Charles L. Fox

Mechanism of silver sulfadiazine action on burn wound infections.

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.

Inhibitory Effect of Cortisone on Anaphylaxis in the Mouse.

Summary The administration of Cortisone to 42 sensitized mice 18 hours before the intravenous injection of a challenging dose of antigen prevented fatal anaphylactic shock in 38 animals. In contrast, 2S of 34 sensitized but unprotected control mice died in anaphylactic shock. The authors with to thank Mr. Bernard K. Friedman and Mrs. Jacqueline Isola for their technical assistance in this work. The Cortisone used in this investigation was purchased by funds from The United States Public Health Service.

Control of prosthetic bacterial infection: Evaluation of an easily incorporated, tightly bound, silver antibiotic PTFE graft

Despite the use of prophylactic antibiotics in vascular surgery, prosthetic infection rate remains 2-5%. Antibiotics bound to vascular prostheses can control experimentally induced infection but prolonged antibacterial activity has not been achieved. This study evaluates the in vivo efficacy and antibiotic retention of an easily prepared silver-antibiotic prosthesis. Prostheses were prepared by combining silver with oxacillin or amikacin using an organic solvent. After evaporation of the solvent, the graft was left impregnated with the antibiotic complex. In vivo retention studies were performed by implanting PTFE 110Ag-oxacillin prostheses in four canine abdominal aortas. When prostheses were explanted at 1 week, mean antibiotic retention was found to be 20% of original activity, higher than the mean inhibitory concentration for Staphylococcus aureus. In three groups of five dogs, 20 X 7-mm prostheses of PTFE alone, PTFE silver-oxacillin, or PTFE silver-amikacin were implanted in the abdominal aorta and the grafts were inoculated with 10(7) S. aureus of a known bacteriophage type, in a closed retroperitoneal pocket. The animals were sacrificed at 1 week and the prostheses were excised for quantitative bacterial culture. PFTE silver-oxacillin, and PTFE silver-amikacin prostheses had 1.7 X 10(2) and 2.0 X 10(2) colonies, respectively, significantly less (P less than 0.05) than controls (1.3 X 10(6) colonies). These data suggest that antibiotic prostheses can be easily prepared without binding agents. They retain the bound antibiotic for a prolonged period and are effective in reducing graft infection in a stringent direct contamination model.

Ionization of Sulfonamides

A recent quantitative analysis of bacteriostasis by sulfanilamide, sulfapyridine, sulfadiazine and sulfathiazole showed that for inhibition of Es. coli decreasing amounts of each drug in the order named were required. 1 Actually over six hundred times more sulfanilamide is required than sulfathiazole or sulfadiazine, and similar results have also been obtained with a variety of other microörganisms, 2 indicating that this regular increasing order of bacteriostatic potency is characteristic of these N1 sulfonamides (Col. A, Table I) and not attributable to the selective action of one drug against a certain organism. Furthermore, the quantitative relationships between these sulfonamides and para aminobenzoic acid (PAB) differ just as widely; e. g., over 600 times more PAB is needed to block sulfathiazole and sulfadiazine than to block sulfanilamide. (Col. F.) When the minimum effective concentration of each drug was tested, the same amount of PAB was required to block each drug. (Col. E.) In other words, going from sulfanilamide to sulfadiazine a progressively larger proportion of each drug actually present in the cultures appears to possess activity against either bacteria or PAB; the active moiety presumably being similar for each drug. It seems possible that such a partition into active and inactive portions might be controlled by the extent to which the drugs are ionized in the cultures. Accordingly the dissociation constants were measured∗ (Col. B) and the percent of each drug ionized at pH 7.0 (Col. C) was computed. (Some shift in the apparent pK may be expected to occur in complex biological media.) Based on these values and using the minimum effective amounts of drug added to the culture (Col. A), the concentration of ionized drug was estimated (Col. D).

