Screening for mutations related to atovaquone/proguanil resistance in treatment failures and other imported isolates of Plasmodium falciparum in Europe.
BACKGROUND
Two single-point mutations of the Plasmodium falciparum cytochrome b gene (Tyr268Asn and Tyr268Ser) were recently reported in cases of atovaquone/proguanil (Malarone) treatment failure. However, little is known about the prevalence of codon-268 mutations and their quantitative association with treatment failure.


METHODS
We set out to assess the prevalence of codon-268 mutations in P. falciparum isolates imported into Europe and to quantify their association with atovaquone/proguanil treatment failure. Isolates of P. falciparum collected by the European Network on Imported Infectious Disease Surveillance between April 2000 and August 2003 were analyzed for codon-268 mutations, by use of polymerase chain reaction-restriction fragment-length polymorphism.


RESULTS
We successfully screened 504 samples for the presence of either Tyr268Ser or Tyr268Asn. One case of Ser268 and no cases of Asn268 were detected. Therefore, we can be 95% confident that the prevalence of Ser268 in the European patient pool does not exceed 0.96% and that Asn268 is less frequent than 0.77%. In 58 patients treated with atovaquone/proguanil, Tyr268Ser was present in 1 of 5 patients with treatment failure but in 0 of 53 successfully treated patients.


CONCLUSIONS
Tyr268Ser seems to be a sufficient, but not a necessary, cause for atovaquone/proguanil treatment failure. The prevalence of both codon-268 mutations is currently unlikely to be >1% in the European patient pool.
Wichmann
Ole
O
Institute of Tropical Medicine, Charité, Humboldt University, Berlin, Germany. ole.wichmann@charite.de.
Muehlberger
Nikolai
N
Jelinek
Tomas
T
Alifrangis
Michael
M
Peyerl-Hoffmann
Gabriele
G
Muhlen
Marion
M
Grobusch
Martin P
MP
Gascon
Joaquim
J
Matteelli
Alberto
A
Laferl
Hermann
H
Bisoffi
Zeno
Z
Ehrhardt
Stephan
S
Cuadros
Juan
J
Hatz
Christoph
C
Gjorup
Ida
I
McWhinney
Paul
P
Beran
Jiri
J
da Cunha
Saraiva
S
Schulze
Marco
M
Kollaritsch
Herwig
H
Kern
Peter
P
Fry
Graham
G
Richter
Joachim
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone; D003062:Codon; D045303:Cytochromes b / Q000235:genetics / Q000502:physiology; D016054:DNA, Protozoan / Q000032:analysis / Q000302:isolation & purification; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D005060:Europe; D005260:Female; D017125:Genes, Protozoan; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D020125:Mutation, Missense; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D002727:Proguanil / Q000494:pharmacology* / Q000627:therapeutic use; D015800:Protozoan Proteins / Q000235:genetics / Q000502:physiology; D017211:Treatment Failure
D000962:Antimalarials; D003062:Codon; D016054:DNA, Protozoan; D004338:Drug Combinations; D009285:Naphthoquinones; D015800:Protozoan Proteins; C109496:atovaquone, proguanil drug combination; D045303:Cytochromes b; D002727:Proguanil; D053626:Atovaquone