulfamylon is effective in treatment of burn wound infection, controversy exists regarding its effect on the healing process. METHODS: A partial thickness skin donor site wound was created on the back and indwelling catheters were placed in the carotid artery and jugular vein in rabbits under general anesthesia. Sulfamylon cream (8.5%, BERTEK Pharmaceuticals Inc., Morgantown, W Va) was applied on the wound, with either open or occlusive dressing. The control wound was covered with dressings only. On day 7 after injury, stable isotope tracers were infused to determine the fractional synthetic rate (FSR) of DNA, and FSR and fractional breakdown rate (FBR) of protein in the wound. RESULTS: In the Sulfamylon-open dressing group, the DNA FSR was 1.3 +/- 0.6%/day, the protein FSR was 8.0 +/- 3.5%/day, and the net protein deposition (FSR - FBR) was -0.3 +/- 3.7%/day. These values were lower (P < .01 to .05) than the corresponding values in the control group (DNA FSR: 2.9 +/- 0.9%/day; protein FSR: 20.5 +/- 8.4%/day; net protein deposition: 7.9 +/- 6.0%/day). Sulfamylon cream selectively inhibited DNA FSR from the de novo base synthesis pathway (2.3 +/- 1.2 vs 0.8 +/- 0.5%/day, P < .05 vs control). With the occlusive dressing Sulfamylon cream did not decrease wound DNA FSR due to a stimulation of the base salvage pathway, but still decreased protein FSR (11.5 +/- 5.1%/day, P < .05 vs control). Histologic slides indicated that Sulfamylon cream inhibited re-epithelialization, collagen formation, and angiogenesis in the wound. CONCLUSIONS: Topical Sulfamylon cream application inhibited DNA and protein synthesis in the wound, which would be expected to retard the healing process.

Opportunistic infections in severely burned patients.

The risk of infection in burn patients, which is proportional to the extent of burn, reflects the combined effect of impairment of all aspects of the host defense system and microbial factors. The microbial flora colonizing the burn wound changes with time following injury and provides the organisms causing infections in burn patients. The temporal pattern of the predominant gram-negative organisms causing infections in a burn unit resembles that of a succession of mini-epidemics necessitating an active program of microbial surveillance to guide treatment of infections. Topical chemotherapy has significantly reduced the occurrence of invasive burn wound infections, but microbial control is imperfect and the burn wound, as well as the patient as a whole, must be closely monitored (using wound biopsies as indicated) to diagnose and treat infection in a timely manner. The treatment of burn wound infections is guided by extent and depth of microbial invasion, density of microorganisms, and systemic changes. As a manifestation of immunologic impairment, infection in sites other than the burn wound remains the most frequent cause of death in burn patients. The use of broad spectrum serologic agents to enhance immuno-competence in extensively burned patients may reduce the occurrence of life threatening opportunistic infections.

Evaluation of a prototype therapeutic system for prolonged, continuous topical delivery of homosulfanilamide in the management of Pseudomonas burn wound sepsis.

The ability of homosulfanilimide (HS) delivered from two different dressing vehicles to limit bacterial proliferation was evaluated in burned animals deliberately infected with virulent Pseudomonas organisms. Treatment consisted of once daily topical application of one of two vehicles: (1) an experimental prototype system that utilized micronized HS in a hydrophobic, bioerodible, polymeric matrix, impregnated on a fabric backing; or (2) a commercially available dressing that contained the same mass of drug in a hydrophilic cream base impregnated on the same backing. Wounds on control animals were covered with fabric backing with or without the bioerodible matrix. The experimental system was designed to maintain a finite local concentration of HS on the burn wound for at least 24 hours. It is known that the cream base presents a rapidly decreasing concentration of drug to the burn surface. HS delivered from the experimental system produced a significant reduction in deaths compared with the HS delivered from the cream base. In addition, the new method of delivering HS provided better control of local and systemic infection, and better wound hydration and also promoted earlier eschar separation. The experimental system was at least as convenient to apply as the cream and had an advantage with respect to inspection of the wound, since it could be removed and reapplied easily.

Studies of the pain produced by mafenide acetate preparations in burns.

In a double-blind triple cross-over clinical study, 37 patients were exposed to several formulations of mafenide acetate (Sulfamylon Cream) and their pain responses were recorded and converted to a semiquantitative pain index. The 11.2% concentration in cream was two to three times more painful than the 5% concentration. Hypertonicity and not the pH level appears to be the cause of the pain produced by the high (11.2%) concentration. The tonicity of the cream carrier and 11.2% mafenide acetate are 1,080 mOsm/kg and 1,100 mOsm/kg, respectively, for a total of 2,180 mOsm/kg. The carrier cream without glycerol and a 5% concentration of mafenide cream were much less painful than the 11.2% concentration of mafenide. Both afforded a great deal of relief to the patients who received the medications.

Fungal burn wound infection. A 10-year experience.

To evaluate our experience with fungal burn wound infection, we performed a 10-year review for comparison with our experience with bacterial burn wound infection. During the study period, a marked decline occurred in bacterial wound infection but not in fungal wound infection. Patients with either bacterial or fungal burn wound infection had massive injury, with burn size averaging greater than 50% of the total body surface area. Factors that appear to have markedly reduced bacterial burn wound infection, including patient isolation, topical chemotherapeutic agents, and burn wound excision, do not appear to have had a similar effect on fungal wound infection. The mechanism of spread and colonization of fungi, and the lack of effective topical chemotherapeutic antifungal agents, may explain in part our findings.

Effects of topical antimicrobial agents on the human neutrophil respiratory burst.

The neutrophil oxidative burst plays an important role in killing intracellular microorganisms. We studied the effects of topical antimicrobial agents on the N-formyl-L-methionyl-L-leucyl-L-phenylalanine-stimulated oxidative burst of human peripheral blood neutrophils, using a flow cytometric assay. Mafenide acetate, sulfadiazine silver, gentamicin sulfate, neomycin sulfate-polymyxin B sulfate (Neosporin GU irrigant), acetic acid, amphotericin B, and povidone-iodine inhibited the neutrophil oxidative burst at or below clinical concentrations, while 0.25% modified diluted sodium hypochlorite (Dakin's) solution caused cell death. Bacitracin-polymyxin B sulfate (Polysporin) greatly augmented the respiratory burst; this effect was due to the bacitracin component. Diluted gentamicin and acetic acid also augmented intracellular hydrogen peroxide production, but to a lesser extent than Polysporin. Inhibition of the respiratory burst of neutrophils might be considered when these agents are used for topical wound care, although clinical correlates of these effects have not been determined.

Inhibition of Pseudomonas burn wound infection by mafenide dry foam.

The results of an in vivo evaluation of 8.5% mafenide dry foam are described. Using burned guinea pigs infected with Pseudomonas aeruginosa, mafenide was applied every 12 hr as the dry foam or as the commercially available ointment. After 156 hr of therapy with the medicated dosage forms, the previously infected areas did not demonstrate the presence of Pseudomonas. However, all nonmedicated, infected controls produced positive cultures. Both medicated dosage forms demonstrated equivalent efficacy in the inhibition of Pseudomonas on burn wounds.

Comparison of silver sulphadiazine 1 per cent, silver sulphadiazine 1 per cent plus chlorhexidine digluconate 0.2 per cent and mafenide acetate 8.5 per cent for topical antibacterial effect in infected full skin thickness rat burn wounds.

Silver sulphadiazine 1 per cent (SS), silver sulphadiazine 1 per cent plus chlorhexidine digluconate 0.2 per cent (SS + CD 0.2 per cent) and mafenide acetate 8.5 per cent (MA) were compared to assess the antibacterial effect of once daily application on experimental rat 20 per cent full skin thickness burn wounds seeded 24 h earlier with 10(8) microorganisms originally isolated from infected wounds of burned patients. Separate series evaluated Staph. aureus, Enterococcus faecalis, Enterobacter cloacae and Ps. aeruginosa. The mean concentration of all four organisms recovered after 1 week from full thickness biopsies of eschar and from separate biopsies of subjacent muscle was less in MA and SS + CD 0.2 per cent treated animals compared with those treated with SS alone. The mean concentration in muscle and eschar following treatment with MA was less for wounds seeded with Staph. aureus and Ps. aeruginosa than with SS + CD 0.2 per cent treatment, while the mean concentration in eschar application of SS + CD 0.2 per cent was less than with MA for E. faecalis seeded wounds.

An in vivo comparison of topical agents on wound repair.

Selection of the ideal antiseptic or antimicrobial treatment for contaminated wounds remains a controversial decision. Clinical decisions are often made on the basis of in vitro studies and personal preference. Although topical solutions are widely used, their comparative in vivo effects on wound healing are largely unreported.A porcine wound model was used to compare five commonly used topical agents-5% mafenide acetate (Sulfamylon solution), 10% povidone with 1% free iodine (Betadine), 0.25% sodium hypochlorite ("half-strength" Dakin), 3% hydrogen peroxide, and 0.25% acetic acid-with a control group. Reepithelialization, angiogenesis, neodermal regeneration, fibroblast proliferation, collagen production, and bacterial colony counts were analyzed at 4 and 7 days after wounding (n = 4). Reepithelialization was not significantly influenced among the various treatment modalities tested. Sulfamylon and Dakin solutions significantly increased neodermal thickness (p < 0.05), whereas hydrogen peroxide and acetic acid significantly inhibited neodermal formation (p < 0.001). All treatments except hydrogen peroxide significantly increased fibroblast proliferation. Sulfamylon and Betadine significantly enhanced angiogenesis (p < 0.05). Sulfamylon proved most effective in maintaining an aseptic environment while concomitantly increasing angiogenesis, fibroblast proliferation, and dermal thickness compared with control. These data show that selection of a particular topical treatment can affect various aspects of wound repair in an animal model. These results suggest that the selection of topical treatments in the clinical setting should be carefully tailored to match unique wound situations and therapeutic endpoints.

Use of 5% sulfamylon (mafenide) solution after excision and grafting of burns.

In previous reports, 5% sulfamylon solution has been utilized on unexcised burns and granulation tissue. We prospectively evaluated 67 burn patients to determine graft take and the incidence of side effects with use of sulfamylon solution dressings after excision and grafting. Of patients excised and grafted, the mean graft take for a total of 100 procedures was 86%. Rash occurred in 18% of patients and sulfamylon was discontinued with no sequelae. Twenty-five percent had at least one positive fungal wound culture, yet only 3% required treatment for candidemia. Those patients who developed a rash and fungal colonization had a significantly larger percent burn and were treated with sulfamylon for a longer period of time. Pain intensity was rated on a Visual Analog Scale with a mean score of 2.4; in no case was the pain considered severe enough by the patient to terminate treatment. Acidosis was present in 3% of patients but felt to be unrelated to the sulfamylon treatment. As an antimicrobial agent, 5% sulfamylon solution is a viable alternative for fresh autografts with excellent graft take and acceptable side effects.

Preventing postoperative burn wound aspergillosis.

Between January 1, 1984, and December 31, 1988, 35 patients at the Los Angeles County + University of Southern California Burn Center had postoperative cultures from their burn wounds that grew Aspergillus species; clinical burn-wound aspergillosis occurred in 66% of these cases and death occurred in 53% of these cases. Beginning in November 1984, several modifications in the air-conditioning system and topical antimicrobial wound therapy were undertaken. Cleaning and 8Cu-quinolinolate treatment of air ducts every 2 months did not reliably clear Aspergillus species from the air in patient care areas. Several changes in topical therapeutic regimen failed to prevent both burn wound culture positivity and clinical aspergillosis. Finally, installation of high-efficiency particulate air filters, installation of new air ducts, and inception of wound irrigation with a solution of mafenide hydrochloride plus nystatin both during and after operation were associated with a reduction in wound culture positivity rate to one occurrence in 1988 (Poisson probability less than 0.01 versus the rate in 1984) and no occurrences during the 18 months after the false ceiling of the burn ward was sealed.

The management of burns under conditions of limited resources using topical aqueous sulfamylon (mafenide) hydrochloride spray.

The burn unit establishment in a Vietnamese military hospital (1970 to 1971) is an example of the management of burns under conditions of limited resources. The problems encountered and methods used in their solution are still relevant. This is the first (and possibly still the only) instance of such clinical use of topical Sulfamylon (mafenide) aqueous spray as the sole pregraft antibacterial agent for patients with deep partial-thickness and full-thickness burns (and associated injuries). The mafenide spray open treatment resulted in a bacteriostatic film permitting eschars to remain uninfected while more superficial burns healed and general status improved, enabling delayed grafting to be effective. Use of operating rooms, supplies, and personnel was minimized. The study group contained 211 patients; 86 (approximately 40%) had burns that exceeded 20% body surface area, and 26 (approximately 12%) had burns that exceeded 40% body surface area. As the procedures became fully established, all of the last 110 patients of this series survived. Only 17 deaths occurred in the total series; none were attributed to infection.

Topical sulfamylon reduces engraftment of cultured skin substitutes on athymic mice.

Sulfamylon (mafenide acetate) remains extremely valuable for the control of the bacterial contamination of burn wounds, but it is cytotoxic to cultured keratinocytes used for wound closure. Because composite skin substitutes develop a partial epidermal barrier in vitro, they may hypothetically tolerate the use of topical Sulfamylon. To test this hypothesis, cultured skin substitutes were prepared from cultured human fibroblasts; keratinocytes were attached to these collagen-based substrates, which were grafted to full-thickness wounds in athymic mice (n = 8 per group). Wounds were irrigated twice daily with 5% (wt/vol) Sulfamylon solution or with a formulation of noncytotoxic antimicrobials (0% Sulfamylon). On day 9 after grafting, the wounds were treated with dry dressings and assessed at 4 weeks for expression of human leukocyte antigens-A, B, C and at 2, 3, and 4 weeks for percentage of original wound area and surface electrical capacitance in picofarads (pF). Data were analyzed for statistical significance (P < .05) by Fisher's exact test, Student's t test, and repeated measures analysis of variance: [table: see text] The data demonstrate that irrigation of cultured skin substitutes with a solution of 5% Sulfamylon results in smaller wound area, fewer wounds that contain human cells, and greater surface hydration (higher surface electrical capacitance) than irrigation with noncytotoxic antimicrobial agents. These results support the conclusion that cultured skin substitutes of this type do not tolerate the chemical toxicity of Sulfamylon as well as skin autografts. Further improvements in the properties of the epidermal barrier of cultured skin substitutes may facilitate the use of Sulfamylon or other potent antimicrobial agents for the management of microbial contamination during engraftment of transplanted skin cells.

Five percent mafenide acetate solution in the treatment of thermal injuries.

A 5% mafenide acetate solution was used in the treatment of 669 patients with thermal injuries. This solution was used as the initial topical antibacterial agent in the treatment of the acute burn wound in 276 patients. It was initiated during the intermediate and chronic phases of burn wound therapy in 393 patients. Acid-base derangements did not occur. Discontinuation of therapy because of the patient's pain was necessary in fewer than 1% (17 of 669) of all patients treated. The incidence of rash and pruritus was extremely low. Effective antibacterial activity was achieved. This solution appears to be an effective, safe, and versatile antibacterial agent that produces minimal side effects and is useful in all phases of burn wound management.

Does the addition of nystatin to 5% mafenide acetate and genitourinary irrigant solutions interfere with their antimicrobial activity? Assessment by two topical antimicrobial test assay systems.

