Concurrence of Plasmodium falciparum dhfr and crt mutations in northern Ghana.
BACKGROUND
Both chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) are failing drugs in much of sub-Saharan Africa. Previous findings suggest an association between resistance to CQ and to SP in vivo, in vitro, and on the molecular level.


METHODS
In 126 Ghanaian children with uncomplicated malaria, associations between mutations conferring resistance in the Plasmodium falciparum dihydrofolate reductase (dhfr; SP) and chloroquine resistance transporter (crt; CQ) genes, concentrations of residual antimalarial drugs, and gametocyte carriage were examined.


RESULTS
Mutant dhfr alleles and the CQ-resistance allele crt T76 were strongly associated with each other. Isolates exhibiting the dhfr triple mutation seven times more likely also contained crt T76 parasites as compared to isolates without the dhfr triple variant (P = 0.0001). Moreover, both, isolates with the dhfr triple mutation (adjusted OR, 3.2 (95%CI, 1.0-10.4)) and with crt T76 (adjusted OR, 14.5 (1.4-150.8)) were associated with an increased likelihood of pre-treatment gametocytaemia. However, crt T76 did not correlate with gametocytaemia following SP treatment and no selection of crt T76 in SP treatment failure isolates was observed.


CONCLUSIONS
These results confirm an association between CQ and SP resistance markers in isolates from northern Ghana. This could indicate accelerated development of resistance to SP if CQ resistance is already present, or vice versa. Considering the enhanced transmission potential as reflected by the increased proportion of isolates containing gametocytes when resistant parasites are present, co-resistance can be expected to spread in this area. However, the underlying mechanism leading to this constellation remains obscure.
Mockenhaupt
Frank P
FP
Institute of Tropical Medicine, Charité-University Medicine Berlin, Spandauer Damm 130, 14050 Berlin, Germany. frank.mockenhaupt@charite.de
Bousema
J Teun
JT
Eggelte
Teunis A
TA
Ehrhardt
Stephan
S
Otchwemah
Rowland N
RN
Sauerwein
Robert W
RW
Bienzle
Ulrich
U
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D002675:Child, Preschool; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005869:Ghana / Q000453:epidemiology; D006801:Humans; D007223:Infant; D008288:Malaria / Q000453:epidemiology / Q000469:parasitology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
D000962:Antimalarials; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine; D013762:Tetrahydrofolate Dehydrogenase