Emanuel B. Schoenbach

The treatment of systemic blastomycosis with stilbamidine.

Excerpt Although infrequent in occurrence, blastomycotic infections are important because of the morbidity and mortality associated with the systemic form of the disease. Treatment has been varied ...

IN VITRO STUDIES OF POLYMYXIN

Studies of the in vitro activity of polymyxin have been in progress a t this laboratory since October, 1947. The preparation used is the hydrochloride of the partially purified concentrate, supplied by the Lederle Laboratories Division of the American Cyanamid Co., in 20-mg. ampoules labeled “B 71 Hydrochloride.” Observations have been made on the stability of the agent to heat and changes in the hydrogen ion concentration, its range of action and potency, and its effect upon the growth of Escherichia coli. The likelihood of the development of dmg fastneçs to polymyxin has been investigated. A method has been devised for assaying the concentration in body fluids and a search for antagonists has been started. EnvZronmentall+‘actors. The medium used in most of the tests about to be described was Difco Heart Infusion Broth with 0.05 per cent dextrose added, but the constitution of the medium appears to be unimportant in titrations with polymyxin. The end-points are not raised by the presence of serum in the tests. In fact, with serum they have averaged somewhat lower in 17 instances when comparisons were made. However, heating polymyxin in the presence of serum does result in a raising of the end-points as much as 8 times, the average in 20 tests being 4.3 times. On the other hand, the agent, at pH 7.2 in broth or salt solution, appears to be quite stable to heat, there being little or no change in activity after i t has stood at room temperature or in the 37°C. incubator for 18 hours, after heating at 56’C. for as much as 4 hours or after treatment in a boiling water bath for 10 minutes. Nevertheless, it keeps best, over long periods of time, in an acid environment in the deep freeze, -20°C. The loss of activity upon heating in the presence of serum is not only puzzling, but also inconvenieni. The sera of human beings and animals often contain antibodies for gram-negative bacteria which confuse the readings, and which must be eliminated by heating the sera a t 56’C. for 30 minutes. In assaying for polymyxin in the blood, i t is, therefore, essential to prepare a standard in serum and to heat it at the same time as the unknown sera. After heating, the standard and the unknown are diluted out in broth, in seria1 two-fold dilutions of 3 cc. each, and the tuhes are inoculated with

Treatment of H. influenzae meningitis with aureomycin and chloramphenicol: Experience in thirty consecutive cases

cc. of a 1:10,000 dilution af a 20-hour old culture of E. coli. The least amount of polymyxin which can be detected in this way is 0.62 to 1.25 pg./cc. The titrations are read a t 18 to 22 hours.

The clinical use of polymyxin.

Abstract Thirty children with bacteriologically confirmed meningitis due to H. influenzae type b have been treated with aureomycin and sulfadiazine or with chloramphenicol. Eighteen patients received intravenous and oral aureomycin supplemented by parenteral and oral sulfadiazine. There were three deaths among these eighteen patients of which two could be attributed to the infection. Some residual neurologic damage was observed in five patients. Twelve patients received oral, intramuscular or intravenous chloramphenicol therapy No deaths occurred and only two patients showed residual neurologic disturbances. The neurologic complications diminished considerably several months later in four of the seven patients. Because of the difference in age selection between the two groups, no distinction between the two types of therapy can be made with any assurance. Chloramphenicol appeared to possess certain advantages in the clinical care of these acutely ill children, many of whom were infants. No toxic manifestations which could be attributed to the medication were encountered among any of the patients in this series. Subdural collections of fluid were often observed and the importance of recognizing this complication is re-emphasized.

Studies on bacterial resistance to streptomycin.

