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Silver sulfadiazine-resistant organisms are arising at an irregular rate and may eventually interfere with wound management. To counter this problem several new antibacterial agents were tested in combination with silver sulfadiazine. Only sodium piperacillin (Pipracil, Lederle) exhibited synergism with silver sulfadiazine both in vitro (against various species of organisms) and in burned animals. The MIC of AgSD and Pipracil was 50 nmole/ml and 250 nmole/ml, respectively, but a combination of 6 nmole/ml of AgSD and 7.5 nmole/ml of Pipracil inhibited the growth of Pseudomonas aeruginosa. In burned mice infected with either AgSD-resistant or sensitive strains, the mortality in groups receiving combinations of topical Pipracil and silver sulfadiazine was 0-10%; in contrast, treatment with Pipracil or silver sulfadiazine alone resulted in much higher mortality. Thus it would appear that a combination of silver sulfadiazine and Pipracil, each of which have long been used in patients topically and parenterally, may prove valuable in patients with burn wound infections related to or caused by organisms resistant to silver sulfadiazine.

Atypical mycobacteria of the fortuitum-chelonei complex are being identified with increasing frequency as causes of resistant, cutaneous infection. We report a case of Mycobacterium fortuitum infection of the face, unresponsive to conventional antimicrobial therapy, which resolved following adjunctive surgical resection. We believe that prompt surgical debridement of affected tissue in such infections, combined with appropriate antimicrobial therapy, will shorten both the duration and morbidity often associated with this disease.

This study was performed in order to investigate serum and tissue silver levels in burns which were used 10 percent silver nitrate as a topical agent. We formed four groups of animals and pulverized 10 percent silver nitrate solution to the first group (GI) that included ten rabbits of which backs were burned by boiling water and silver sulphadiazine cream to second group (GII) with nine rabbits. We carried out 10 percent silver nitrate solution to the first control group (GIII) and silver sulphadiazine cream to the second control group (GIV) each of which had seven animals with unburned skin. We obtained blood samples from every animal before and after application of topical agent on the 1st, 3rd, 7th, 15th, 21st and 28th. We determined serum and tissue silver levels by atomic absorption spectrophotometer in kidney and liver of the animals which were sacrificed on the 28th day. In first and second groups we found that serum silver values reached on 3rd day to the maximum level and then the values decreased gradually. We also determined that diminution of the serum silver levels were prominent following on 15th day. It was shown that there was no silver in the serum on 28th day except four animals. The silver deposition in the liver was much more than in the kidney. Between these two groups there was significant difference neither in the serum on the same days nor the tissue silver levels. According to these data it was concluded that serum and tissue silver levels with 10 percent silver nitrate used in burns produced no difference from that of 1 percent silver sulphadiazine cream.

A randomized trial of three treatment methods for the ambulatory management of minor burns in children has shown Op-site to be superior. The dressing is cost-effective and well tolerated, with the advantage that children can return to their normal activities without jeopardizing the healing process.

Topical chemoprophylaxis of extensive burns with silver sulphadiazine cream led to a large increase in the proportion of sulphadiazine-resistant Gram-negative bacilli in a burns unit. When all sulphonamide treatment in the ward was stopped; the incidence of sulphonamide-resistant strains fell back to levels similar to those recorded when silver sulphadiazine treatment was introduced. This was associated with a large reduction in the incidence of resistance of certain Gram-negative bacilli (especially Klebstella sp) to several antibiotics. Transferable resistance to sulphadiazine, shown by conjugation experiments with Escherichia coli K12, was found in a majority of the strains of Klebsiella sp tested, and in other species. A pattern of transferable resistance to tetracycline, cephaloridine, chloramphenicol, ampicillin, carbenicillin, and sulphadiazine (T Ce Cl A Ca S) was found in four of the 22 strains of Klebsiella tested, and closely related patterns were transferred by five other strains. These patterns of resistance were commonly found in Klebsiella sp isolated from burns in the period before the withdrawal of sulphonamides from the ward but were found in none of the Klebsiella strains isolated in the first six months after that period. Strains of Acinetobacter and Proteus, in which transferable resistance was not found, showed no appreciable fall or rise in sulphadiazine resistance; there was no fall in resistance of these organisms to tetracycline, cephaloridine, chloramphenicol, ampicillin or carbenicillin on withdrawal of sulphonamides from the ward, but there were substantial falls in resistance of Acinetobacter to kanamycin, gentamicin, trimethoprim, and tetracycline which were probably not caused by the withdrawal of sulphonamides.

