Rapid dissemination of Plasmodium falciparum drug resistance despite strictly controlled antimalarial use.
BACKGROUND
Inadequate treatment practices with antimalarials are considered major contributors to Plasmodium falciparum resistance to chloroquine, pyrimethamine and sulfadoxine. The longitudinal survey conducted in Dielmo, a rural Senegalese community, offers a unique frame to explore the impact of strictly controlled and quantified antimalarial use for diagnosed malaria on drug resistance.


RESULTS
We conducted on a yearly basis a retrospective survey over a ten-year period that included two successive treatment policies, namely quinine during 1990-1994, and chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) as first and second line treatments, respectively, during 1995-1999. Molecular beacon-based genotyping, gene sequencing and microsatellite analysis showed a low prevalence of Pfcrt and Pfdhfr-ts resistance alleles of Southeast Asian origin by the end of 1994 and their effective dissemination within one year of CQ and SP implementation. The Pfcrt resistant allele rose from 9% to 46% prevalence during the first year of CQ reintroduction, i.e., after a mean of 1.66 CQ treatment courses/person/year. The Pfdhfr-ts triple mutant rose from 0% to 20% by end 1996, after a mean of 0.35 SP treatment courses/person in a 16-month period. Both resistance alleles were observed at a younger age than all other alleles. Their spreading was associated with enhanced in vitro resistance and rapidly translated in an increased incidence of clinical malaria episodes during the early post-treatment period.


CONCLUSIONS
In such a highly endemic setting, selection of drug-resistant parasites took a single year after drug implementation, resulting in a rapid progression of the incidence of clinical malaria during the early post-treatment period. Controlled antimalarial use at the community level did not prevent dissemination of resistance haplotypes. This data pleads against reintroduction of CQ in places where resistant allele frequency has dropped to a very low level after CQ use has been discontinued, unless drastic measures are put in place to prevent selection and spreading of mutants during the post-treatment period.
Noranate
Nitchakarn
N
Unité d'Immunologie Moléculaire des Parasites, Centre National de la Recherche Scientifique URA 2581, Institut Pasteur, Paris, France.
Durand
Rémy
R
Tall
Adama
A
Marrama
Laurence
L
Spiegel
André
A
Sokhna
Cheikh
C
Pradines
Bruno
B
Cojean
Sandrine
S
Guillotte
Micheline
M
Bischoff
Emmanuel
E
Ekala
Marie-Thérèse
MT
Bouchier
Christiane
C
Fandeur
Thierry
T
Ariey
Frédéric
F
Patarapotikul
Jintana
J
Le Bras
Jacques
J
Trape
Jean François
JF
Rogier
Christophe
C
Mercereau-Puijalon
Odile
O
D000293:Adolescent; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D018895:Microsatellite Repeats; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D015800:Protozoan Proteins / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use; D012189:Retrospective Studies; D012675:Senegal / Q000453:epidemiology; D017422:Sequence Analysis, DNA; D013413:Sulfadoxine / Q000494:pharmacology / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
D000962:Antimalarials; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D013413:Sulfadoxine; D002738:Chloroquine; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine