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The malaria parasite has caused untold grief throughout human history. The name originated from Italian mal aria (bad air) because the ancient Romans believed the disease was caused by the decay in marshes and swamps and was carried by the malodorous “foul” air emanating from these areas.8 In the 1880s, both the Plasmodium protozoa and its mosquito vector were ­identified.8 Today, nearly half of the world’s population lives in areas where malaria is endemic. Despite markedly decreased mortality rates over the last 7 years, malaria remains a significant cause of morbidity and mortality worldwide. In 2015, there were 212 million estimated malaria cases, leading to 429,000 deaths.119 Most of these deaths were from Plasmodium falciparum infections of young children and primigravid pregnant women in Africa.15 Included among those at risk of becoming infected are 50 million travelers from industrialized countries who visit the developing countries each year. Despite using prophylactic medications, an estimated 30,000 of these travelers will acquire malaria.96


Malaria is an infection of protozoan parasites in the Plasmodium genus with a unique life cycle involving the Anopheles mosquito as vector. Today malaria is primarily endemic in tropical and subtropical areas worldwide. It was once endemic in temperate areas, including Western Europe and the United States, but economic development and improvements in ­public health hastened its retreat.45 Malaria was fully eradicated from the United States between 1947 and 1951 owing in large part to the powerful insecticidal effects of dichloro diphenyl trichloroethane (DDT).45 The emergence of DDT-resistant Anopheles mosquitoes and chloroquine-resistant Plasmodium spp has impeded eradication in other parts of the world.45

Malaria has a unique life cycle (Fig. 55–1) beginning with inoculation of sporozoites from an infected female Anopheles saliva. The sporozoites travel to the liver, where they invade the host’s hepatocytes and undergo asexual division (asexual exoerythrocytic cycle), ultimately causing rupture of the infected hepatocyte (tissue schizont) and release of thousands of merozoites into the bloodstream.5 The tissue phase is complete at this point with the exception of Plasmodium vivax and Plasmodium ovale, which can remain dormant in liver cells (hypnozoites), causing recurrent infections years later. The erythrocytic cycle begins when merozoites penetrate erythrocytes (trophozoites), undergoing additional cycles of asexual division (erythrocytic schizont), leading to cell rupture and the release of a new wave of merozoites to infect additional erythrocytes. This erythrocytic cycle is responsible for the clinical manifestations of malaria. Some erythrocytic merozoites differentiate into sexual forms (macrogametocytes {female} and microgametocytes {male}). Ingestion of both sexual forms by the female Anopheles during a blood meal allows fertilization and zygote formation in the mosquito midgut epithelium (sporogenic cycle), ultimately leading to rupture of an oocyst and release of sporozoites that migrate to the salivary glands, awaiting injection into another victim.115

FIGURE 55–1.

Life cycle stages during which antimalarials exert their ...

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