Antimalarial drug resistance

Abstract

Malaria, the most prevalent and most pernicious parasitic disease of humans, is estimated to kill between one and two million people, mainly children, each year. Resistance has emerged to all classes of antimalarial drugs except the artemisinins and is responsible for a recent increase in malaria-related mortality, particularly in Africa. The de novo emergence of resistance can be prevented by the use of antimalarial drug combinations. Artemisinin-derivative combinations are particularly effective, since they act rapidly and are well tolerated and highly effective. Widespread use of these drugs could roll back malaria.

Figure 1

The life cycle of malaria parasites in the human host and anopheline mosquito vector.

Figure 2

Pharmacodynamics: the parasite reductions produced by the different antimalarial drugs in vivo (in an adult patient with 2% parasitemia). Parasite reduction ratios (PRR; fractional reduction per asexual cycle) vary from less than 10 (antibiotics with antimalarial activity, antimalarials for which resistance is high grade) to 10,000 (artemisinin derivatives). Antimalarial drugs must be present at levels greater than the minimum inhibitory concentration (MIC) until eradication of the infection in nonimmune patients to ensure cure of the infection. Adapted with permission from from Trends in Parasitology (60).

Figure 3

Pharmacokinetic properties of the generally available antimalarial drugs. The origin represents the maximum concentration (100%) achieved after a therapeutic dose. A, artemisinins; Q, quinine; P, pyrimethamine; C, chloroquine; M, mefloquine. Adapted with permission from from Trends in Parasitology (60).

Figure 4

The dose-response curve in malaria. Increasing drug resistance leads to a rightward shift in the dose-response or concentration-effect relationship. The principal effect in uncomplicated malaria is parasite killing. This shift can be parallel, or the shape of the curve and the maximum effect can change. Adapted with permission from Trends in Parasitology (60).

Figure 5

Total numbers of malaria parasites (log scale), from inoculation by an anopheline mosquito, through the development of infection in the human host, to the total estimated in the world today.

Figure 6

A slowly eliminated antimalarial such as chloroquine or piperaquine presents a lengthy opportunity for the selection of resistance among sensitive parasites (MIC A), but once resistance has become established (MIC B), the terminal elimination phase is no longer selective, because the blood concentrations are no longer inhibitory.

Figure 7

Opportunities for the de novo selection of antimalarial drug resistance in an area of high transmission (entomological inoculation rate 50 per year; each inoculation is depicted as a green arrow) in a young child treated for acute falciparum malaria with a slowly eliminated drug such as mefloquine (red dotted line). The initial infection (infection 1) is eliminated. The next infection acquired (infection 2) is also eliminated. Infections 3 and 4 are suppressed temporarily but eventually reach detectable densities. Infections 5 and 6 are under no selection pressure and also reach detectable densities. The inset shows the pharmacodynamic events, the relationship between concentration (C) and effect (E). When mefloquine levels fall below the minimum parasiticidal concentration (MPC) giving maximum parasite killing (E_max), then the rate of decline in parasitemia (PRR) falls until the PRR reaches 1. This results from an MIC of mefloquine and occurs in infection 3. Thereafter, parasitemia rises again and becomes detectable nearly 6 weeks after initial treatment.