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Objective: Thermal burn is a serious cause of morbidity and mortality that affects millions of people worldwide. The aim of this experimental study was to investigate the efficacy of Arnebia euchroma (AE) to treat burn wounds in a rat model., Method: A total of 80 male rats (200-250g) were shaved over the back of the neck (2×3cm 2 ) and a second-degree burn wound was induced at this site under general anaesthesia. The rats were then randomly assigned to one of four groups (each n=20) and the burns were treated daily for 14 days as follows: (1) dressed with animal fat; (2) dressed with sulfadiazine; (3) dressed with a mixture of AE and animal fat; (4) no treatment (control). Five rats from each group were sacrificed on days 3, 5, 9 and 14 post-burn and the wounds were evaluated histologically and immunohistochemically for the expression of interleukin (IL)-1 and IL-6., Results: There was a significant increase at day 3 and decrease on day 5 samples for the expression of IL-1 in the AE plus fat group and IL-6 in the AE plus fat and sulfadiazine groups, compared to the control and fat treatment groups, respectively. Both AE plus fat and sulfadiazine treatments reduced inflammation and granulation tissue formation by day 5 post-burn, while re-epithelialisation commenced by day 9 post-burn. In addition, burns treated with AE plus fat exhibited keratinised epidermis, associated with regular collagen fibres, compared to moderately dense collagen fibres without vascularisation in the sulfadiazine group., Conclusion: These findings suggested that AE plus fat was superior to sulfadiazine in enhancing burn wound healing in rats.

Two new zinc sulphadiazine (Zn(SD)2)-amine complexes, zinc sulphadiazine-methylamine (Zn(SD)2(CH3NH2)2) and zinc sulphadiazine-ethylenediamine (Zn(SD)2(C2H8N2)3.H2O), were prepared and compared with silver sulphadiazine (AgSD). The compounds were readily obtained by reaction of zinc nitrate hexahydrate with sulphadiazine or its salt in methylamine and ethylenediamine, respectively. Structure was established by X-ray crystallography and ultraviolet-visible, infrared and nuclear magnetic resonance spectroscopy. The products were effective, in-vitro, against Gram-positive and Gram-negative bacteria as well as fungus. However, their activity is partially reversed by p-aminobenzoic acid. Further investigations in burned mice revealed that these compounds displayed a potential value in the prevention and treatment of wound healing, and diminution of mortality and weight loss. The toxicity of Zn(SD)2 derivatives was much lower than that of AgSD. The better aqueous solubility and skin permeability may explain the reason for their superiority over AgSD in the efficacy for topical therapy. Zn(SD)2(CH3NH2)2 was consistently more potent and was chosen for further development in clinical uses. The similarity in complexation between Zn(SD)2(CH3NH2)2 and AgSD may be significant to distinguish that from any other Zn(SD)2 derivative in bioactivity.

The effect of zinc sulfadiazine (ZnSD) and silver sulfadiazine (AgSD) on reducing plaque formation and gingivitis was studied in 12 beagle dogs over a 14-week period. 12 beagle dogs were scaled, root planed and pumiced to bring them to a similar level of gingival health, prior to placing them on a diet of Purina Dog Chow softened with canned gravy and molasses to promote the build-up of plaque and the initiation of gingivitis. At the end of 8 weeks, the dogs were determined to have substantial bacterial plaque accumulation and apparent gingivitis. Thereafter, 4 dogs were treated 2 x daily with topical applications of 3% zinc sulfadiazine; 4 dogs were treated with 2% silver sulfadiazine while 4 dogs were treated with placebo gel serving as control over a 14-week treatment period. By week 2, the zinc and silver sulfadiazine dogs showed a significant decrease in gingival index which was maintained throughout the study. Additionally, by week 2, the % of sites with bleeding was also seen to decrease significantly in the experimental groups. The plaque index remained consistent in all 3 groups until week 6 when the 2 experimental groups indicated significant decrease in plaque accumulation as compared to controls. Probing depths were also seen to decrease significantly in the experimental groups after 10 weeks of therapy. The mean stain index was similar in all 3 groups of dogs throughout the study. Data indicate that both zinc and silver sulfadiazine inhibit plaque formation and reduce existing gingivitis in beagle dogs.

The effect of zinc sulfadiazine (ZnSD) and silver sulfadiazine (AgSD) on developing plaque formation and gingivitis was studied in 12 beagle dogs over a 14-week period. Plaque and gingival indices were used to measure plaque formation and gingivitis. During a 2-wk baseline period each dog was brought to optimal gingival health with prophylaxis and tooth brushing. Thereafter, 4 dogs were treated twice daily with topical application of 3.0% zinc sulfadiazine; 4 dogs were treated with 2.0% silver sulfadiazine while 4 dogs treated with placebo gel served as controls over a 12-wk treatment period. At wk 2 of treatment, all three groups of dogs showed an increase in plaque build-up on their teeth from baseline. By wk 6, plaque accumulation on the teeth was significantly less in dogs treated with either ZnSD or AgSD compared to control dogs. At wk 2 of treatment, gingival inflammation was increased from baseline in all three groups. Thereafter, over the course of the 12-wk treatment period, gingival inflammation in the ZnSD and the AgSD treated dogs was significantly less than the placebo treated dogs. The data indicate that both ZnSD and AgSD inhibit developing plaque formation in beagles. This significant inhibition of plaque formation was accompanied by a significant reduction in gingival inflammation.

Reducing the quantitative level of bacterial contamination in an open, acute or chronic, soft tissue wound below the critical level of 10(5) bacteria per gram of viable tissue is essential to delayed primary closure. First step in the management of the contaminated or infected wound is accurate local debridement, preferably with pulsating jet irrigation. Topical antibacterial agents, specifically silver sulfadiazine cream, are then usefully employed to reduce the bacterial count. Contrary to systemic antibiotics, these agents penetrate adequately into the open, granulating wound with a direct bacteriostatic or bactericidal action on a wide spectrum of gram positive and negative organisms, without the effect of local tissue injury typical of topical antiseptics. The use of topical antibacterials, traditionally confined to the treatment of the burn wound, the open "difficult" wound for excellence where control of local infection is first priority, provides a rapid local reduction of the bacterial level and paves the way to the final goal of primary delayed closure of the wound, either direct or with the use of grafts or local, distant, or free flaps.

One percent silver sulfadiazine has been commonly used as a topical antimicrobial agent after a burn injury. Incidence of burn wound colonization by Staphylococcus aureus in patients treated with silver sulfadiazine has spurred research for other agents. A topical preparation that contains zinc and sulfadiazine (Zad-G) was evaluated for in vitro antibacterial spectrum and in vivo efficacy. Muscle biopsy specimens of rats treated with Zad-G appear to have fewer colonies of S. aureus than groups treated with silver sulfadiazine. Topical therapy with Zad-G for patients with burns was comfortable, reduced wound infection, and was comparable to therapy with silver sulfadiazine. A topical Zad-G preparation that contains zinc sulfadiazine appears to be an effective alternative to silver sulfadiazine in the treatment of burn wounds.

A randomized, prospective study comparing the use of Biobrane (group 1) with the use of 1% silver sulfadiazine (group 2) in treating 56 partial-thickness burn wounds was carried out in 52 outpatients with burns that comprised less than 10% of their total body surface area. The two groups were similar in age, gender, race, and extent of burn. Wounds of patients in group 1 (30) were compared with those of group 2 (26) for healing time, pain, compliance with scheduled visits, and costs. Infected and skin-grafted wounds were excluded from healing time analysis. Infection rates of the two groups were similar (three of 30 vs two of 26). One patient in each group underwent skin grafting. Healing times of group 1 wounds were significantly less than those of group 2 (10.6 +/- 0.8 vs 15.0 +/- 1.2 days, P less than .01). Using a pain scale of 1 to 5, Biobrane-treated patients averaged lower pain scores at 24 hours after the burn (1.6 +/- 0.8 vs 3.6 +/- 1.3 P less than .001) and used less pain medication. Compliance with scheduled outpatient visits was also improved in the Biobrane-treated group (88.6% vs 63.2% attendance, P less than .001). Idealized total treatment costs averaged $434 for patients in group 1 compared with $504 for patients in group 2. We conclude that when used on properly selected wounds, Biobrane therapy can significantly decrease pain and total healing time without increasing the cost of outpatient burn care. Improved patient compliance may be an added benefit.