We report the results of a prospective study of 45 burn patients in whom serum and urine levels of cream constituents (sulfadiazine and propylene glycol) were determined and correlated with clinical parameters and the presence of an immune response to sulfadiazine. Propylene glycol, measured by gas chromatography, was found in the serum of 53% of study patients. Sulfa, determined by spectroscopy, was found in the serum of all patients, with values as high as 9.1 mg/dl within 24 hours of topical application. Ninety percent of tested patients had circulating sulfadiazine antibodies, predominantly IgG. Fourteen patients died, 11 of whom had interpretable renal biopsies. Five of these biopsies showed positive immunofluorescent linear or granular staining for IgG, IgM, IgA, or C'3; none of these 5 patients had clinical evidence for the nephrotic syndrome. The association between antisulfadiazine antibodies, circulating immune complexes, immunoglobulin disposition on glomerular basement membranes, and topical application of silver sulfadiazine provides evidence for sulfadiazine sensitization in patients with severe burns.

The superior efficacy of quinolones (norfloxacin, pefloxacin, and enoxacin) in controlling burn wound infections signals the discovery of new topical agents. However, there are a few reports on the emergence of resistant mutants to quinolones. Since attempts to develop AgSD resistant strains in vitro were unsuccessful and the emergence of AgSD resistance in vivo is a rare occurrence, we decided to investigate if the combined use of AgSD with other effective antibiotics, especially quinolones, would minimize the development of resistant bacteria. Our in vitro results indicate that when Ps. aeruginosa cultures were serially transferred 10 times through subinhibitory concentrations of norfloxacin, pefloxacin, etc., the MIC increased 40 times while when the cultures were passed through a combination of AgSD and these quinolones, the MIC of quinolones increased only tenfold. In vivo, when burned mice infected with either AgSD sensitive or resistant Ps. aeruginosa strains were treated with a topical cream containing 10mM silver sulfadiazine and 5mM norfloxacin or 5mM pefloxacin, the mortality was much lower than that of 10mM silver sulfadiazine alone or 5mM quinolones alone. Thus, combined use of silver sulfadiazine and quinolones appears to diminish the ability of Ps. aeruginosa strains to form resistant mutants. Furthermore, when the combination is used as a topical agent in burn wounds, lesser amounts of the individual drug are needed to control infection thereby reducing the toxic effects, if any, associated with these drugs. This combination does not in any way interfere with the antifungal or antibacterial properties of these individual drugs.

These experimental data indicate that cerium compounds exert a measurable antimicrobial action in vitro. In vivo the simultaneous use of cerium sulfadiazine and silver sulfadiazine was more effective than silver sulfadiazine alone or the combination of cerous nitrate and silver sulfadiazine. When cerous nitrate was used clically, gram-positive bacteria predominated. In contrast, wounds exposed to silver salts alone harbor a predominately gram-negative flora. The combination of cerous nitrate and silver sulfadiazine appears to provide a broad spectrum inhibitory to both types of organisms. It is apparent that a sampling problem exists in any attempt to monitor wounds that may exceed a square meter in extent. These bacteriologic data pertain only to the surface flora. The need to culture tissue samples of burn wounds has been emphasized. Our experience, however, is that invasion of deep tissue without dense surface colonization, greater than 10(5), is infrequent. Furthermore, fragments of eschar were submitted regularly for culture; those results confirmed the surface culture findins. The characteristic yellow-green color of cerium nitrate treated eschars may results from oxidation of trivalent cerium to yellow ceric ions. Free silver and sulfadiazine ions are available also in small amounts because of limited ionization of the highly insoluble silver sulfadiazine. This might promote the in vivo formation of cerous sulfadiazine and would provide a continuous source of ionic cerium for microbial inhibition. The modification of silver sulfadiazine cream by incorporating cerous nitrate into it strikingly enhances its topical antiseptic effect in burn wounds without increasing toxicity.

The advantages of treatment with betadine and glycerol are: cost containment of agent and dressings, ease of observing wounds, reduction of direct nursing care and, most importantly, reduction of ward epidemics, especially Pseudomonas. Major disadvantages are increased time to grafting, potential psychological effects on patients and visitors upon viewing the wounds and the relatively minor pain during application.

Silver sulphadiazine has been used as a topical antimicrobial agent in a large group of children with burns and scalds. Four developed neutropenia and two an erythema multiforme rash which were thought to be due to sulphadiazine sensitivity. To assess the extent of sulphadiazine absorption in children, the urinary excretion was measured in a group of 8 patients with a mean area of injury of 13 per cent BSA. The mean urinary concentration of sulphadiazine was 31.8 mg/l.

In a prospective, randomized study of 34 patients with thermal burns, treatment with the topical agent Cerium nitrate-silver sulfadiazine was compared with therapy with silver sulfadiazine alone. Despite randomization, there was a significant difference in mean burn size, being larger in the silver sulfadiazine group. There was no significant difference between the two groups in clinical course, mortality, septic deaths, or quantitative microbiology of the burn wound. It is concluded that from these preliminary data no clearcut superiority for one cream over the other can be demonstrated at this time.

Forty-six neonates with omphaloceles seen at the Children's Hospital and Medical Center in Seattle from 1975 to 1985 were reviewed. There was an 87 percent survival rate in those surgically managed. The 23 neonates who underwent primary closure all survived. The 13 neonates with giant omphaloceles with the liver in the defect who received silon chimneys had a 46 percent mortality rate and a high complication rate, with prolonged hospitalization. Two neonates with giant omphaloceles were managed by leaving the sac intact, and silver sulfadiazine cream was used as an escharotic agent. We believe it is a safer alternative than the silon chimney in neonates whose defects cannot be closed primarily.

A controlled trial of the use of either 0.05 per cent chlorhexidine for bathing burn wounds or the topical application of a cream containing cerium nitrate and silver sulphadiazine showed that the cerium-flamazine cream significantly reduced the degree of Pseudomonas aeruginosa contamination of the burn wounds of patients with burns covering more than 15 per cent of the body surface area. The adherent eschar produced by treatment with cerium-flamazine provided a satisfactory wound cover until tangential excision could be carried out.

Much progress has been made in recent years in the field of topical burn therapy. Preparations are now available which meet most of the requirements for ideal topical agents and further improvements have been demonstrated. However, much work has to be done to find even better products, in particular agents that are sufficiently inexpensive, so that they could well be used in countries with limited resources for medical care.

The large mass of devitalized tissue that comprises the burn eschar is gradually becoming recognized as the principal source of complications in the burn patient. Clinical observations suggest that the topical agent silver sulfadiazine does not penetrate the eschar sufficiently to prevent bacterial infection from becoming established in the deeper levels of the wound but does penetrate to a depth of approximately 1.5 mm in bactericidal concentrations. A new technique that takes advantage of this fact, early laminar excision, has been developed at the Children's Hospital of Michigan Burn Center. The eschar is excised layer by layer with the electric dermatome under general anesthesia within the first 72 hr post burn, and the thickness of the devitalized tissue is reduced to a remnant of less than 1 mm. This is less than the depth to which silver sulfadiazine is capable of penetrating in bactericidal concentrations, and greatly enhanced control of burn wound sepsis is achieved. Early laminar excision of the eschar, combined with silver sulfadiazine dressings, aggressive resurfacing of the wound, and increased emphasis on nutrition, is an approach to management of the victims of thermal trauma that should significantly improve survival in patients with burn injuries greater than 60% body surface area.

A retrospective chart review was conducted of 5418 culture and sensitivity reports from 93 paediatric burn patients to determine profiles of wound flora and invasive organisms, trend analysis and patterns of antibiotic resistance. Coagulase-positive Staphylococcus was the predominant burn wound pathogenic isolate and the predominant invasive organism for burns less than 60 per cent BSA. Pseudomonads were the predominant invasive organism for burn wounds greater than or equal to 60 per cent BSA. Only 7 per cent of all pathogenic isolates were fungi. A significant association was demonstrated between increasing burn size and an increasing incidence of Gram-negative and invasive organisms. Silver sulphadiazine remains a very effective topical agent for the control of bacterial and fungal growth in burn wounds after 10 years of intensive use in this burn unit. Pseudomonad isolates were routinely multi-drug resistant. Pseudomonad isolates from wounds treated topically with a silver sulphadiazine-cerium nitrate mixture were frequently resistant to aminoglycosides, colistin and carbenicillin. It is concluded from this review that severe restrictions on antibiotic usage within burn units, and strict internal environmental control within burn units may help to decrease the incidence of nosocomial resistant strains and cross infection. Regular monitoring of burn wound flora, and the protocol for wound care used in treating these patients have been effective in preventing septic episodes and death due to sepsis.

The improvement in infusion therapy of burn patients in the last decades has led to a marked reduction of the early mortality rate and to an increase in the importance of severe wound infection and septicaemia. For the control of infection, detailed bacteriological monitoring is recommended. The main therapeutic fields for prevention of infection are: immunotherapy, antisepsis, aseptic techniques, and rapid restoration of the destroyed body surface. The most important part of antisepsis in burns is topical treatment. The good bacteriological and clinical results with povidone-iodine (PVP-I), in combination with open treatment are described. A possible disadvantage of this therapy was the extensive iodine resorption. However, no disorders of thyroid function were revealed, and the TRH test indicated no abnormal reactions of the hypothalamus-pituitary axis. The high serum and urine iodine levels returned rapidly to normal after discontinuing the PVP-I application.

One hundred patients with superficial burns were treated by the exposure method under ordinary ward conditions. Topical 1% Silver Sulphidiazine ("Flamazine") was used under controlled conditions. The exposure technique, with judicious local cleaning, resulted in spontaneous healing in 42% of cases. Topical "Flamazine" was used in 58% of cases. It was found to be soothing, giving patients instant relief of pain. It arrested crack and fissure formation with bleeding, especially in burnt areas in the neck and about major joints. It expedited healing; an astringent effect was also observed. It was concluded that the exposure technique, with topical "Flamazine", was beneficial in the treatment of superficial burns, obviating the routine daily bathing of the burnt.

Topical therapy is a selective approach to the prevention and treatment of infection in burns and other surgical wounds. Effective compounds possess certain chemical and physical properties. Prerequisites include low solubility, slow absorption, nonreactivity with wound exudates, proteins and ions and ability to achieve prolonged antimicrobial activity in the wound. These compounds yield much higher levels in the zone of infection than can be achieved by diffusion into the wound after systemic administration. The wide spectrum of antibacterial activity, the low toxicity, minimal tissue reaction, ease of application suggest that topical silver sulfadiazine therapy can safely be extended to other wound infections, wound covers and certain transplant materials.

