Atovaquone—Proguanil Combination

Abstract

Development of an atovaquone—proguanil combination, trademarked Malarone, during the 1990s has been a major step in addressing the need for antimalarial drugs with targets different from those of agents for which resistance is already rampant in the field (1). Atovaquone affects parasite mitochondrial functions in a selective manner (2,3) and, thus, constitutes an entirely new class of antimicrobial agents. While atovaquone as a single agent has been used for treating Pneumocystis carinii pneumonia and toxoplasmosis in immunodeficient patients (4,5), it met with unacceptable rates of treatment failure when used against malaria (6,7). The inclusion of proguanil as a synergistic agent with atovaquone appears to have overcome the high rate of treatment failure, and the resulting drug, Malarone, has been approved for treatment of falciparum malaria in more than 30 countries. This chapter aims to provide a perspective on the development of this new drug and its clinical efficacy. Furthermore, recent studies on mechanisms of action as well as resistance to this drug will be discussed. It is important to note that the atovaquone—proguanil combination maybe one of the few antimalarials for which significant details of drug action and resistance are available before its widespread introduction. This information may prove useful in devising strategies for drug usage as well as in the development of the next generation of antimalarials with mitochondrion-specific modes of action.