Atovaquone and Proguanil for Children
ABSTRACTS & COMMENTARY
Synopsis: The combination of atovaquone and proguanil is effective both for antimalarial chemoprophylaxis and for therapeutic cure of multidrug-resistant falciparum malaria in children.
Sources: Lell B, et al. Randomized placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet 1998;351:709-713; Sabchareon A, et al. Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug-resistant Plasmodium falciparum malaria. Trans Royal Soc Trop Med Hyg 1998;92:201-206.
Lell and associates report that, over a three-month period, 265 Gabonese children, ages 4-16 years, received either daily placebo or daily atovaquone plus proguanil in a randomized, double-blinded study. At entry, each child was given a curative dose of atovaquone and proguanil. During the course of the study, adverse events did not differ between control and treatment groups. No treated child had a positive malaria smear, but 25 (18%) of 140 placebo-treated children had positive smears. The combination of atovaquone and proguanil was well-tolerated and highly effective for these children.
Sabchareon and colleagues studied 28 Thai children, aged 5-12 years, with uncomplicated multidrug-resistant falciparum malaria. The combination of atovaquone and proguanil, given as an oral daily dose following a meal on three consecutive days, was curative for all children. Parasite clearance was achieved in 47 (range, 8-75) hours, and fever resolved in 50 (range, 7-111) hours. Pharmacokinetic studies showed rapid absorption of each component of the combination drug. No major adverse effects were noted.
COMMENT BY PHILIP R. FISCHER, MD
As plasmodial parasites become increasingly resistant to currently available antimalarials, new products and combinations are being evaluated. Atovaquone, a hydroxynaphthoquinone, inhibits electron transport of the parasites' mitochondria and results in decreased nucleic acid synthesis. Initial studies showed that it allowed unacceptably high rates of recrudescence when used alone in patients with malaria. Proguanil and its metabolite, cycloguanil, inhibit dihydrofolate reductase. Together, these two agents have a synergistic effect against intraerythrocytic malaria parasites.
In Asia, South America, and Africa, atovaquone-proguanil has proven itself to be effective against malaria in adults. The two recent reports summarized above extend the known usefulness of this combination drug to both preventive and curative use in school-aged children.
While atovaquone-proguanil holds promise for widespread use, it is not yet available in the United States. In endemic areas, its cost could limit its availability to local populations. To combat this, the manufacturer is organizing controlled donation programs to facilitate drug distribution in targeted populations.
Another concern with new antimalarials is the potential for malaria resistance to develop. Hence, new products should not be used when other effective products are still available. Mefloquine is tolerated by and effective in children traveling to most areas of the world. Thus, atovaquone-proguanil is not currently needed by most traveling children, but it could become both available and useful in the coming years.
There is not much reason to expect either toxicity or decreased effectiveness of atovaquone-proguanil with long-term prophylactic use. Nonetheless, the current data on prophylaxis in children only extend over a three-month period. Compliance would also need to be encouraged, since consistent daily dosing is not easy for many families. Further studies are needed to evaluate the effectiveness and side effects of this product in younger children, who are at particular risk of death from malaria.
It is quite impressive that atovaquone-proguanil was effective along the Thai border, an area recognized as the home of the world's most resistant malaria. While P. falciparum in this area resists treatment by chloroquine, Fansidar, mefloquine, and quinine, atovaquone-proguanil could fill a needed therapeutic niche. In addition, the three-day dosing was easier and better tolerated than the longer courses of quinine that are currently used.
While malaria continues to kill more than 1 million children each year, these new pediatric data are encouraging. The combination of atovaquone-proguanil offers hope for effective prophylaxis and cure of malaria for children both traveling to and residing within areas endemic for multidrug-resistant malaria.