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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.

The apparent efficacy of zinc and cerium sulfadiazine and the metabolic role of other trace metals suggested that sulfonamide salts of these might be of therapeutic value. There is also a possibility that metal salts of other sulfonamides might be useful. Accordingly other sulfonamide salts of zinc were prepared and studied in vitro and in vivo. Only zinc sulfathiazole and zinc methoxazole were as effective as zinc sulfadiazine in animal studies. The sulfadiazines of aluminum, chromium, cobalt, copper and iron were prepared and compared in vitro and in vivo. Only cobalt sulfadiazine appeared comparable to zinc and cerium sulfadiazine in healing burn wounds in rats. Studies on the molecular structure of silver sulfonamides disclosed the polymeric structure peculiar to silver sulfadiazine which appears to account for its unique properties. It is not yet known whether other metal sulfadiazines have this attribute.

A procedure for the bonding of antibacterial agents directly to prosthetic vascular grafts has been developed. This method does not involve the use of carriers or surfactants which may cause local toxicity or thrombogenesis. Using this procedure, antibiotics can be bonded to the graft alone or in combination with a metal, such as silver. Incorporation of silver along with the antibiotic enhances the antibacterial activity and prolongs retention of the antibiotics in the prosthetic grafts. Silver mediated bonding appears to release the antibiotic biphasically. In the initial phase (40 to 50 per cent), the drug is rapidly released and, in the second phase, the rest is diffused gradually enabling the graft to retain antibacterial activity for a longer period of time.

Silver sulfadiazine (Silvadene, U.S.; Flamazine, U.K.; Flammazine, N.; Sulplata, S.A.) is the newest topical antimicrobial agent available following worldwide clinical trials. Good control of infection is achieved without pain or other demonstrable side effects, using either dressings or the exposure technic. Many burned areas kept free of infection heal without grafting. Where necessary, early preparation for and good take of grafts has been attained by utilizing this new therapeutic agent. Markedly reduced mortality from burn wound sepsis has generally been observed.

Zinc sulfadiazine is a new compound which is effective in vitro and in vivo against Pseudomonas aeruginosa infections in burned mice and rats. It contains an important body constituent, zinc, and appears to expedite wound healing, diminish weight loss after infected burns and improve food intake. Like silver sulfadiazine, it prevents the postburn changes in plasma proteins. After topical application, the uptake of the radioactively labeled zinc is significant in the zone of injury and negligible in organs and body fluids. The binding to deoxyribonucleic acid by zinc is similar to, but less than, that by silver. The data indicate that zinc sulfadiazine may be a valuable addition to the therapeutic armamentarium for the control of burn wound sepsis.

The addition of silver sulfadiazine to cultures of varicella zoster virus resulted in inactivation of the viral infectivity. At a concentration of 10 micrograms/ml or higher the virus was inactivated after thirty minutes exposure at 37 degrees C. Forty-two patients with herpes zoster were treated topically with 1 percent silver sulfadiazine cream applied four times a day. All patients experienced complete drying of vesicles, marked reduction erythema and edema, and striking elimination of pain and burning sensation within twenty-four to seventy-two hours. The sooner the treatment began after the onset of symptoms, the more dramatic was the response. Postherpetic neuralgia was either mild or did not occur. Signs of local, systemic, or laboratory-documented toxicity were not observed.

The role of silver and sulfadiazine in the mechanism of action of silver sulfadiazine on burn wound infections was investigated. Silver, but not sulfadiazine, was bound by bacteria. Sulfadiazine did not act as an antibacterial agent in low concentrations, but exhibited specific synergism in combination with subinhibitory levels of silver sulfadiazine. The efficacy of silver sulfadiazine is thought to result from its slow and steady reactions with serum and other sodium chloride-containing body fluids, which permits the slow and sustained delivery of silver ions into the wound environs. In this circumstance, a relatively minute amount of sulfadiazine appears active.

Norfloxacin is a new synthetic antibiotic with a broad spectrum of activity against gram-positive and gram-negative bacteria, and is more effective than the aminoglycosides against P aeruginosa. In this study norfloxacin was particularly effective in treatment of P aeruginosa infection of the rabbit cornea, and caused no toxicity in normal rabbit eyes after prolonged administration. The addition of silver to norfloxacin enhances its antipseudomonal activity, and broadens its spectrum to include antifungal activity. In this study, silver norfloxacin appears to be the most effective antibiotic against P aeruginosa corneal ulcer in the rabbit. Because of its broad antibacterial spectrum, silver norfloxacin may be useful in the initial treatment of bacterial corneal ulcer before the identity of the bacteria is known. Because of its low toxicity in topical administration, and its antifungal and antibacterial activity, silver norfloxacin may be helpful in prophylaxis against infection in chronic corneal ulcers.

As might be anticipated, strains of Pseudomonas aeruginosa resistant to silver sulfadiazine have appeared. We have found an analogue of nalidixic acid (pefloxacin) which, along with its silver derivative, is highly effective against these resistant strains. In vitro the minimal inhibitory concentrations are 10 to 20 times lower than that of silver sulfadiazine against bacteria. In burned mice and rats infected with silver sulfadiazine resistant pseudomonas strains, mortality in groups receiving topical therapy with pefloxacin and silver pefloxacin is about 10 per cent compared to 80 per cent with silver sulfadiazine (100 per cent in untreated controls). There is little systemic absorption of pefloxacin and no absorption of silver from topical treatment. In addition, silver pefloxacin exhibits higher antifungal activity in vitro.

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 designed to ascertain the most effective sodium solution for resuscitation after potentially fatal thermal injury. Solutions containing from 75 to 300 mEq/L of sodium were administered in various doses to mice subjected to a standarized scald. Their effectiveness was evaluated by comparison of the 24-hour mortalities, and also by the changes in body weight, urine and plasma electrolytes, etc. A wide range of solutions was effective; the optimal intake was approximately 22.5 mEq of sodium per kilogram of body weight. This was most efficiently given in a solution containing 225 mEq of sodium and 160 mEq of chloride per liter. Survival increased when the sodium to chloride ratio more closely approximated that oe plasma. Hypotonic solutions were less effective at all dosage levels.

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.

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.

Sulfadiazine silver-resistant strains of Pseudomonas aeruginosa isolated from burned patients from several countries are sensitive to sulfadiazine silver in vitro, but in burned mice and rats resist topical therapy with sulfadiazine silver. In searching for an effective topical agent against these resistant organisms, we found that FPQC (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7[1-piperazinyl]-quinoline-carboxylic acid) and its silver salt are effective both in vitro and in vivo. In vitro, their minimal inhibitory concentrations are ten to 20 times lower than that of sulfadiazine silver. In burned mice infected with resistant Pseudomonas strains, mortality in groups receiving topical therapy with FPQC or FPQC silver is 0%, but 80% to 100% with sulfadiazine silver and 100% without treatment. Similar results were obtained in burned rats. The efficacy of FPQC and FPQC silver in vivo may represent discovery of new agents of known low toxicity that are useful in topical burn therapy.