Antimalarial Drugs Resistance

Malaria sickens and kills people through several pathological mechanisms, understood to varying degrees. In addition to first- and second-line antimalarial drug treatments, adjunctive and supportive care measures may be needed for severe manifestations. The aims of treatment are to prevent death or long-term deficits from malaria, to cut short the morbidity of an acute episode of illness, and to clear the infection entirely so that it does not recur.

Fever, sweating, and chills triggered by the release of plasmodia into the bloodstream from mature blood schizonts, are the most common symptoms heralding the onset of a clinical case of uncomplicated falciparum malaria. Without treatment or an active immune response primed by repeated previous malaria infections the number of parasites will increase with every 2-day cycle of reproduction. A mature infection may involve up to 10¹² circulating plasmodia.

At any time after the infection is established, the vast majority of plasmodia will be in some stage of asexual maturation leading to another round of multiplication within the patient's bloodstream. However, a few parasites will have transformed into sexual stages (gametocytes) that, once ingested by mosquitoes, can perpetuate the transmission cycle. Because each stage of the malarial life cycle exhibits distinct biochemical and other characteristics, a drug may kill one stage but have little effect on another. In other words, in each life-cycle stage the parasite manifests unique biological properties that can offer a target for the action of one or more antimalarial drugs.

In general, antimalarial drug resistance to mefloquine, quinine, lumefantrine, and halofantrine is linked, whereas chloroquine, and mefloquine resistance are not. Cross-resistance between antimalarials is related to common aspects of their modes of action as well as their resistance mechanisms. Parasites with high-level chloroquine resistance are generally resistant to amodiaquine as well; in residents of Southeast Asia, amodiaquine may thus fail as a back-up treatment. The same relationship holds true for halofantrine, and mefloquine. On the other hand, there may be an inverse correlation between chloroquine and mefloquine sensitivity: in Africa, for example, chloroquine-sensitive strains are substantially less sensitive to mefloquine or halofantrine, and vice versa.

Atovaquone is a component of Malarone, a new combination drug used for treatment and prevention of chloroquine-resistant P. falciparum. Atovaquone interferes with mitochondrial electron transport, and also blocks cellular respiration. High levels of atovaquone resistance result from single-point mutations in a gene encoding cytochrome b found on a small, extrachromosomal DNA-containing element in the parasite.

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