Resistance to Atovaquone-Proguanil?

Abstract & Commentary

Synopsis: These cases of post-travel malaria in multiple members of the same family provide important "teaching points" about malaria prevention in travelers, yet they raise a significant concern that resistance to atovaquone-proguanil might already be appearing.

Source: Farnert A, et al. Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguanil hydrochloride: Case reports. BMJ. 2003;326:628-629.

In September 2000, 2 febrile brothers were diagnosed with Falciparum malaria in Sweden following a 2-month visit to the Ivory Coast, where they used chloroquine and proguanil as prophylaxis. Their asymptomatic and possibly semi-immune mother was also parasitemic. Each of them was treated with the combination agent atovaquone-proguanil (AP). One boy became sicker and recovered following mefloquine treatment. The other boy’s illness resolved but then recurred 4 weeks later when it was also successfully treated with mefloquine. The mother recovered following her initial treatment.

Each of these individuals had adequate serum levels of both atovaquone and proguanil metabolites. Parasite analysis revealed that 1 boy and the mother were infected with single parasite clones, while the other child was infected with 5 genetically diverse parasite populations. A cytochrome b mutation that had been previously linked to atovaquone resistance was found in the mother and only 1 of the boys. Only the other boy, and not the mother, had mutations in a dihydrofolate reductase gene previously related to proguanil resistance.

Comment by Philip R. Fischer, MD, DTM&H

It was clear during the recent International Society of Travel Medicine meeting in New York that AP is one of the preferred prophylactic agents for travelers visiting malaria-endemic areas. Nonetheless, enthusiasm for the long-term future of AP was tempered a bit because of growing awareness of the cases just noted above. It seems that already, just a few years after the introduction of AP, parasite resistance has been identified.

Atovaquone is an antiprotozoal agent that interferes with mitochondrial electron transport and pyrimidine biosynthesis.1 When used orally, it is rapidly effective but is associated with a high, approximately 30%, recrudescence rate.2 Parasites initially isolated from patients with recrudescent illness had a mutation in the parasites’ cytochrome b gene.1 Proguanil potentiates the effect of atovaquone, and the combination product is usually not associated with recrudescence of infection.

Together, atovaquone and proguanil have proven efficacy in the prevention3,4 and treatment1 of malaria. The combination product has been licensed for prophylaxis and curative treatment of malaria in the United States since July 2000. Due to a lack of data, this product is not widely recommended for use in children weighing less than 11 kg or during pregnancy and lactation of small children.5 Recommended dosing is shown in the Table.5

Table
Daily Dosing of Atovaquone-Proguanil
Body Weight, kg Prophylactic,* mgA/mgP Curative,** mgA/mgP
11-20 62.5/25 250/100
21-30 125/50 500/200
31-40  187.5/75 750/300
> 40 250/100 1000/400

* daily dose beginning 1-2 days prior to departure and continuing 7 days after leaving malarial area

** daily dose for 3 consecutive days

These reports of persistent and recurrent malaria due to AP-resistant P falciparum just a few years after AP’s introduction raise important concerns. What can we learn from these cases? First, travelers should use personal protective measures appropriately along with chemoprophylaxis. More apparent now than when the reported family visited West Africa, the combination of chloroquine and proguanil is not an adequate prophylactic agent for travelers to West Africa. Second, no antimalarial treatment is perfect. Physicians treating malaria must vigilantly follow their patients during and after treatment so that good outcomes result, as in the reported cases, even in the face of rare and unexpected resistance. Third, it is certainly too early to "give up" on AP. Extensive, recent experience from around the world1 has documented that AP is either better than, or similarly effective to, other antimalarial agents. Finally, we still have much to learn. The parasites identified in this family were complex, and the mechanisms of resistance are still quite poorly understood.

By what mechanisms are P falciparum parasites resistant to the combination of atovaquone and proguanil? Mutations in the cytochrome b gene had been previously identified1 in atovaquone-resistant parasites and were identified in the boy with recurrent illness in the recent report. Nonetheless, such a mutation was not found in the boy with early treatment failure and yet was found in the mother who did respond well to AP treatment. In addition, the dihydrofolate reductase gene mutation was found in the boy with recrudescent illness but might not relate to AP resistance; the role of proguanil in AP is likely more for a synergistic effect in boosting atovaquone effectiveness than in a primary antiparasitic action by proguanil.6

For now, travel medicine practitioners can continue to use AP as a valued component of malaria prevention and therapy. At the same time, however, we must carefully watch our own experiences and the reports of others as AP resistance might become more common.

References

1. Looareesuwan S, et al. Malarone (atovaquone and proguanil hydrochloride): A review of its clinical development for treatment of malaria. Am J Trop Med Hyg. 1999;60:533-541.

2. Wongsrichanalai C, et al. Epidemiology of drug-resistant malaria. Lancet Infect Dis. 2002;2:209-218.

3. Overbosch D, et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: Results from a randomized, double-blind study. Clin Infect Dis. 2002;33:1015-1021.

4. Hogh B, et al. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travellers: A randomised, double-blind study. Lancet. 2000;356:1888-1894.

5. CDC. Malarone for malaria treatment and prophylaxis—for health care providers. http://www.cdc.gov/travel/diseases/malaria/malarone.htm, accessed 6/6/2003.

6. Srivastava IK, Vaidya AB. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother. 1999;43:1334-1339.

Dr. Fischer is Professor of Pediatrics, Department of Pediatric & Adolescent Medicine, Mayo Clinic, Rochester, MN.