The attachment of Ag110-labeled sulfadiazine silver (AgSU) to the burn wound of humans and full and partial thickness scald burns of rats was studied over time. The duration of Ag adherence to burned skin and the absorption and organ distribution of ingested AgSU was studied. Peak attachment to human burns was 1% of the administered dose in 24 hours. Rat wounds showed greater attachment. Dissections of the wounds showed 81% to 98.7% of this attachment to be in the most superficial layers of cells and no silver was observed in organs of surface-treated animals. Duration of attachment after one application was until wound slough with percent attachment dropping from 5% to 1.7% over that time. Oral ingestion resulted in substantial silver deposition, particularly in liver and lungs. Clearance occurs in three weeks. The basic function of AgSU may be through the slow release of silver into the superficial wound environment.

Using a standardized laboratory rat model of burn wound sepsis, a regimen of once a day application of Silvadene has been found to be more effective treatment than Sulfamylon or cerium-Silvadene. Delaying treatment following infection resulted in decreased survival. Possible reasons for difference in mortality are once-daily application, or perhaps a change in sensitivity between drugs and the infective organism (Ps. aeruginosa) over time.

Seven hundred and twenty-five children were hospitalized in the paediatric burn unit of Brugmann University Hospital during the past 10 years. The majority of the patients were under 5 years of age and presented with scalds on less than 10 per cent of the body surface area. As burn depth was difficult to assess on admission, a conservative form of treatment was performed including a daily bath containing chlorhexidine and silver sulphadiazine dressings. Contamination of the wounds was observed in 80 per cent of the larger than 20 per cent surface burns but only 18 cases (2.4 per cent) of the series needed administration of systemic antibiotics for repeated contamination. No lethal septicaemia was observed. Mean inpatient time ranged between 16 days for ungrafted patients to 69 days for over 20 per cent surface grafted patients. The lower iatrogenic risks (anaesthesia and donor site morbidity) seemed important enough to justify conservative treatment in children despite a slightly longer hospitalization time.

A retrospective study was undertaken to examine the incidence and clinical significance of enterococcal bacteremia in burned patients with enterococcal burn-wound infections. During a 26-month period from 1983 to 1985, 38 patients were found to have enterococcal burn-wound infections. Twenty of these patients developed positive blood cultures for enterococcus with no other identifiable source for the bacteremia. Cases occurred sporadically during the study period without evidence of a specific epidemic. Ten patients died within ten days of the bacteremia, while nine others eventually died from other complications. Only one patient survived to discharge. Prior antibiotic therapy did not appear to increase the risk for enterococcal infection, and specific therapy against the enterococcus after the bacteremia was identified appeared to have no effect on mortality. Mortality was significantly greater for bacteremic patients than for patients with enterococcal wound infection alone or for burned patients without enterococcal infections. Although previously not considered pathogenic, enterococcal burn-wound infections should prompt aggressive therapy to prevent the development of enterococcal sepsis with its associated high mortality.

In this study, we investigated the effects of a combination of topical Cyclosporin A (CyA) and silver sulphadiazine on infected and normal skin allografts in burned and unburned rats. Buffalo (Buf) allografts on unburned Lewis (Lew) recipients survived 16.8 +/- 0.9 days after a 10-day course of topical CyA and silver sulphadiazine, as compared to 7.4 +/- 1.1 days for untreated allografts and 18.6 +/- 0.9 days for those receiving CyA only for 10 days. Allografts infected with Pseudomonas aeruginosa and placed on burned recipients survived significantly longer (13.7 +/- 1.1 days) when treated with silver sulphadiazine and topical CyA for 7 days compared to a similar group of animals treated with silver sulphadiazine alone (8.4 +/- 1.0 days). The mortality rate for burned, infected and allografted animals receiving no medication or topical CyA was 50 per cent compared with zero in animals treated with silver sulphadiazine only or combined silver sulphadiazine and topical CyA.

A randomized controlled study was undertaken to compare the effectiveness of three umbilical cord treatment regimens in controlling neonatal bacterial colonization. The regimens studied included daily application of castile soap, triple dye and silver sulfadiazine. The triple dye and silver sulfadiazine regimens inhibited bacterial colonization. Staphylococcal colonization was inhibited most effectively by triple dye treatment. Group B streptococcal colonization was equally inhibited by triple dye and silver sulfadiazine. Silver sulfadiazine was more effective in controlling colonization with gram-negative microorganisms.

