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LETTERS TO THE EDITOR

First Case of Emergence of Atovaquone-Proguanil Resistance in Plasmodium falciparum during Treatment in a Traveler in Comoros

Helene Savini, Hervé Bogreau, Lionel Bertaux, Housem Bouchiba, Philippe Kraemer, Daniel Parzy, Eric Garnotel, Christophe Rogier, Fabrice Simon, Bruno Pradines
Helene Savini
Service de Pathologies Infectieuses et Tropicales Hôpital d'Instruction des Armées Laveran Marseille, France
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Hervé Bogreau
Unité de Recherche en Biologie et Epidémiologie Parasitaires Unité mixte de recherche 6236 Institut de Médecine Tropicale du Service de Santé des Armées Marseille, France
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Lionel Bertaux
Unité de Recherche en Physiologie et Pharmacocinétique Parasitaires Institut de Médecine Tropicale du Service de Santé des Armées Marseille, France
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Housem Bouchiba
Unité de Recherche en Biologie et Epidémiologie Parasitaires Unité mixte de recherche 6236 Institut de Médecine Tropicale du Service de Santé des Armées Marseille, France
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Philippe Kraemer
Service de Pathologies Infectieuses et Tropicales Hôpital d'Instruction des Armées Laveran Marseille, France
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Daniel Parzy
Unité de Recherche en Physiologie et Pharmacocinétique Parasitaires Institut de Médecine Tropicale du Service de Santé des Armées Marseille, France
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Eric Garnotel
Service de Biologie Médicale Hôpital d'Instruction des Armées Laveran Marseille, France
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Christophe Rogier
Unité de Recherche en Biologie et Epidémiologie Parasitaires Unité mixte de recherche 6236 Institut de Médecine Tropicale du Service de Santé des Armées Marseille, France
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Fabrice Simon
Service de Pathologies Infectieuses et Tropicales Unité mixte de recherche 6236 Hôpital d'Instruction des Armées Laveran Marseille, France
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Bruno Pradines
Unité de Recherche en Biologie et Epidémiologie Parasitaires Unité mixte de recherche 6236 Institut de Médecine Tropicale du Service de Santé des Armées Boulevard Charles Livon, Parc du Pharo, BP46 13998 Marseille Armées, France
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  • For correspondence: bruno.pradines@free.fr
DOI: 10.1128/AAC.00282-08
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Atovaquone-proguanil (Malarone; GlaxoSmithKline) is now commonly used for the treatment and prophylaxis of falciparum malaria in France. We report here a treatment failure of atovaquone-proguanil in a patient who was infected during a 33-day visit without antimalarial prophylaxis in Comoros.

The patient presented with fever 10 days after the end of his trip, and a diagnosis of falciparum malaria was made. Treatment with atovaquone-proguanil was well tolerated. Isolated fever in association with falciparum parasites appeared 23 days after therapy. The patient was successfully treated with quinine.

In vitro susceptibility tests performed on blood samples from day 0 and day 23 showed a 50% inhibitory concentration (IC50) value for atovaquone that was more than 100-fold greater on day 23 than on day 0 (Table 1). In addition, the IC50 for cycloguanil was increased by 18-fold.

Sequencing of the cyt b gene, encoding the atovaquone target (12), showed a wild-type P. falciparum strain on day 0 and a Y268S mutation on day 23.

Genotyping of the dhfr gene, encoding the proguanil target (5), showed a double mutation, C59R and S108N, on day 0, while a triple mutation, N51I, C59R, and S108N, was observed on day 23. However, proguanil likely does not act by itself in atovaquone-proguanil treatment but only facilitates the atovaquone activity (11).

Genotyping of the Pfcrt gene (wild type, K76), encoding a transport protein involved in chloroquine resistance, and of the dhps gene (wild type, S436, A437, K540, A581, and A613), encoding the sulfadoxine target (5), showed wild-type, identical alleles.

The genotyping of the two isolates, using three of six microsatellite loci (7A11, Pf2802, C4M79, Pf2689, TRAP, and C4M69) (1), msp1, and msp2 (5), showed differences between days 0 and 23 (Table 1).

The day 23 parasites presented a high IC50 for atovaquone associated with a Y268S mutation in Cyt b. Since 2002, fewer than 20 cases of genetically confirmed clinical resistance to atovaquone-proguanil had been reported (2-4, 6, 7, 9, 13, 14). Clinical failures were associated with in vitro-increased IC50s for atovaquone between day 0 and the failure day only in five isolates (4, 7, 9). In some cases, the increased IC50 was moderate (7, 8). An in vitro atovaquone threshold of 1,900 nM was recommended to discriminate resistant isolates (10). Considering our results, this cutoff must be adjusted to >350 nM.

We were unable to detect Cyt b mutations on codon 268 and high IC50 to atovaquone in the pretreatment isolate. Reinfection was excluded because the patient was treated after returning to France. The atovaquone-resistant strain was probably present in the initial isolate but in the minority, making it undetectable by classical genotyping methods and in vitro testing. The isolate was polyclonal on day 0 and monoclonal on day 23.

This is the first observation of the clinical failure of atovaquone-proguanil treatment of P. falciparum infection in a traveler in Comoros, an area where the in vitro prevalences of isolates with reduced susceptibilities to classical antimalarial drugs were <7% (12).

Although clinical failures of atovaquone-proguanil therapy remain rare in travelers, an increased vigilance is required during their treatment followup, and surveillance of the parasite population should be reinforced as well.

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TABLE 1.

In vitro drug susceptibility profiles and changes in genotyping profiles of the day 0 and day 23 P. falciparum parasitesa

ACKNOWLEDGMENTS

We thank Rémy Amalvict, Nicolas Benoit, Eric Baret, and Julien Cren for technical support.

This work was support by the French Ministry of Health (Institut de Veille Sanitaire) and French Ministry of Defense (Direction Centrale du Service de Santé des Armées).

  • Copyright © 2008 American Society for Microbiology

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First Case of Emergence of Atovaquone-Proguanil Resistance in Plasmodium falciparum during Treatment in a Traveler in Comoros
Helene Savini, Hervé Bogreau, Lionel Bertaux, Housem Bouchiba, Philippe Kraemer, Daniel Parzy, Eric Garnotel, Christophe Rogier, Fabrice Simon, Bruno Pradines
Antimicrobial Agents and Chemotherapy May 2008, 52 (6) 2283-2284; DOI: 10.1128/AAC.00282-08

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First Case of Emergence of Atovaquone-Proguanil Resistance in Plasmodium falciparum during Treatment in a Traveler in Comoros
Helene Savini, Hervé Bogreau, Lionel Bertaux, Housem Bouchiba, Philippe Kraemer, Daniel Parzy, Eric Garnotel, Christophe Rogier, Fabrice Simon, Bruno Pradines
Antimicrobial Agents and Chemotherapy May 2008, 52 (6) 2283-2284; DOI: 10.1128/AAC.00282-08
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KEYWORDS

antimalarials
Atovaquone
drug resistance
Malaria, Falciparum
Plasmodium falciparum
proguanil
Travel

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