PTFE graft treated with silver norfloxacin (AgNF): Drug retention and resistance to bacterial challenge

Norfloxacin (NF) and silver norfloxacin (AgNF) were used to coat polytetrafluoroethylene (PTFE) vascular prostheses by using triododecylmethylammonium chloride as a cationic surfactant. The relative retention of the drug on the graft after subjecting it to the biological environment for 3 weeks and antibacterial activity against coagulase-positive Staphylococcus aureus and Escherichia coli were determined. In addition, the ability of AgNF-coated PTFE grafts to sterilize perigraft tissue after mixed bacterial contamination was studied and compared with control PTFE grafts in 10 dogs. At the end of 21 days, 15 and 18% of AgNF were retained on the grafts tested in in vitro and in vivo experiments, respectively. During the same time AgNF-coated grafts from in vitro experiments exhibited significant antibacterial activity (25 mm zone of inhibition (z.i.)), but antibacterial activity was negligible (10 mm z.i.) in the grafts from in vivo experiments. NF retention on the grafts could not be determined because of spectral interference by blood. The antibacterial activity of NF-coated grafts significantly declined after 24 hr in in vivo experiments, hence further evaluation of NF-coated grafts was not done. Seven perigraft sites surrounding AgNF-coated grafts were sterile, but only one perigraft site surrounding control grafts was sterile (P less than 0.05). Cultures from six of nine perigraft infections surrounding control grafts yielded heavy bacterial growth. There was only one wound infection at the site of AgNF graft while there were seven severe wound infections at control graft sites. AgNF-coated grafts exhibited prolonged antibacterial activity compared to NF-coated grafts and offered significant protection against infection from local bacterial contamination.

Synergistic action of silver sulfadiazine and sodium piperacillin on resistant Pseudomonas aeruginosa in vitro and in experimental burn wound infections.

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.

RESPIRATORY TRACT DAMAGE IN BURNS: PATHOPHYSIOLOGY AND THERAPY

(1) Of the 27 burn fatalities with respiratory tract involvement, this internal damage was the primary cause of death in 20 cases.

Simple methods for direct antibiotic protection of synthetic vascular grafts.

Two simple methods for direct antibacterial protection of synthetic vascular grafts were investigated. In the first protocol the highly protein-bound antibiotics nafcillin (90% protein bound), cefazolin (80%), and cefamandole (70%) were added directly to preclotting blood. Knitted Dacron grafts preclotted in the presence of one of these drugs absorbed significant amounts. Although at high concentrations these antibiotics exhibited anticoagulant effects, significant antibacterial protection was obtained at lower antibiotic levels. Washing treated grafts for 6 hours failed to eliminate the antibacterial activity. Antibiotics remained on the grafts for at least 96 hours. In the second protocol knitted Dacron grafts were soaked in a suspension of silver-pefloxacin, a silver-nalidixic acid analogue with intense antistaphylococcic activity. Using 110Ag-labeled complexes, significant antibiotic activity was documented on the graft after 19 days of washing. Four nafcillin-treated prostheses, six silver-pefloxacin-coated grafts, and 11 control grafts were interposed in the infrarenal aorta of dogs and immediately challenged with an intravenous infusion of 1 X 10(7) Staphylococcus aureus. None of the four nafcillin-treated grafts was infected at 3 weeks. One of the six silver-pefloxacin-coated grafts grew staphylococci, and 9 of 11 controls had positive graft cultures for Staphylococcus when harvested. These studies suggest that prosthetic grafts can be simply coated at the time of implantation with antibiotics selected for appropriate binding and antibacterial characteristics to obtain an infection-resistant prosthesis.

Cerium sulphadiazine as a topical agent for burn wound infections: a comparison with silver sulphadiazine and zinc sulphadiazine

Abstract Cerium sulphadiazine was synthesised and compared with silver and zinc sulphadiazine. All three of these metal sulphadiazines are effective, both in vitro and in the prevention of bacterial infection and mortality in burned mice and rats. Animals treated with zinc sulphadiazine exhibit superior wound healing and longer survival. Cerium sulphadiazine, unlike silver and zinc sulphadiazine, binds to DNA instantaneously, forming an insoluble cerium-DNA complex. The toxicity of cerium sulphadiazine is much lower than that of silver or zinc sulphadiazine. The efficacy of silver sulphadiazine, the wound-healing potential of zinc sulphadiazine and the low toxicity of cerium sulphadiazine can be combined to create a superior topical therapy.

Metal Sulfonamides as Antibacterial Agents in Topical Therapy

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.