Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread

Abstract

The emergence of resistance to former first-line antimalarial drugs has been an unmitigated disaster. In recent years, artemisinin class drugs have become standard and they are considered an essential tool for helping to eradicate the disease. However, their ability to reduce morbidity and mortality and to slow transmission requires the maintenance of effectiveness. Recently, an artemisinin delayed-clearance phenotype was described. This is believed to be the precursor to resistance and threatens local elimination and global eradication plans. Understanding how resistance emerges and spreads is important for developing strategies to contain its spread. Resistance is the result of two processes: (i) drug selection of resistant parasites; and (ii) the spread of resistance. In this review, we examine the factors that lead to both drug selection and the spread of resistance. We then examine strategies for controlling the spread of resistance, pointing out the complexities and deficiencies in predicting how resistance will spread.

Fig. 1

Life cycle of the malaria parasite. Transmission of malaria occurs through a vector, the mosquito, that ingests gametocytes—the sexual form of the parasite—when feeding on an infected human. Gametocytes, which are both male and female, mate within the gut of the mosquito and undergo meiosis and then migrate through the midgut wall of the mosquito and form an oocyst [41], within which thousands of sporozoites develop [42]. These are then injected into a human during the next blood meal(s), where they rapidly make their way to the liver and infect hepatocytes and begin asexually (mitotically) replicating [43]. After a period of ca. 6–15 days, the liver schizonts rupture, releasing thousands of merozoites into the blood where they invade red blood cells. Over the next ca. 48 h, the parasite begins replicating mitotically, progressing through a set of stages (ring, trophozoite and schizont), and produces an average of 16 new daughter merozoites per schizont [44]. The schizonts then burst in near synchrony with other parasites, producing the characteristic fever cycle that embodies the clinical manifestations of the disease. With each replication, some of the merozoites, instead of producing new merozoites, develop into gametocytes, which can then infect susceptible mosquitoes, bringing the transmission cycle full circle.