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JAC Advance Access published online on November 30, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki420
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received March 5, 2005
Revised July 22, 2005
Accepted October 24, 2005

Original article

Apparent absence of atovaquone/proguanil resistance in 477 Plasmodium falciparum isolates from untreated French travellers

Lise Musset 1, Bruno Pradines 2, Daniel Parzy 3, Rémy Durand 1, Patricia Bigot 3, and Jacques Le Bras 1 *

1 Centre National de Référence pour la Chimiosensibilité du Paludisme, APHP, Hôpital Bichat-Claude Bernard, Paris, France; Laboratoire de Biologie Animale et Parasitaire, EA 209, Université Paris Descartes, Paris, France
2 Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Parc du Pharo, Marseille, France; Institut Fédératif de Recherche 48, Marseille, France
3 Institut Fédératif de Recherche 48, Marseille, France; Unité de Recherche en Pharmacogénétique Parasitaire, Institut Médecine Tropicale du Service de Santé des Armées, Parc du Pharo, Marseille, France

* To whom correspondence should be addressed.
Jacques Le Bras, E-mail: jacques.lebras{at}bch.ap-hop-paris.fr


  Abstract

Objectives: We examined the atovaquone in vitro susceptibility and the cytochrome b (cytb) gene polymorphism of African Plasmodium falciparum isolates during the first years of atovaquone/proguanil use.

Patients and methods: Between 1999 and 2004, we collected blood samples from French P. falciparum-infected patients returning from African countries. Atovaquone susceptibility was determined using an in vitro isotopic test and cytb genotyping was performed by restriction fragment length polymorphism analysis and sequencing. These results were analysed according to the clinical response to atovaquone/proguanil treatment.

Results: No in vitro atovaquone resistance (IC50 > 1900 nM) and no cytb mutation leading to the Y268S substitution were detected among 477 unexposed African P. falciparum isolates. Eight cytb polymorphisms were found outside the ubiquinone reduction site by sequencing the entire gene of 270 isolates. One atovaquone/proguanil treatment failure was documented; the post-treatment isolate had an atovaquone susceptibility of 8230 nM and the Ser268 Cytb change; the pre-treatment isolate, obtained 4 weeks previously, was Cytb Tyr268 (wild-type).

Conclusions: No atovaquone/proguanil resistance was detected by phenotyping or genotyping among 477 unexposed African P. falciparum isolates. Atovaquone/proguanil-resistant parasite was detectable only in the post-treatment isolate from a treatment failure.

Keywords: susceptibility; malaria; antimalarials; P. falciparum.
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