Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins

Polyclonal Plasmodium falciparum malaria in travelers and selection of antifolate mutations after proguanil prophylaxis.

“…This most likely reflects a frequent natural occurrence of dhfr mutations in P. falciparum parasites and may be related to previous use of pyrimethamine-sulfadoxine in a specific area. 7,27,28 Surprisingly, the Leu-164 mutation was found in four patients who had traveled to East and West Africa. This mutation has previously been reported only in two samples from Africa.…”

“…This confirms that these mutations are generally rare. 27,28 A wide spectrum of dhfr mutations was also observed in the patients without previous proguanil prophylaxis. This most likely reflects a frequent natural occurrence of dhfr mutations in P. falciparum parasites and may be related to previous use of pyrimethamine-sulfadoxine in a specific area.…”

Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment

“…The mutation at DHPS codon 581 has been associated with high-level in vitro resistance (8), as well as treatment failure in children (9,10). Single-dose treatment of children with SP has been associated with an increase in parasite resistance alleles (11,12), but little work has been done to examine the relationship between IPTp and selection for drug resistance alleles. One recent study observed an increased prevalence of placental infections harboring the DHFR triple mutant in women who had received pyrimethamine prophylaxis during pregnancy, as compared with women who had not (13).…”

Antimalarial Drug Resistance: Surveillance and Molecular Methods for National Malaria Control Programmes

“…A serine in position 108 of the DHFR gene is linked to in vitro sensitivity to both pyrimethamine and cycloguanil. A mutation to asparigine at position 108 seems to be the key mutation for conferring in vitro pyrimethamine resistance (de Pecoulas et al 1996), although a genotype without this mutation has been recently described (Wang et al 1997). An asparagine to isoleucine change at position 51 and a cysteine to arginine at position 59 appear to modulate higher levels of in vitro pyrimethamine resistance when they occur with the asparagine-108 mutation, and an isoleucine to leucine mutation at position 164 in combination with the asparagine-108 and arginine-59 mutations has been found in P. falciparum lines that are highly resistant to both pyrimethamine and cycloguanil (Basco et al 1995, Reeder et al 1996.…”

“…Point mutations of the DHPS gene have been less extensively studied. Thirteen variants over the wild type have been identified so far in samples from different countries, the most common alteration being in position 437 (Wang et al 1997). A certain amount of correlation was found between the prevalence of known DHFR and DHPS mutations and increasing levels of in vivo SP resistance in four different countries: Mali, Kenya, Malawi, Bolivia .…”