Novel Mutation in Cytochrome B of Plasmodium falciparum in One of Two Atovaquone-Proguanil Treatment Failures in Travelers Returning From Same Site in Nigeria

Mateusz M Plucinski, Curtis S Huber, Sheila Akinyi, Willard Dalton, Mary Eschete, Katharine Grady, Luciana Silva-Flannery, Blaine A Mathison, Venkatachalam Udhayakumar, Paul M Arguin, John W Barnwell, Mateusz M Plucinski, Curtis S Huber, Sheila Akinyi, Willard Dalton, Mary Eschete, Katharine Grady, Luciana Silva-Flannery, Blaine A Mathison, Venkatachalam Udhayakumar, Paul M Arguin, John W Barnwell

Abstract

Background: Atovaquone-proguanil (AP) is the most commonly used treatment for uncomplicated Plasmodium falciparum malaria in the United States. Apparent AP treatment failures were reported 7 months apart in 2 American travelers who stayed in the same compound for foreign workers in Rivers State, Nigeria.

Methods: We analyzed pretreatment (day 0) and day of failure samples from both travelers for mutations in the P falciparum cytochrome B (pfcytb) and dihydrofolate reductase (pfdhfr) genes associated with resistance to atovaquone and cycloguanil, the active metabolite of proguanil, respectively. We genotyped the parasites and sequenced their mitochondrial genomes.

Results: On day 0, both travelers had proguanil-resistant genotypes but atovaquone-sensitive cytb sequences. Day of failure samples exhibited mutations in cytb for both travelers. One traveler had the common Y268S mutation, whereas the other traveler had a previously unreported mutation, I258M. The travelers had unrelated parasite genotypes and different mitochondrial genomes.

Conclusions: Despite the infections likely having been contracted in the same site, there is no evidence that the cases were related. The mutations likely arose independently during the acute infection or treatment. Our results highlight the importance of genotyping parasites and sequencing the full cytb and dhfr genes in AP failures to rule out transmission of AP-resistant strains and identify novel mechanisms of AP resistance.

Keywords: Malarone; Plasmodium falciparum; dihydrofolate reductase; drug resistance; malaria.

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