CAT Current practice is to deploy antimalarial drugs individually in sequence. When one drug fails, another is introduced. Unfortunately, there are few antimalarials and, as for many microbial pathogens, the evolution of resistance in P falciparum seems to be outstripping the development of new drugs. The rationale for combining drugs with independent modes of action to prevent the emergence of resistance was first developed in antituberculous chemotherapy. This approach has since been adopted for cancer chemotherapy, and, more recently, for the treatment of AIDS and early HIV-1 infection.
Resistance arises from mutations.
The chance that a mutant will emerge that is simultaneously resistant to two different antimalarial drugs is the product of the mutation rates per parasite for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Compared with sequential use of single drugs, which is current policy, combinations will thus impede the development of resistance substantially. On the northwest border of Thailand, which harbours the most resistant P falciparum in the world, combination chemotherapy has halted the progression of mefloquine resistance. First, combinations ensure high cure rates because treatment for 3 days with an artemisinin derivative eliminates most of the infection, and the residuum of parasites remaining is exposed to maximum concentrations of the more slowly eliminated mefloquine. This spread is prevented by the artemisinin derivatives.