Viewpoint reduced mefloquine sensitivity is lessened substantially. 8 Second, the artemisinin derivatives decrease gametocyte carriage by roughly 90%. 9 Recrudescent (ie, resistant) infections are associated with increased gametocyte carriage rates, which provide a powerful selection pressure to the spread of resistance. 9, 1 0 This spread is prevented by the artemisinin derivatives. These benefits are particularly important in areas of low or unstable transmission where morbidity and mortality are high, and most malaria is treated. In this context, the antimalarial drugs are under intense selective pressure and resistance has, in the past, often developed rapidly. In areas of high transmission, where infections occur frequently, and are usually asymptomatic in older children and adults, the rapidly eliminated artemisinin derivative will not protect its more slowly eliminated partner during the elimination “tail” of declining blood concentrations. Infections newly acquired during this tail will therefore be under selection pressure. But, provided the patients with these infections are treated with the combination if they become symptomatic, and provided the combination partner retains some efficacy against any selected mutants, the infections will usually be cured and the resistant parasites will not be transmitted. The reduction in the risk of selecting resistant mutants in the primary symptomatic infection is not affected by the prevailing rate of malaria transmission. Thus, combinations should slow the evolution of drug resistance in all malarious areas. There are additional benefits to artemisinin combinations. The rapid therapeutic response ensures that patients are able to return to school or work earlier and, in the unlikely event of complete resistance to the combination partner, a therapeutic response will still occur—ie, there will not be a high-grade or dangerous failure to respond to treatment. Thus, for several reasons, combination therapy with artemisinin or a derivative makes therapeutic sense. 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. There are compelling reasons to believe that resistance to the available antimalarial drugs would be slowed or prevented by the addition of artemisinin or one of its derivatives, as has been the case with mefloquine. Combination of an artemisinin derivative with chloroquine and PSD in areas where partial sensitivity to these compounds is still retained should extend their useful life. So what are the objections to combination antimalarial chemotherapy?

Will artemisinin resistance be encouraged? Some have argued that artemisinin derivatives are so effective in the management of severe malaria that they should be withheld from use in uncomplicated malaria in those areas where they are not needed, so as to protect them from the development of resistance. However, combination chemotherapy does protect the artemisinin derivatives from the development of resistance. If the drug is always used in combination with another unrelated antimalarial drug, then, provided they are at least partially susceptible to the second drug, parasites are never exposed to the antimalarial activity of the artemisinin derivative alone. Given the reassuring lack of