Thomas H. Haight

Terramycin therapy of pneumonia: clinical and bacteriologic studies in 91 cases.

Excerpt The wide variety of bacterial and other microbial agents which may be implicated in the causation of acute pulmonary infections makes such infections particularly suitable for treatment wit...

Resistance of Bacteria to Erythromycin.

Summary and Conclusions 1. Variants with high degrees of resistance to erythromycin were not isolated from small volumes of cultures of erythromycin-sensitive bacteria which had not previously been exposed to that antibiotic. 2. When cultures of erythromycin-sensitive staphylococci (which were completely inhibited by 0.4 μg/ml in the plate-dilution test) were grown from a 10% inoculum in broth in the presence of 16 |mUg/ml of erythromycin, strains of varying resistance could be recovered after 48 hours; these required concentrations of erythromycin ranging from 0.2 to 25 |mUg/ml for complete inhibition. 3. By repeated subcultures of erythromycin-sensitive bacteria on blood agar containing graded concentrations of erythromycin it was possible to obtain strains of increased resistance to this antibiotic. The rate at which this resistance increased varied markedly with the strain. Several strains of Staphylococcus aureus, an enterococcus and a pneumococcus each increased more than 512-fold in from 3 to 12 such subcultures. Strains of only moderately increased resistance were obtained after 20 similar subcultures of a strain of hemolytic streptococcus and one of Streptococcus viridans. 4. The strains of increased resistance resulting from repeated subcultures on the erythromycin-containing agar retained that resistance after 10 further subcultures in antibiotic-free broth. 5. Strains of increased resistance to erythromycin derived by repeated subcultures in that antibiotic were almost invariably similar to their respective parent strains in their sensitivity to 8 other antibiotics; however, an erythromycin-resistant strain of type 3 pneumococcus had apparently increased in sensitivity to neomycin following its repeated subcultures in erythromycin. 6. Staphylococcal strains of markedly increased resistance to erythromycin were obtained from blood cultures of 2 patients with endocarditis following 7-10 days of treatment with this antibiotic. 7. The colonial, morphologic and biochemical characteristics of the erythromycin-resistant strains obtained by repeated subcultures in erythromycin-containing media resembled those of the respective parent strains from which they were derived in almost every instance. The strains of Staphylococcus aureus, however, lost their ability to produce coagulase and exhibited other changes in their biochemical properties following their repeated subcultures in the presence of erythromycin. Similar changes were not observed in the 2 strains of Staphylococcus aureus which had apparently become resistant during erythromycin therapy.

The Antibacterial Action of Erythromycin.

Summary and Conclusions The results of studies on some properties of erythromycin which may be important in its clinical and laboratory applications have been reported. 1. Erythromycin solutions retained their activity after prolonged storage in the cold or in the frozen state but showed progressive deterioration after several days at room or incubator temperatures or after brief exposures to 60°C or higher. 2. Filtration of erythromycin through bacterial filters entailed the loss of some activity. 3. The antibacterial action of erythromycin increased progressively with increasing alkalinity of the culture medium, within the pH range of bacterial growth. 4. Many substances which may affect the action of other antimicrobial agents had no important effect on the action of erythromycin. 5. Erythromycin inhibiting substances could not be demonstrated in cultures of erythromycin-resistant bacteria. 6. The size of the inoculum affected the results of sensitivity tests with erythromycin, but there was considerable tolerance within the range of inocula used in clinical testing. 7. The broth-dilution and agar-plate dilution methods generally gave comparable results in tests for sensitivity of bacteria to erythromycin but the values obtained by the agar method often were higher, particularly with some coliform organisms. 8. Tests done on more than 1000 bacterial strains, most of them recently isolated from patients, indicated that erythromycin was most active against the Gram-positive cocci and was quite active against strains of Neisseria, diphtheria bacilli and Hemophilus, but for practical purposes it could be considered inactive against most coliform and enteric bacilli. 9. Concentrations of erythromycin in plasma after single oral doses varied widely but in general were proportional to the dose. Maximum concentrations were found 1 or 2 hours after a dose, and no activity was demonstrated at 6 hours except following doses of 1.0 g. Significant concentrations were maintained in the plasma with oral doses of 250 mg or more every 3 or 4 hours. 10. The amounts of erythromycin activity recovered in the urine appeared to be small and erratic after ingestion of single doses or after repeated small doses, particularly early in the course of therapy; however, on continuous therapy with divided doses, up to 15% of the amount ingested daily could be demonstrated in active form in the urine. Results of studies on the mode of action of erythromycin and on the resistance of bacteria to that agent are presented in the succeeding papers.

Observations on Mode of Action of Erythromycin.

Conclusions Erythromycin may be either bacteriostatic or bactericidal depending on the sensitivity of the organism and on the concentration of the antibiotic. Erythromycin exerts its effect only against multiplying bacteria.