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.
Institute of Tropical Medicine, Charité, Humboldt University, Berlin, Germany. ole.wichmann@charite.de.
Ole
O
Wichmann
Nikolai
N
Muehlberger
Tomas
T
Jelinek
Michael
M
Alifrangis
Gabriele
G
Peyerl-Hoffmann
Marion
M
Muhlen
Martin P
MP
Grobusch
Joaquim
J
Gascon
Alberto
A
Matteelli
Hermann
H
Laferl
Zeno
Z
Bisoffi
Stephan
S
Ehrhardt
Juan
J
Cuadros
Christoph
C
Hatz
Ida
I
Gjorup
Paul
P
McWhinney
Jiri
J
Beran
Saraiva
S
da Cunha
Marco
M
Schulze
Herwig
H
Kollaritsch
Peter
P
Kern
Graham
G
Fry
Joachim
J
Richter
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