The WHO recommends five artemisinin-based combinations for the treatment of uncomplicated falciparum malaria (Table 52–4). One of these, artesunate-sulfadoxine-pyrimethamine is not recommended in many areas owing to unacceptable levels of resistance to sulfadoxine-pyrimethamine, but it is the first-line therapy in some countries. The other recommended regimens are available as combination formulations, although manufacturing standards may vary. Artesunate-mefloquine is highly effective in Southeast Asia, where resistance to many antimalarials is common; it is the first-line therapy in some countries in Southeast Asia and South America. This regimen is less practical for other areas, particularly Africa, because of its relatively high cost and poor tolerability. Either artesunate-amodiaquine or artemetherlumefantrine is the standard treatment for uncomplicated falciparum malaria in most countries in Africa and some additional endemic countries on other continents. Dihydroartemisininpiperaquine is a newer regimen that has shown excellent efficacy; it is a first-line therapy for falciparum malaria in parts of Southeast Asia. Artesunate-pyronaridine (Pyramax) was recently approved, and it appears to offer efficacy similar to that of other combinations, but data are limited, especially for young children. Of concern, increased failure rates for artesunate-mefloquine and dihydroartemisinin-piperaquine have been reported recently in parts of Southeast Asia, in the setting of decreased activity of both components of the regimens.
Artemisinins also have outstanding efficacy in the treatment of complicated falciparum malaria. Large randomized trials and meta-analyses have shown that intramuscular artemether has an efficacy equivalent to that of quinine and that intravenous artesunate is superior to intravenous quinine in terms of parasite clearance time and—most important—patient survival. Intravenous artesunate also has a superior side-effect profile when compared with intravenous quinine or quinidine. Thus, intravenous artesunate has replaced quinine as the standard of care for the treatment of severe falciparum malaria. Artesunate and artemether have also been effective in the treatment of severe malaria when administered rectally, offering a valuable treatment modality when parenteral therapy is not available.
Artemisinins are generally very well tolerated. The most commonly reported adverse effects are nausea, vomiting, diarrhea, and dizziness, and these may often be due to underlying malaria rather than the medications. Rare serious toxicities include neutropenia, anemia, hemolysis, elevated liver enzymes, and allergic reactions. In addition, delayed hemolysis after artemisinins for severe malaria appears to be quite common (estimated in 13% of cases), typically beginning 2–3 weeks after therapy, with 73% of identified cases requiring transfusion. Irreversible neurotoxicity has been seen in animals, but only after doses much higher than those used to treat malaria. Artemisinins have been embryotoxic in animal studies, but rates of congenital abnormalities, stillbirths, and abortions were not elevated in women who received artemisinins during pregnancy, compared with those of controls. Based on this information and the significant risk of malaria during pregnancy, the WHO recommends artemisinin-based combination therapies for the treatment of uncomplicated falciparum malaria during the second and third trimesters of pregnancy (quinine plus clindamycin is recommended during the first trimester), and intravenous artesunate for the treatment of severe malaria during all stages of pregnancy.
Quinine and quinidine remain important therapies for falciparum malaria—especially severe disease—although toxicity may complicate therapy.