Polymyxin is an antibacterial agent uniquely active against several species of gram-negative microorganisms. Adequate protection of experimentally infected animals was demonstrated with doses of the antibiotic far smaller than those a t which any toxic manifestations were noted. Trial in patients, therefore, appeared warranted. These early cases cannot be considered therapeutic trials to establish the clinical use of this antibiotic, but rather as eariy explorations into the pharmacology and human hostdrug relationships. The small series of patients treated thus far, the varied types of infections, and the great age range of these patients render any generalization or statistical treatment untenable. Gram-negative infections differ markedly from many gram-positive infections in that complications often exist which aid in the initiation of the disease or its maintenance. Many of the cases treated were suffering from an underlying dermatitis, neoplasm, burn, etc. Thus, the clinical course of the untreated case is more difficult to predict, and that of the treated case, to evaluate. Reçort to bacteriological procedures coupled with objective and subjective clinical observations of each case is necessary. The observations on these patients will be presented, and data as to tolerance, blood levels attained, urinary excretion, untoward reactions, and cultural examinations reported. The coune of the patient while on polymyxin therapy may be followed, but no definite deductions as to cause and effect will be attempted. Some cases were treated with a daily dose of 3 mg./kg. per day, divided into 8 equal amounts and given a t 3-hour intervals. Others were given a daily dose of 7 mg./kg./day. In these patients, an initial dose of 3 mg./kg. followed by two doses of 2 mg./kg. at 8-hour intervals was employed, and thereafter the drug was continued at equal amounts given three times a day. This dosage was not tolerated for more than three to four days and then was oftea reduced to 3 mg./kg. per day. A few cases have been treated with doses of 4 mg./kg. per day, given as four divided doses at 6 hour intervals. AI1 dmg was dissolved in a phosphate buffer pH 7.4 and administered via the intramuscular route. A concentration of 60 to 120 mg. in two cubic centimeters was tolerated locally. At the higher concentrations, dull drawing pain was noted for several minutes following the injection. In several individuals, after repeated injections, small, reddened, tender areas persisted a t the injection site. However, almost a11 patients preferred this discomfort to two doses of more dilute material. The injections were not discontinued in any patient because of local reactions. On m e occasion, The dosages of polymyxin employed in these trials varied.

An Evaluation of Aureomycin Therapy in Primary Atypical Pneumonia

Summary 1. Resistance to streptomycin can be induced by repeated transfer of various organisms in streptomycin containing media. 2. In the early logarithmic stage of growth, highly resistant mutants can be isolated, by chance selection, in a single transfer. 3. In most instances, acquired resistance to streptomycin is maintained. 4. Organisms resistant to streptomycin may retain their original virulence as measured by the bactericidal test. 5. The acquisition of resistance to streptomycin with the maintenance of virulence may have certain therapeutic implications.

PHARMACOLOGY OF POLYMYXIN

AUREOMYCIN has been reported as an effective agent in the therapy of primary atypical pneumonia.1 2 3 4 5 6 Most observers have noted a consistent pattern of response, but only one study in which c...

The sulfhydryl content of normal and abnormal human sera.

_ _ 250 11 45 275 I 5 ~ 2; I 5 1 50 300 10 50 10 50 350 1 7 I 70 I 3 I 30 Polyrnyxin (B-71) is an antibiotic derived from cultures of Bacillus polymyxa?-* Its activity appears to be restricted to certain gram-negative species of bacteria. Aero~porin~-~ is a similar antibiotic derived from B. aerosporus Greer. It is the purpose of this presentation to describe some of. the pharmacological studies which have been performed on experimental animals. Toxicity. The acute toxicity of polymyxin was determined for albino Swiss mice by single subcutaneous injection and the L.D.W was 250 to 300 mg./kg. A one per cent solution of drug was used and occasional loss of fur and skin irritation a t the injection site was noted with doses above 200 mg./kg. Deaths occurred within 6 hours with scratching of the head, ataxia, convulsions, paralysis, and respiratory arrest. Intraperitoneal injection of 250 to 275 mg./kg. produced convulsions followed by paralysis and death in 5 to 20 minutes. Stansly, Shepherd, and White2 also recorded an L.D.60 of 300 mg./kg. in mice receiving a single subcutaneous dose. TABLE 1 reveals, in the outlined area, the doses of polymyxin in mg./kg.

The pharmacology, mode of action and therapeutic potentialities of stilbamidine, pentamidine, propamidine and other aromatic diamidines a review.

Summary The sulfhydryl content of serum proteins has been quantitatively determined through an adaptation of an amperometric titration. Among normal adults, the values noted, expressed as milligrams of cysteine, were uniform, reproducible and averaged 6.5±0.2 mg per 100 ml serum or 5.5±0.3 mg per gram serum nitrogen. The albumin component of serum contained 80% of the total sulfhydryl. The addition of desoxyribonucleic acid, creatine or formaldehyde did not change the sulfhydryl content of the serum. The addition of an SH reagent such as para-chloro-mercuri-benzoate abolished all reactant groups measured with this method. Sera obtained from patients with various diseases showed a significant reduction in the sulfhydryl available for this titration. This quantitative reduction in sulfhydryl was still evident when corrected for differences in the albumin and globulin components and thus represented a qualitative change in the serum proteins. At the present time, the alteration in the sulfhydryl content of serum or its components is not characteristic enough to permit specific differentiation among the neoplastic, metabolic, or infectious diseases. The possible application of serial serum sulfhydryl determinations in animals and patients may be of value as an objective indicator of response and for study of the mechanism of action of chemotherapeutic and other agents.