Why is it that antimalarial drug treatments do not always work?

Abstract

The objective of antimalarial drug treatment in severe malaria is to save the patient's life. In uncomplicated malaria it is to reduce the parasite biomass to zero, or down to a level where host defences can deal with the remainder. Treatment regimens with rapidly eliminated drugs must generally cover four asexual life-cycles (i.e. > 6 days for Plasmodium falciparum and P. vivax) to eradicate all the parasites in the blood. For slowly eliminated drugs, blood concentrations must exceed the parasites' minimum inhibitory concentration (and preferably the minimum parasiticidal concentration) until all parasites have been eradicated. Resistance means that there is a right shift in the concentration-effect relationship. This may be large and abrupt, as with the point mutations that confer pyrimethamine, sulphonamide or atovaquone resistance, or slow and gradual, as with the processes that determine resistance to chloroquine, quinine or mefloquine. Although treatment failure in malaria usually results from poor compliance, inadequate dosing, pharmacokinetic factors or resistance, some infections will recrudesce when none of these factors operates. How parasites persist despite apparently adequate antimalarial treatment remains unresolved.