Wound care is painful for the patient with a burn injury and tedious for the burn unit staff but necessary to remove exudates and debris and to limit infections. In an effort to circumvent daily dressing changes while ensuring optimal wound protection, Sildimac (Marion Laboratories, Kansas City, Mo.), a new drug delivery system for silver sulfadiazine, was developed. When silver sulfadiazine, a topical antimicrobial commonly used for the treatment of burns, is incorporated into the delivery system, the drug is released in a sustained fashion. We report here the results of a multicenter evaluation of the safety and efficiency of Sildimac for treatment of full-thickness burn wounds. Sildimac, when left in place for up to 4 days, appears to be as effective as twice-daily wound cleansing and application of Silvadene cream 1% (Marion Laboratories, Kansas City, Mo.) for the treatment of full-thickness burns.

Silver sulfadiazine, in cream form, has been mostly used in the treatment of burns. Its trial in the treatment of leg ulcers has been satisfactory. This preparation is well tolerated, and effective on wound cleansing and granulation tissue formation. It is particularly indicated in cases of superinfected ulcers, effective on most Gram + and Gram - bacteria.

The presence of bacteria and local infection is an important factor in the local management of chronic pressure ulcers. For successful closure of the ulcer, the bacterial count should be 10(5) or less per gram of tissue in the granulating wound. In a prospective randomized study of 45 (eventually 40) hospitalized patients, silver sulfadiazine (Silvadene) cream and povidone-iodine (Betadine) solution were compared to physiologic saline for effectiveness in preparing pressure ulcers for closure. Quantitative bacteriologic techniques on tissue biopsy specimens were used for objective evaluation. In 100 percent of the ulcers treated with silver sulfadiazine cream (15 patients) the bacterial counts were reduced to 10(5) or less per gram of tissue within the three-week test period, compared to 78.6 percent in those treated with saline (14 patients) and 63.6 percent in those treated with povidone-iodine solution (11 patients). Moreover, the ulcers treated with silver sulfadiazine cream responded more rapidly, with one-third showing bacterial levels of less than 10(5) within three days, and half within a week.

The antimicrobial activity of cerium nitrate and silver sulfadiazine was assessed in vitro and in vivo using Pseudomonas aeruginosa. In vitro, the activity of silver sulfadiazine was significantly greater than that of cerium nitrate. Synergism between silver sulfadiazine and cerium nitrate was observed in water or saline solution suspensions, but not in broth. In vivo, cerium nitrate offered no therapeutic benefit in reducing wound infection in contaminated wounds. Treatment of similar wounds with silver sulfadiazine resulted in a significant decrease in wound infection and in the level of viable bacteria when compared with that for untreated controls. The addition of cerium nitrate to silver sulfadiazine in aqueous soultion reduced the therapeutic benefit of silver sulfadiazine.

The effect of drug-loaded synthetic dressings on the contraction, epithelialization, and collagen synthesis of deep second-degree burns was followed for 21 days in 44 guinea pigs. Two symmetrical burns were inflicted on the back of each animal; the animals were then divided at random into the following test groups: Group 1 (n = 10), a prefabricated, precut, pliable, and noncracking dressing designated as Dimac (DM), versus Dimac plus 2% silver sulfadiazine (DM+); Group 2 (n = 10), Hydron loaded with 2% silver sulfadiazine (HAgS) one versus fine mesh gauze and 1% silver-sulfadiazine cream (GAgS); Group 3 (n = 12), Hydron (Hyd) versus fine mesh gauze (G); Group 4 (n = 4), fine mesh gauze versus Telfa (Tel); Group 5 (n = 6), Telfa versus Telfa; Group 6 (n = 2), gauze versus gauze. Epithelialization and contraction rates were measured at dressing changes on postburn days 6, 12, 18, and 21, with a computerized sonic digitizer. Collagen biosynthesis was measured from the wound scar on PBD 21 and expressed as relative collagen biosynthesis. Contraction on PBDs 18 to 21 was significantly lower (p less than 0.05) in the DM and DM+ treated burns. Epithelialization of the DM and DM+ treated groups on PBD 21 was significantly (p less than 0.05) higher than in the Hyd, HAgS, GAgS, and Tel treated burns, and did not differ from the G treated wounds. The relative collagen biosynthesis method was inapplicable to this burn wound model.

Topical antibacterial treatment is of major importance in the burn patient. Silver sulfadiazine is an effective agent with low toxicity and few side effects. Deposition of silver in tissues, and absorption of sulfadiazine are both minimal. Present and future problems are represented by the emergence of resistant Gram negative bacilli, including Pseudomonas aeruginosa. The development of related metal sulfadiazines to be used against resistant bacteria is on an investigational stage, and clinical trials are few. Silver sulfadiazine may be used in a variety of other conditions than burns.

Compared to nonoperative treatment with silver sulfadiazine cream, early excision and grafting of 22 patients with indeterminant burns of less than 20% TBSA resulted in an average shorter hospitalization, lower cost, and less time away from work than 25 patients treated nonoperatively. While early excision and grafting resulted in increased use of blood products and operating room facilities, this did not result in increased patient morbidity. Long-term followup demonstrated no difference in need for reconstruction, incidence of blisters, incidence of loss of motion, or contour irregularities. Those patients treated nonoperatively required more late grafts for closure and demonstrated more hypertrophic scarring. Those treated by early excision demonstrated more mesh graft irregularity. We conclude that in otherwise healthy patients with dermal burns of indeterminant depth less than 20% total body surface area, early excision and grafting is the preferred form of treatment.

Infection is an uncommon but unfortunate complication of prosthetic arterial bypass grafting. Because previously described methods of treatment of such infections which do not involve excision of the graft have not met with uniform success, we undertook a study of the efficacy of silver sulfadiazine cream in the treatment of Staphylococcus aureus infections of polytetrafluoroethylene carotid artery bypass grafts in dogs. At the time of bilateral grafts placement in 14 dogs, wounds were inoculated with at least 2 X 10(7) organisms. Three days later all wounds were opened. The wounds of seven dogs were treated with daily applications of silver sulfadiazine cream and the wounds of the other dogs were treated with daily applications of povidone iodine ointment. The dogs were sacrificed at 30 days or at the earliest evidence of arterial beeding from the wounds, whichever came first. Cultures of the wound were taken, and graft and artery histologic findings were studied at the time of sacrifice. Although survival of the dogs treated with silver sulfadiazine was marginally better than that of the dogs treated with povidone iodine, viable bacteria were present in microabscesses in many apparently healed wounds in the former group. We conclude that daily applications of silver sulfadiazine cream does not reliably eradicate staphylococcal infections involving polytetrafluoroethylene arterial bypass grafts.

Analysis of 300 consecutive hospitalized children with burns. To prevent infection, patients are given a bath with chlorhexidine (0.03%) every day and their burns covered by silver sulfadiazine (1%) and occlusive dressings. In 5.3% of the children positive swabs were obtained during hospitalization and in only 2.3% on several occasions. No case of septicemia could be documented.

The addition of 1% chlorhexidine digluconate to 1% silver sulfadiazine cream (CDSS) was compared with 1% silver sulfadiazine (SS) alone to assess the antibacterial effect of a once-daily application of the therapies on an experimental rat model with a 20% full-thickness burn wound seeded with 10(8) microorganisms originally isolated from infected wounds of burn patients. Separate series evaluated Staphylococcus aureus, Pseudomonas aeruginosa, Enterobacter cloacae, and Streptococcus faecalis. The mean concentration of all four organisms recovered after one week from biopsy specimens of full-thickness eschar was less in the CDSS-treated animals compared with the SS-treated animals. Microbial invasion into subjacent muscle was less frequent in animals seeded with S faecalis, while the mean concentration of bacteria recovered from muscle of animals seeded with S aureus and E cloacae was less in animals treated with CDSS compared with those treated with SS (P less than 0.05). The addition of 1% chlorhexidine digluconate to 1% silver sulfadiazine increased the antibacterial effectiveness of the latter agent.

This is a case report of a patient who developed severe drug eruptions suspected to have been caused by sulphamethoxazole-trimethoprim (ST) administered orally for the treatment of urinary infection after burn injury. He had been treated topically with silver sulphadiazine (AgSD) after injury. The immunological examinations revealed positive reactions to both drugs, so that it is surmised that AgSD created the sensitivity and might be concerned in these drug eruptions. For such reasons, it is advisable, especially in patients who have been previously treated with topical or oral sulphonamides or have had episodes of hypersensitivity to such drugs, to administer sulphonamides carefully, or if possible to avoid administration.

Silver and cerium in the liver and the kidney from severely burned infant were analyzed by neutron activation method. The patient was treated topically with cerium nitrate/silver sulfadiazine cream and cerium nitrate solution for 3 months. Then, the treatment with these drugs was stopped because of abdominal distention. The patient died 1 month after the cessation of the treatment with these drugs. The tissue specimens, blank liver sample and reference standards were irradiated with TRIGA MARK II Reactor of Rikkyo University. About 1 month after the irradiation, the activities were measured with a Ge(Li) detector coupled to a 4096 channel pulse height analyzer. A large amount of silver was detected both in the liver and in the kidney and a trace of cerium only in the liver. A considerable amount of silver was detected in the liver and its quantity was about 1600 times more than that of normal livers reported by Hamilton, Minski and Cleary (1972-73). Neither silver nor cerium were detected in the blank liver. These results suggest that prolonged topical chemotherapy of cerium nitrate/silver sulfadiazine cream and cerium nitrate solution for the extensive burn injuries causes considerable absorption of silver and cerium into the liver and the kidney.

A clinical trial was devised to determine whether the healing of partial thickness burns was retarded by the use of silver sulphadiazine cream (SSD) compared with simple, non-bacteriocidal dressings. Biopsy-confirmed partial thickness burns of at least 2% confluent area were dressed according to a strict protocol to compare the rate of epithelialisation of the control dressing, tulle gras, with that obtained with the use of silver sulphadiazine. The same comparative dressing regimen was carried out on a series of split thickness graft donor sites. Twenty such donor sites and fifteen burn areas were admitted to the trial. The mean time to healing of SSD-treated burn areas was longer than that for tulle gras; the difference when analysed by paired t-test was statistically significant (p less than 0.05). There was very little difference in the compared healing rates of the donor sites, which implies that SSD does not retard epithelialisation of dermal depth injuries but rather that the delayed healing is a unique response of the partial thickness burn wound to the presence of SSD. A review of the relevant literature is included in the discussion.

Silver sulphadiazine has been applied to the burn wounds of 509 patients during the past 10 years. Eleven patients with burns covering more than 20 per cent of the body surface showed silver deposits in the mucosa of the lips, gingiva and cheeks. The colour of the burn wound was also slightly darker than in patients not treated with silver compounds. This darker colour spontaneously disappeared during the year following discharge from hospital. The pathogenesis of silver deposition has been discussed in relation to other published studies.

Patients with fresh full-thickness burn wounds were randomly assigned to receive wound treatment with daily applications of either 1 per cent silver sulfadiazine plus 0.2 per cent chlorhexidine digluconate cream (Silvazine) or 1 per cent silver sulfadiazine (Flamazine). Fifty-four patients treated with Silvazine were comparable to 67 treated with Flamazine with respect to extent and distribution of burn, age and all aspects of wound and associated treatment. Overall incidence of wound bacterial colonization was less in the Silvazine treated patients (65 per cent versus 88 per cent; P = 0.002). With Silvazine, wound colonization by Staphylococcus aureus was less (41 per cent versus 64 per cent; P = 0.01). Clinical wound infection with Staph, aureus developed in one Silvazine treated patient and five Flamazine treated patients (P = 0.16). Colonization by and infection due to all other organisms did not differ in the two groups. The incidence of graft failure was similar with both agents. In future increasing the concentration of chlorhexidine digluconate above 0.2 per cent might produce an improved prophylactic effect against Gram negative bacteria reported by other authors using the combined agent in in vitro and clinical trials. Silvazine was effective in reducing the incidence of Staph. aureus burn wound colonization without fostering supervening opportunistic infection.

Epi-Lock, a 1-mm-thick semipermeable sheet of modified polyurethane dressing material, was compared with silver sulfadiazene cream (Silvadene) in a prospective, randomized, cross-over-controlled study in which 50 patients alternated changing antibiotic cream daily with leaving the polyurethane sheet in place for a week. Overall, patient and physician preference for Epi-Lock was statistically significant (P less than 0.004), based on less pain, easier care, and faster healing. The collection of fluid under the polyurethane dressing and the necessity of leaving the wound covered for a week were less well accepted. Epi-Lock represents a major advance in wound dressing materials and should eventually gain wide application in outpatient treatment of partial thickness burns and abrasions.

Silver sulfadiazine (Silvadene(R), US; Flamazine UK; Flamazine, Netherlands; Sulplata South America) is proving to be a highly successful topical antimicrobial agent for control of burn wound infections. The advantages of wide spectrum of activity, painless application, negligible toxicity and ease of application contribute to the usefulness of this compound. These advantages have led to its use for wound infections other than burns, for skin ulceration and for certain dermatologic lesions; also for the prevention and treatment of various vaginal infections. Described also are zinc sulfadiazine which can provide zinc for wound healing and cerous sulfadiazine which contains the rare earth metal cerium. Their unique effects on cell biology may determine their specific roles in topical therapy.

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.

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.

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.

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.

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.

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.