Using the methods and protocol outlined, we have found that hyperbaric oxygen functions as a mild antiseptic agent and provides no advantage in the treatment of full-thickness and partial-thickness burns, alone or in combination with topical treatment with silver sulfadiazine. No effects were observed on metabolic balance in the postburn state determined by percentage of weight change, the time to complete healing in partial-thickness burns or the rate of eschar separation and vascular proliferation in granulation tissue formation in full-thickness burns.

The results of this study indicated that there were no statistically significant differences between the effectiveness of 1% silver sulfadiazine in DMSO and 1% silver sulfadiazine in a hydrophilic base (Silvadene), when these formulations were used as antimicrobials applied topically to thermal burn wounds. The antimicrobial efficacy of silver sulfadiazine was not destroyed by mixing this agent with DMSO, since the recovery of Pseudomonas aeruginosa was significantly lower in all animals treated with silver sulfadiazine, whatever the formulation, when compared to animals not treated with silver sulfadiazine. Further studies with higher concentrations of silver sulfadiazine in DMSO may be useful. Although the concept of DMSO as a medicinal "carrier" is not novel, with further investigation, it may prove to be germane in the treatment of eschar-covered thermal burns.

In an effort to find an enzyme preparation for chemical debridement of burns, we treated 463 burn patients with Sutilains ointment (Travase) from 1972 through 1975. This method allowed earlier application of the first skin graft and resulted in a shorter hospital stay without significantly altering mortality compared with results obtained before 1972 and with national results. Travase appears to be effective in the treatment of burn patients when used in this method.

Burn shock in infants and children is satisfactorily treated by the initial intravenous administration of balanced hypertonic sodium solutions; monitoring of plasma sodium and/or osmolarity permits necessary adjustment of the sodium concentration of administered fluids. This approach has been safe. Its principal advantage is in minimizing acute gains in body weight, which may be alarming otherwise, especially in children. Clinical and bacteriological data are presented indicating that cerium nitrate-silver sulfadiazine cream is a highly efficient topical antiseptic agent for both major and minor burn wounds and that it has low toxicity. Cerium nitrate-silver sulfadiazine cream can be readily employed in any clinical setting.

Oxygen consumption (VO2) and colonic temperature (Tc) were measured in groups of rats before and after 30% total body surface, full thickness burns. Some wounds were seeded with Pseudomonas aeruginosa or Staphylococcus epidermidis, and some seeded wounds were treated with Sulfamylon or Silvadene. Three groups became bacteremic (B) during the 2-3 week period of observation. At an ambient temperature (Ta) of 32 C, VO2 of the B group rose from 0.83 +/- 0.01 to 1.20 +/- 0.01 ml/hr/g (mean +/- S.E., p less than 0.001) versus 0.81 +/- 0.01 to 0.99 +/- 0.02 for nine nonbacteremic (NB) groups (p less than 0.001). Tc increased only in the B groups--from 36.8 +/- 0.1 to 37.7 +/- 0.1 C (p less than 0.001). In the second or third week postinjury, VO2 of the NB rats was reduced when Ta was increased to 34 C; Tc followed changes in Ta. Sulfamylon lowered VO2 of P. aeruginosa seeded, NB rats. The metabolic cost of wound contamination appeared to vary with bacterial strain. The metabolic effects of infection appear to be a continuum, beginning with a modest rise in VO2 and progressing to greater increases in VO2 and Tc with wound invasion and systemic infection.

The overwhelming majority of burns are minor and can be treated on an ambulatory basis if hospitalization is not indicated. Recommended are topical antimicrobial agents in the acute phase and pressure garments after wound healing. Sound principles of burn wound management determine the ultimate outcome of treatment, the degree of function and the cosmetic appearance of the healed wound.