Rationale:

• Drug resistance is increasingly widespread among P. falciparum isolates.
• P. falciparum infections that are not treated appropriately can be rapidly fatal, especially in nonimmune returned travelers.

Evidence:

• Mortality from P. falciparum malaria in travelers returning to the U. S. has been associated with failure of or delay in seeking medical care, inappropriate prophylaxis regimens (e.g., taking chloroquine while traveling in areas with chloroquine-resistant parasites), delays in receiving antimalarial therapy, receiving antimalarial therapy that is inappropriate for the species or region of acquisition, or receiving no antimalarial therapy at all (24; 45).
• In a randomized, controlled trial involving 158 uncomplicated malaria cases in Thailand (an area where mefloquine-resistant malaria has been reported), cure rates for atovaquone-proguanil and mefloquine were 100% and 86%, respectively (105).
• In a randomized, controlled trial involving 98 uncomplicated malaria cases in the Amazon Basin of Peru (an area where chloroquine and sulfadoxine-pyrimethamine-resistant malaria is prevalent), cure rates for both mefloquine (single dose) and mefloquine-artesunate were 100% (106).
• In a randomized, controlled trial involving 154 uncomplicated malaria cases in Brazil, cure rates for oral quinine-tetracycline (7-day regimen) and atovaquone-proguanil were 100% and 98.7%, respectively. Compliance with the quinine-tetracycline regimen was assured by directly observed therapy (107).
• In a randomized, controlled trial involving 137 uncomplicated malaria cases in Thailand, the cure rate for oral quinine-tetracycline (7-day regimen) was 77.4%. Compliance with this regimen was only 71.7% (108).
• Randomized, controlled trials have shown 100% efficacy of quinine-clindamycin in women in the second and third trimesters of pregnancy (109) and in adults with multidrug-resistant uncomplicated malaria (110).

Comments:

• Other factors that may influence the treatment regimen for uncomplicated malaria include: patient's age (contraindication of tetracyclines in young children due to adverse effects on bone growth and teeth discoloration, and the bitter taste of quinine is not tolerated by young children), prior use of prophylactic drug (which may indicate to which drug the parasite may be resistant), known drug allergies, and drug availability.
• Although background immunity may help to clear drug-resistant parasites and favorably influence the patient's clinical course, this consideration should not be used to determine the drug regimen used in actual practice (e.g., shorter courses of therapy).
• Failures of initial treatment of malaria with atovaquone-proguanil have been described in nonimmune travelers returning from Nigeria, Mali, Cameroon, Ivory Coast, Kenya, and the Democratic Republic of Congo (111; 112; 113; 114; 115).
• Use of sulfadoxine-pyrimethamine in treatment of malaria is now limited because of drug resistance in South America, Southeast Asia, and in parts of southern and eastern Africa. Although no longer recommended for use in travelers, it remains effective as single-dose therapy for uncomplicated malaria in some parts of Africa where the prevalence of chloroquine resistance is high and where alternative therapies may not be affordable or available. In a randomized, controlled trial involving 142 children with uncomplicated malaria in Ghana, for example, cure rates for chloroquine and sulfadoxine-pyrimethamine were 70% and 90%, respectively (116).
• Amodiaquine, an antimalarial drug chemically related to chloroquine, has advantages over chloroquine that include some effectiveness in treating chloroquine-resistant P. falciparum malaria (117), more palatable taste (facilitating its administration to children), and less likelihood to cause pruritus (118). A review of 40 trials available in the Cochrane library showed that amodiaquine was more effective than chloroquine in clearing parasites and that there were no significant differences in adverse events between amodiaquine, chloroquine, and sulfadoxine-pyrimethamine (119). Reports of serious adverse reactions, such as agranulocytosis, hepatotoxicity, and aplastic anemia have been rare and associated with long-term prophylactic rather than therapeutic use (28; 29). Amodiaquine has been removed from the U.S. market.