Burden of Drug Resistance in Malaria: Important Role of Antimalarial Combination Therapy

All antimalarial drugs available for the treatment and prevention of malaria are limited primarily by resistance and cross-resistance. The concept of combination therapy is based on the presence of two or more drugs with different mechanisms of action which enhances treatment efficacy and aids in deterring the emergence and spread of drug resistance. WHO has endorsed Artemisinin based Combination Therapies (ACTs) as a “policy standard”, and these drug combinations are first-line treatment for all malaria infections in areas where P. falciparum is the predominant infecting species. The frequent failures of 7 day artemisinin monotherapy has been overcome through the administration of 3 day oral ACT drug combination treatment where artemisinin compounds are coadministered with long-acting antimalarial drugs which facilitate the elimination of the residual malarial parasites not killed by the artemisinin component. ACTs can improve the efficacy of failing individual component drugs, lower the incidence of malaria, and provide some protection for individual component drugs against the development of higher levels of resistance. Artemisinins are the most important class of antimalarial agents in the world today. These drugs are widely used, particularly for treatment of multidrug-resistant P. falciparum malaria. The first-generation artemisinins have their limitations, which include poor oral bioavailability, short half-lives, and recent development of drug resistance in Southeast Asia characterized by delayed parasite clearance. Second- and third-generation artemisinins will likely be cheaper, less prone to drug resistance, and have better pharmacokinetic properties. ACTs are more effective for treatment of falciparum malaria than other antimalarials, they are prescribed for limited periods of treatment, which enhances drug compliance, and they have a well-demonstrated ability to reduce transmission by decreasing gametocyte carriage. In the absence of an effective malaria vaccine, new combinations are also needed to protect patient populations in years to come. In this review, we will define the ideal and minimally acceptable characteristics of clinical partner drugs and combination treatments needed in the future. Continued investment over the next decade in discovery and development of new drugs and drug combinations are essential to combat malaria and avoid emergence of antimalarial drug resistance.