Delaying antimalarial drug resistance with combination chemotherapy

Abstract

Resistance to antimalarial drugs arises when spontaneously occurring mutants with gene mutations or amplifications which confer reduced drug susceptibility are selected, and are then transmitted. Simultaneous use of two or more antimalarials with different modes of action and which therefore do not share the same resistance mechanisms will reduce the chance of selection, because the chance of a resistant mutant surviving is the product of the parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. The artemisinin derivatives are very active antimalarials, which produce large reductions in parasite biomass per asexual cycle, and reduce malaria transmissibility. To date no resistance to these drugs has been reported. These drugs therefore make particularly effective combination partners. This suggests that antimalarial drugs should not be used alone in treatment, but always in combination, as in the treatment of tuberculosis or HIV, and that the combination should include artemisinin or one of its derivatives.