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.⁵

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. For example, if one in 10⁹ parasites are resistant to drug A and one in 10¹³ are resistant to drug B, and the genetic mutations that confer resistance are not linked, only one in 10²² parasites will be resistant simultaneously to both A and B. Most patients who are ill with malaria have between 10⁸ and 10¹² parasites at presentation, and a biomass of more than 10 ¹³ parasites in a single person is physically impossible. In this example, therefore, most patients will have at least one parasite resistant to drug A, between 0·1% and 1·0% will have a parasite resistant to drug B, but a parasite simultaneously resistant to the two drugs would only occur about once every 10 ¹² treatments (ie, less than once a century). Compared with sequential use of single drugs, which is current policy, combinations will thus impede the development of resistance substantially. ⁵

Combinations of artemisinin, or one of its derivatives, with more slowly eliminated drugs such as mefloquine or lumefantrine (benflumetol) have proved highly effective, even against multidrug-resistant Plasmodium falciparum. 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. This is attributed to two factors:

.   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.^{14 16}

   Second, the artemisinin derivatives decrease gametocyte carriage by roughly 90%. Recrudescent (ie, resistant) infections are associated with increased gametocyte carriage rates, which provide a powerful selection pressure to the spread of resistance. This spread is prevented by the artemisinin derivatives.^{13, 20}

There are further therapeutic benefits from using artemisinin combinations⁵

  In the event of complete resistance to the combination drug, a therapeutic response will still occur, averting life-threatening failure to respond to therapy

  More rapid therapeutic response enables patients to return to work or school earlier

Map of Sites where CAT is being evaluated
 

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