Atovaquone is a highly active antiplasmodial drug based on the natural product lapachol (1) (from Surinam greenheart wood). Atovaquone and lapachol are 2-hydroxynaphthoquinones mimicking ubiquinone in the mitochondrial cytochrome B-C1 complex. In early therapeutic studies on the new agent, recrudescence of Plasmodium falciparum was often seen after a course of treatment (2), and the isolate was found to be drug resistant. Experimental studies showed that including proguanil (Paludrine) in the treatment prevented the development of resistance (3). The combination, Malarone, has since been introduced successfully as a malaria prophylactic and therapeutic drug (4).
There have been isolated reports of Malarone treatment failure, as with most drugs, but no instance of confirmed resistance has been seen until recently. A resident of the United Kingdom returned from a visit to Lagos, Nigeria, without prophylaxis, and developed falciparum malaria two weeks later. The patient was treated in hospital with a standard three day course of Malarone, and discharged. Twenty-eight days later, the fever and parasitaemia returned. Parasites cultured at this point were resistant to atovaquone. The cytochrome B gene showed a single mutation in the ubiquinone active site, specifying a new residue change (5).
This case, in itself, has no implications for prevention or treatment, but emphasises the importance of monitoring for breakthrough infections and performing genetic analysis of any recrudescent parasites.