Antimalarial drug resistance and combination chemotherapy

TLDR

Antimalarial drug resistance arises when spontaneous parasite mutants with reduced susceptibility are selected and transmitted, especially when a single point mutation confers marked resistance and low drug clearance or shallow concentration–effect relationships increase the selection risk. Combining antimalarials that target different mechanisms lowers the probability of selecting resistant mutants, and artemisinin derivatives are ideal partners because they are highly potent, reduce parasite biomass and transmissibility, and have no reported resistance. There are strong arguments for abandoning monotherapy and always using a combination with artemisinin or its derivatives.

Abstract

Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration–effect relationship increase the chance of selection. Use of combinations of antimalarials that 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 per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly effective combination partners because (i) they are very active antimalarials, producing up to 10 000–fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives.