The evolution of multiple drug resistance in malaria parasites.

Forces determining the rate of spread of drug resistance in malaria were explored using a genetics transmission model which took account of the strong population structure of these parasites. The rate of change of frequency of drug resistant mutants in the parasite population is primarily a function of the proportion of hosts treated with drugs, and parasite transmission rates. With high transmission rates, selection by drugs is more effective than with lower rates because the resistant mutant passes on more copies of itself to the next generation of hosts. Thus reducing transmission rates, either at the overall population level or from drug-treated individuals, should be effective in curbing the spread of resistance. An exception to this is when 2 unlinked genes act jointly (not independently) to confer resistance, when the prevailing transmission rate is already low, drug use is minimal, and resistance genes are rare. Reductions in fitness of the mutant in the absence of drugs (i.e., a fitness cost to resistance) and the degree of epistasis and the mode of gene action of the drugs do not alter these conclusions.