Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2020 Jan 21;19(1):37.
doi: 10.1186/s12936-020-3126-y.

Late clinical failure associated with cytochrome b codon 268 mutation during treatment of falciparum malaria with atovaquone-proguanil in traveller returning from Congo

Laurencie Massamba  1 , Marylin Madamet  2   3   4   5 , Nicolas Benoit  2   3   4   5 , Alicia Chevalier  1 , Isabelle Fonta  2   3   4   5 , Véronique Mondain  6 , Pierre-Yves Jeandel  7 , Rémy Amalvict  2   3   4   5 , Pascal Delaunay  1   8 , Joel Mosnier  2   3   4   5 , Pierre Marty  1   9 , Christelle Pomares  1   9 , Bruno Pradines  10   11   12   13
Affiliations
Case Reports

Late clinical failure associated with cytochrome b codon 268 mutation during treatment of falciparum malaria with atovaquone-proguanil in traveller returning from Congo

Laurencie Massamba et al. Malar J. .

Abstract

Background: The drug combination atovaquone-proguanil, is recommended for treatment of uncomplicated falciparum malaria in France. Despite high efficacy, atovaquone-proguanil treatment failures have been reported. Resistance to cycloguanil, the active metabolite of proguanil, is conferred by multiple mutations in the Plasmodium falciparum dihydrofolate reductase (pfdhfr) and resistance to atovaquone by single mutation on codon 268 of the cytochrome b gene (pfcytb).

Case presentation: A 47-year-old female, native from Congo and resident in France, was admitted in hospital for uncomplicated falciparum malaria with parasitaemia of 0.5%, after travelling in Congo (Brazzaville and Pointe Noire). She was treated with atovaquone-proguanil (250 mg/100 mg) 4 tablets daily for 3 consecutive days. On day 5 after admission she was released home. However, many weeks after this episode, without having left France, she again experienced fever and intense weakness. On day 39 after the beginning of treatment, she consulted for fever, arthralgia, myalgia, photophobia, and blurred vision. She was hospitalized for uncomplicated falciparum malaria with a parasitaemia of 0.375% and treated effectively by piperaquine-artenimol (320 mg/40 mg) 3 tablets daily for 3 consecutive days. Resistance to atovaquone-proguanil was suspected. The Y268C mutation was detected in all of the isolates tested (D39, D42, D47). The genotyping of the pfdhfr gene showed a triple mutation (N51I, C59R, S108N) involved in cycloguanil resistance.

Conclusion: This is the first observation of a late clinical failure of atovaquone-proguanil treatment of P. falciparum uncomplicated malaria associated with pfcytb 268 mutation in a traveller returning from Congo. These data confirm that the Y268C mutation is associated with delayed recrudescence 4 weeks or more after initial treatment. Although atovaquone-proguanil treatment failures remain rare, an increased surveillance is required. It is essential to declare and publish all well-documented cases of treatment failures because it is the only way to evaluate the level of resistance to atovaquone.

Keywords: Anti-malarial drug; Atovaquone; Cytochrome b; In vitro; Malaria; Plasmodium falciparum; Proguanil; Resistance.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Similar articles

See all similar articles

Cited by

References

    1. Epelboin L, Rapp C, Faucher JF, Méchaï F, Bottieau E, Matheron S, et al. Management and treatment of uncomplicated imported malaria in adults. Update of the French malaria clinical guidelines. Med Mal Infect. 2019 doi: 10.1016/j.medmal.2019.07.011. - DOI - PubMed
    1. Savini H, Bogreau H, Bertaux L, Bouchiba H, Kraemer P, Parzy D, et al. First case of emergence of atovaquone–proguanil resistance in Plasmodium falciparum during treatment in a traveler in Comoros. Antimicrob Agents Chemother. 2008;52:2283–2284. doi: 10.1128/AAC.00282-08. - DOI - PMC - PubMed
    1. Musset L, Bouchaud O, Matheron S, Massias L, Le Bras J. Clinical atovaquone–proguanil resistance of Plasmodium falciparum associated with cytochrome b codon 268 mutations. Microbes Infect. 2006;8:2599–2604. doi: 10.1016/j.micinf.2006.07.011. - DOI - PubMed
    1. Musset L, Pradines B, Parzy D, Durand D, Bigot P, Le Bras J. Apparent absence of atovaquone/proguanil resistance in 477 Plasmodium falciparum isolates from untreated French travellers. J Antimicrob Chemother. 2006;57:110–115. doi: 10.1093/jac/dki420. - DOI - PubMed
    1. Sutherland CJ, Laundy M, Price N, Burke M, Fivelman QL, Pasvol G, et al. Mutations in the Plasmodium falciparum cytochrome b gene are associated with delayed parasite recrudescence in malaria patients treated with atovaquone–proguanil. Malar J. 2008;7:240. doi: 10.1186/1475-2875-7-240. - DOI - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources