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Antimicrobial Agents and Chemotherapy, June 2007, p. 2280-2281, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01532-06

LETTER TO THE EDITOR

First Case of Emergence of Atovaquone Resistance in Plasmodium falciparum during Second-Line Atovaquone-Proguanil Treatment in South America {triangledown}


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The atovaquone-proguanil combination (Malarone) has been introduced in French Guiana for prophylaxis and second-line treatment for Plasmodium falciparum malaria in 2002. We report here a treatment failure in a patient who was given a second-line atovaquone-proguanil treatment. A nonimmune P. falciparum patient was infected during a 5-day visit without prophylaxis in Maripasoula, a region of malaria endemicity, and while residing in a malaria-free area, the patient experienced three malaria episodes on day 0 (treated with halofantrine [Halfan]), day 25 (treated with atovaquone-proguanil), and day 49 (treated with quinine-doxycline). All treatments were well tolerated. Plasma atovaquone concentration, measured 1 day after atovaquone-proguanil administration, was 1.45 µg/ml, indicating adequate drug absorption (8).

In vitro susceptibility tests, performed on blood samples from day 0 and day 49 (no blood sample was collected before atovaquone-proguanil administration), showed an increased 50% inhibitory concentration (IC50) value for atovaquone on day 49 compared to that on day 0 (Table 1). Genotyping of the parasites from days 0, 26, and 49, using four microsatellite loci (C4M69, 7A11, C4M79, and Pf2802) (1), msp2, and glurp (6), showed identical alleles for each locus in the three samples. The sequencing of cyt b, the atovaquone target (4, 9, 11), showed a wild-type 268 codon in the day 0 and day 26 samples and a 268S mutation in the day 49 sample. The sequencing of Pfdhfr-ts (the target of proguanil) (3) showed the same C50R N51I S108N triple mutant in the three samples, which furthermore had an increased copy number (two gene copies). In brief, the parasite genotypes of the three episodes were indistinguishable for all loci except cyt b. These data indicate that the second and third episodes were recrudescences due to successive treatment failures.


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  		TABLE 1. In vitro drug susceptibility profiles of the day 0 and day 49 parasitesa

 
The day 49 parasites presented elevated IC50 levels for atovaquone and a 268S mutant Cyt b, a mutation consistently associated with in vitro resistance to atovaquone and therapeutic failures (2, 4, 5, 8, 10). The resistance mutation was undetected in both pretreatment samples, indicating the emergence of resistant parasites during the course of the atovaquone-proguanil treatment. The presence of the 268S cyt b mutation was associated with a significantly lower IC50 level for atovaquone than for some atovaquone-proguanil treatment failures associated with the same mutation (2, 8). This result may suggest, in light of lack of cyt b mutation in an atovaquone-proguanil failure (12), additional targets for atovaquone-proguanil. However, a similar moderate increase in IC50 has been reported for recrudescent isolates from Thai patients treated with atovaquone-proguanil (7). Both in Thailand and in French Guiana, therapeutic failure may involve reduced susceptibility to both proguanil and atovaquone. In vitro resistance to cycloguanil, the major metabolite of proguanil, is very high in French Guiana (close to 100% prevalence in 2000 with a mean IC50 of >4,100 nM). The mutant Pfdhfr-ts and cyt b genotypes observed in our atovaquone-proguanil therapeutic failure are consistent with combined resistance to both proguanil and atovaquone.

The observation of this first indigenous case of atovaquone-proguanil treatment failure in South America, due to drug resistance, shows the need for increased vigilance in the follow-up of patients treated with atovaquone-proguanil and in the reinforced surveillance of the parasite population.


   ACKNOWLEDGMENTS
 
This project was supported by the French Ministry of Health (InVS agency, Paris) and the EU commission-funded program RESMALCHIP (QLK2-CT-2002-01503).

We thank B. Maubert (Biomedical Unit, Institut Pasteur de la Guyane, Cayenne, French Guiana) for providing the blood samples.


   FOOTNOTES
 
{triangledown} Published ahead of print on 16 April 2007. Back

{dagger} Present address: Unité d'Immunologie Moléculaire des Parasites, CNRS URA 2581, Institut Pasteur, 75724 Paris Cedex 15, France. Back


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Eric Legrand*
Centre National de Référence sur la Chimiorésistance du Paludisme dans la région Antilles-Guyane
Institut Pasteur de la Guyane
BP 6010
F-97306 Cayenne-Cedex, French Guiana

Magalie Demar
Laboratoire Hospitalo-Universitaire de Parasitologie et Mycologie
Faculté de Médecine Antilles-Guyane et Centre Hospitalier de Cayenne
Equipe EA 3593
Cayenne, French Guiana

Béatrice Volney
Centre National de Référence sur la Chimiorésistance du Paludisme dans la région Antilles-Guyane
Institut Pasteur de la Guyane
BP 6010
F-97306 Cayenne-Cedex, French Guiana

Marie-Thérèse Ekala
Unité d'Immunologie Moléculaire des Parasites
CNRS URA 2581
Institut Pasteur
25 rue du Docteur Roux
75724 Paris Cedex 15, France

Marc Quinternet
Centre National de Référence sur la Chimiorésistance du Paludisme dans la région Antilles-Guyane
Institut Pasteur de la Guyane
BP 6010
F-97306 Cayenne-Cedex, French Guiana

Christiane Bouchier
Pasteur Genopole Ile de France
Institut Pasteur
25 rue du Docteur Roux
75724 Paris Cedex 15, France

Thierry Fandeur{dagger}
Faculté de Pharmacie
UFR sciences pharmaceutiques
UMR INRA-Université d'Immunologie Parasitaire et de Vaccinologie
Tours, France

Christophe Rogier
Unité de recherche en Biologie et Epidémiologie Parasitaire
Institut de Medecine Tropicale du Service de Santé des Armées
Marseille, France

Bernard Carme
Laboratoire Hospitalo-Universitaire de Parasitologie et Mycologie
Faculté de Médecine Antilles-Guyane et Centre Hospitalier de Cayenne
Equipe EA 3593
Cayenne, French Guiana

Odile Mercereau Puijalon
Unité d'Immunologie Moléculaire des Parasites
CNRS URA 2581
Institut Pasteur
25 rue du Docteur Roux
75724 Paris Cedex 15, France

Philippe Esterre
Centre National de Référence sur la Chimiorésistance du Paludisme dans la région Antilles-Guyane
Institut Pasteur de la Guyane
BP 6010
F-97306 Cayenne-Cedex, French Guiana

* Phone: 594 29 26 12
Fax: 594 31 80 83
E-mail: elegrand{at}pasteur-cayenne.fr

Antimicrobial Agents and Chemotherapy, June 2007, p. 2280-2281, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01532-06




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