Results previously reported using the Wet Disc Topical Antimicrobial Assay (WDA) suggested that adding nystatin (NY) to a 0.5% mafenide acetate (MA) suspension or genitourinary irrigant (double antibiotic [DAB]) to expand their antimicrobial activity to include Candida sp. antagonized the antibacterial effect of MA but not DAB. We use DAB solution as described by the authors of the previous study, also, but we use a 5% commercially available mafenide acetate solution instead of the in-house prepared 0.5% mafenide acetate suspension that they used. Further, we use both the WDA and the Agar Well Diffusion Topical Antimicrobial Assay (AWDA) to test topical antimicrobials at this institution. In light of the previously reported results, this study 1) examined whether adding nystatin to DAB or the 5% mafenide acetate solution used at this institution caused any interference in the ability of these substances to migrate through the agar matrices and cause zones of growth inhibition in the two test assay systems and 2) compared the assessment of microbial susceptibility (by very precise definition) between the two systems. The addition of nystatin did not interfere with the ability of either DAB or mafenide acetate to migrate through the agar matrices and cause clear zones. However, on the assessment of susceptibility a significantly larger number of organisms were judged susceptible using the AWDA than the WDA. We believe that the disparity is caused by a large difference in agar diffusion kinetics between the two assays. Therefore, we recommend the AWDA rather than the WDA for susceptibility studies.

The use of 5% mafenide acetate solution in the postgraft treatment of necrotizing fasciitis.

Twenty-nine patients with necrotizing fasciitis who were treated with 5% mafenide acetate solution (MAS) as an adjunct after grafting were compared with 45 patients treated without MAS. Statistical analysis of differences was obtained through P values by chi2 testing. The MAS+ (M) and MAS- (C) groups were similar in percent skin deficit (M = 7.5%; C = 9.8%), with the extremity being the most common area of infection. Streptococcus was the most common single organism but polymicrobial infections were the most prevalent (M = 48%; C = 58%). Patients with necrotizing fasciitis treated with MAS had fewer debridements per patient (M = 3.7; C = 5.4), fewer closure procedures (average per patient: M = 1.2; C = 1.73) and a higher percent of first-time closures (83 vs 59%; chi2 = 4.26; P = 0.039). There is a trend toward a lower mortality rate (3.4 vs 13%; chi2 = 2.00; P = 0.158). We conclude that MAS is a useful adjunct in necrotizing fasciitis wound care protocols.

In vitro susceptibility testing of topical antimicrobial agents used in pediatric burn patients: comparison of two methods.

One hundred and seventy-seven bacterial isolates obtained from pediatric burn victims were tested for in vitro susceptibility against bacitracin, silver sulfadiazine, mafenide acetate, nitrofurazone, and mupirocin by two methods: standard microbroth dilution and Nathan's agar well diffusion (NAWD). Nitrofurazone had the broadest spectrum of activity. Mupirocin was the most potent agent against methicillin-susceptible Staphylococcus aureus. Silver sulfadiazine showed activity against gram-positive organisms and higher minimum inhibitory concentration (MIC) values, and smaller zone sizes were seen for methicillin-resistant S. aureus and gram-negative bacilli. Bacitracin showed activity against S. aureus and Streptococcus pyogenes by the microbroth method; activity could not be assessed by NAWD. Mafenide acetate had the highest MICs for all isolates tested. Correlation between methods for all isolates tested was best for mupirocin and nitrofurazone. NAWD was labor intensive and difficult to interpret; MIC method was easy to perform and reproducible. Clinical correlation is necessary to establish breakpoints for interpretation of test results.

Topical mafenide hydrochloride aqueous spray in initial management of massive contaminated wounds with devitalized tissue.

Since at least WWII, some open, contaminated wounds involving massive soft tissue injury and vascular damage have resulted in "irreversible shock," despite prompt rescue, hemorrhage control, and blood and fluid replacement, without signs of clinical infection. In animal studies, survival time was related statistically to the dosage of Clostridium perfringens in multicontaminated explosive wounds. Survival time was lengthened by the application of some topical antibacterial agents, but actual recovery was achieved only with topical mafenide hydrochloride solution aqueous spray, which resulted in negative clostridium. perfringens cultures. Although not related statistically to survival time, the mafenide hydrochloride spray also controlled the Pseudomonas aeruginosa in these wounds. Mafenide hydrochloride had the American trade name of Sulfamylon from about 1942 until 1998, when another pharmaceutical company patented Sulfamylon as the trade name for mafenide acetate, a weaker antibacterial agent. However, mafenide hydrochloride still is available from chemical companies. Mafenide hydrochloride solution spray has been used successfully in treatment of patients with severe by contaminated wounds and deep burns, and its use in initial care should be revisited.

A simple cost-saving measure: 2.5% mafenide acetate solution.

The optimal concentration of mafenide acetate solution for use in the treatment of burns is unknown. Despite data supporting the use of a 2.5% solution, 5% formulation is traditionally used, and has been the highest-costing medication on formulary. The aim of the current study is to evaluate cost and patient outcomes associated with a new policy implementing the use of 2.5% solution in burn patients and restricting the 5% formulation to specific indications only. A retrospective review of all patients receiving mafenide acetate solution at a single pediatric burn hospital was performed before and after the initiation of the new policy on the use of 5 vs 2.5% solution. Duration of therapy, adverse events, cost, incidence of wound infection, and bacteremia were analyzed. In 2009, 69 patients were treated with 5% mafenide acetate solution for a total cost of $125,000 ($1811 per patient). In 2010, after the initiation of the policy, 48 patients were treated: 19 received 5% mafenide acetate solution with appropriate indication, whereas the remaining 29 received 2.5% solution for a total cost of $38,632 ($804 per patient). There were no significant changes in the incidence of bacteremia or wound infection. No side effects of either solution were noted. Under certain conditions, a 2.5% mafenide acetate solution appears sufficient. In this multinational pediatric burn hospital, the use of a 2.5% solution was not associated with increased bacteremia or wound infection, and proved to be more cost-effective.

In vitro toxicity and activity of Dakin's solution, mafenide acetate, and amphotericin B on filamentous fungi and human cells.

OBJECTIVES: Posttraumatic invasive fungal infections threaten critically injured combat-related injuries and require a combination of extensive surgery and systemic antifungal therapy, along with topical antimicrobials used adjunctively to control the infection. We evaluated the in vitro activity of topical agents in varying combinations and concentrations against molds from patients that were responsible for wound invasive fungal infections and the topical agents' toxicity to human cells. METHODS: Mafenide acetate solutions (2.5%, 5%, and 7.5%), amphotericin B solutions (2 µg/mL, 2 mg/mL, and 20 mg/mL), SMAT (5% mafenide acetate in combination with 2 µg/mL, 2 mg/mL, and 20 mg/mL amphotericin B), and Dakin's solutions (buffered sodium hypochlorite) (0.5%, 0.25%, and 0.125% and 10-fold serial dilutions of 0.25%-0.00000025%) were evaluated for antifungal activity against 4 molds using a time-kill assay using standard conidial suspensions of 5 × 10(4) colony-forming units per milliliter. To assess cellular toxicity, confluent monolayers of human keratinocytes, dermal fibroblasts, and osteoblasts were exposed to these topical agents. Based upon efficacy and toxicity ratios, an additional 10 molds were screened with selected concentrations of the topical agents for antifungal activity and toxicity. RESULTS: All the topical agents seemed to have a dose-dependent killing with only mafenide acetate showing time killing associated with prolonged contact. There was overall evidence of dose-dependent cytotoxicity of the various topical agents against the various cell lines tested, but there did not seem to be increased cell death with continued exposure to the agents over time. Dakin's solution exhibited dose-dependent toxicity and efficacy with 0.00025% appearing to optimize those parameters. CONCLUSIONS: Mafenide acetate and amphotericin B did not seem to persistently meet the toxicity and efficacy balance as consistently as Dakin's solution.