title: Apparent absence of atovaquone/proguanil resistance in 477 Plasmodium falciparum isolates from untreated French travellers.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Centre National de Référence pour la Chimiosensibilité du Paludisme, APHP, Hôpital Bichat-Claude Bernard, Paris, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Musset
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
authors.forename: Daniel
authors.initials: D
authors.lastname: Parzy
authors.forename: Rémy
authors.initials: R
authors.lastname: Durand
authors.forename: Patricia
authors.initials: P
authors.lastname: Bigot
authors.forename: Jacques
authors.initials: J
authors.lastname: Le Bras
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D053626:Atovaquone; D002648:Child; D002675:Child, Preschool; D045303:Cytochromes b / Q000235:genetics; D004351:Drug Resistance / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D005602:France; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D008297:Male; D008875:Middle Aged; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D012150:Polymorphism, Restriction Fragment Length; D002727:Proguanil / Q000494:pharmacology* / Q000627:therapeutic use; D014195:Travel
chemical_list: D000962:Antimalarials; D009285:Naphthoquinones; D045303:Cytochromes b; D002727:Proguanil; D053626:Atovaquone