Eleanor A. Bliss

THE CLINICAL USE OF SULPHANILAMIDE AND ITS DERIVATIVES IN THE TREATMENT OF INFECTIOUS DISEASES

Excerpt INTRODUCTION The experimental observations1, 2, 3, 4, 5, 6, 7which have led to the use of sulphanilamide or its derivatives (chart 1) in the treatment of certain infectious diseases show th...

Bacteriostatic Effects of Sulfathiazole upon Various Micro-Or-ganisms. Its Therapeutic Effects in Experimental Pneumococcal Infections.

Conclusions Sulfathiazole is as effective a bacteriostatic agent as is sulfapyridine in broth cultures of certain strains of Lancefields Groups A, D, and G beta hemolytic streptococci, E. coli, Staphylococcus aureus, Types I and II pneumococci and B. proteus. Under the conditions of our tests sulfathiazole was slighly less effective than sulfapyridine in the control of experimental pneumococcal infections in mice. However, as has been pointed out, the more rapid absorption and excretion of sulfathiazole by the mouse, partially invalidate the results of comparative therapeutic tests in which the drug is administered per os in acacia suspensions at stated intervals. We wish to thank E. R. Squibb and Son and the Calco Division of the American Cyanamid Company for supplying us with sulfathiazole.

Sulfapyridine and Sulfanilamide in Experimental Pneumococcal, Meningococcal, Welch Bacillary and Friedlander's Bacillary Infections in Mice.

We 1 , 2 have discussed the comparative therapeutic efficiency of sulfapyridine and sulfanilamide in the treatment of experimental hemolytic streptococcal and Type I pneumococcal infections in mice. These reports were based upon results obtained in mice the origins of which were unknown. Recently, we have used pure bred mice (strain CF1) whose genetic formula is ccaabb, as test animals for the study of the effects of chemotherapeutic agents upon various types of experimental infections. We believe the use of pure bred mice eliminates the factor of variations in host susceptibility. In this report we will present data concerning the comparative therapeutic effects of sulfapyridine and sulfanilamide upon experimental infections in mice produced by several types of microörganisms. With the exception of the Welch bacillus and meningococcus, the strains of organisms were virulent for mice in dilutions of 108 to 109, and the meningococcus was made highly virulent by suspension in mucin. The technic of producing these infections has already been described by us. 3 , 4 The data presented in each instance represent the average of several experiments. As will be noted in Table I, the chemotherapeutic effect of sulfa-pyridine in experimental Types I, II, and III pneumococcal infections in mice is superior to that of sulfanilamide. The results obtained by us are distinctly inferior to those reported by Whitby, 5 but this may be explained by the higher mouse virulence of the strains of pneumococci which we employed and the fact that we used slightly smaller, though more frequently repeated, doses of sulfapyridine. Little difference was noted in the chemotherapeutic effects of the two compounds in the control of experimental meningococcal or Welch bacillary infections in mice.

THE EFFECT OF SURFACE‐ACTIVE AGENTS ON ANTIBIOTICS: AN INFORMAL REPORT

The observation that traces of green soap, remaining in laboratory glassware after washing, might account for irregularities in titrations with polymyxin D led to an investigation of the effects of surface-active agents on antibiotics in general. The method was to make serial twofold dilutions of the antibiotic in heart infusion broth (pH 7.2) containing the surface-active agent. The tubes were inoculated with a strain of E. coli, about 200,000 organisms, and growth, as shown by visible turbidity, was read after 18-20 hours a t 37 C. The results, expressed as the ratio between minimal inhibitory concentration of drug in the presence of the agent and minimal inhibitory concentration in plain broth, are shown in TABLE 1. From this presentation of the data, one receives the impression that the antibiotics derived from sporebearing bacilli-the polymyxins and circulin-are particularly sensitive to surface-active agents. Soap and Aso-lectin were antagonistic, raising the titration end points of the polymyxins and circulin over 1000 times. Lipositol, tested only against polymyxin D, also was antagonistic, but to a lower degree. Tween 80 had the reverse effect, causing a fourfold increase in activity. End points of aureomycin, chloromycetin, and streptomycin were much less affected. Soap, in fact, was almost inert against the last two antibiotics. Penicillin end points were not altered by soap, Aso-lectin, or Tween 80 in the concentrations tested. The possibility that the alkalinity of broth solutions of soap and Asolectin might be responsible for their antagonistic action was not tenable, because such solutions had a much greater effect than broth adjusted to a higher pH with NaOH. Polymyxin D, as well as polymyxin B, circulin, and aureomycin, deteriorates in an alkaline environment. The fact that its end point on this occasion was the same at pH 8.6 as a t pH 7.2 presumably reflects the rapidity with which it kills E. coli. The organisms were dead before deterioration could occur. On the other hand, the increased activity of streptomycin and chloromycetin in an alkaline medium might explain their lack of response to soap. “Letheen” broth, which has been recommended for the neutralization of cationic antiseptics, failed to antagonize any of the antibiotics in the present series. Apparently, its content of Tween 80-5000 pg./ml.-was sufficient to offset the antagonistic action of the 700 pg./ml. of Aso-lectin present in this medium. An inverse relationship was noted between the efficacy of the antibiotics in inhibiting strains of Proleus and their sensitivity to soap and Aso-lectin. Moreover, a filtrate of a broth culture of a strain of Proteus decreased the

Effect of Sulfapyridine, Sulfathiazole and Sulfamethylthiazole upon Severe Staphylococcal Infection in Mice.∗

Summary and Conclusions Sulfathiazole and sulfamethylthiazole, administered as 1% of the diet showed a distinct and equal therapeutic value in prolonging the lives of mice heavily infected with Staphylococcus aureus. Sulfathiazole proved to be somewhat more efficient in this respect than sulfapyridine. We are indebted to E. R. Squibb and Sons and the Calco Chemical Division of the American Cyanamid Company for the sulfathiazole used in these experiments, and to the Department of Medical Research of the Winthrop Chemical Company for the sulfamethylthiazole.

Comparative Therapeutic Effects of Sulfapyridine in Experimental Staphylococcus aureus Infections in Mice.

It has been shown that sulfanilamide has a slight therapeutic effect in the treatment of experimental staphylococcal infections in mice. 1 , 2 , 3 However, its efficacy has not been great and the drug has been of little value in the treatment of staphylococcal infections in man, in which the tissues or blood stream have been seriously invaded by these organisms. Recently Whitby 4 without giving details of his experiments has shown that sulfapyridine has a definite chemotherapeutic effect in experimental staphylococcal infections in mice. We have been testing the comparative therapeutic effects of sulfapyridine and sulfanilamide in experimental staphylococcus aureus infections produced in mice by the intravenous injections of varying numbers of organisms. The technic of producing such infections and the time and method of treatment have been described previously by us. 3 It is to be noted that in each experiment, the untreated control mice were dead by the sixth day, and at the end of the first week of treatment 73.5% of those mice treated with sulfapyridine were still alive while only 34% of the mice treated with sulfanilamide were surviving. At the end of the second week (4 days after the termination of therapy) 32.6% of the mice treated with sulfapyridine were alive while only 8% of those treated with sulfanilamide were living. The surviving mice are being held for an indefinite period, to determine their eventual fate. It seems from these results, that the chemotherapeutic effect of sulfapyridine in staphylococcal infections in mice is definite enough to warrant careful clinical trials of the drug in severe staphylococcal infections. We are conducting such trials and to date we have noted dramatic clinical results in 2 patients suffering from severe staphylococcal sepsis.