Antimalarial drug resistance and combination chemotherapy

Antimarial drug resistance develops when spontaneously occurring parasite m utants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susce ptibility are particularly vulnerable. Low clearance and a shallow concentr ation-effect relationship increase the chance of selection. Use of combinat ions of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant su rviving is the product of the per parasite mutation rates for the individua l drugs, multiplied by the number of parasites in an infection that are exp osed to the drugs. Artemisinin derivatives are particularly effective combi nation partners because (i) they are very active antimalarials, producing u p to 10 000-fold reductions in parasite biomass per asexual cycle; (ii) the y reduce malaria transmissibility; and (iii) no resistance to these drugs h as been reported yet. There are good arguments for no longer using antimala rial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives.