An analysis of the development of resistance to metachloridine in clones of Plasmodium gallinaceum

Abstract

1. The development of resistance to metachloridine (3-metanilamido-5-chloropyrimidine) was studied in two clones of Plasmodium gallinaceum derived from single erythrocytic parasites and maintained by serial inoculation in young chicks. Resistance developed with equal facility and similarly in the two clones.2. In thirteen strains of these clones an enhancement of resistance was obtained after three to five courses of treatment, each of seven doses of metachloridine over a period of 3½ days.3. The effect of the size of the inoculum (2·5 × 107–109 parasites), and of the dose of drug upon the rate of development of resistance was studied. Although the number of courses of treatment required to produce an enhancement of resistance was not always related to the size of the inoculum, with the largest inoculum an enhancement of resistance was observed after the minimum number of courses of treatment (three), whereas with the smallest inoculum no enhancement of resistance was obtained. The rate of the development of resistance did not appear to be related to the size of the dose of drug.4. In some strains the increase in resistance was sudden, whereas in others it was more gradual. Resistance was retained when parasites of a newly resistant strain were transmitted through Aëdes aegypti or maintained for 43 days in the absence of the drug.5. A comparison of the development of resistance in populations of normal parasites, and of populations composed of mixtures of known numbers of resistant and normal parasites, indicated that the pattern of the development of resistance in normal populations could be explained by the selections of mutations of a frequency of less than 1 in 5 × 107, or probably less than 1 in 109 parasites.