Plasmodium falciparum resistance to sulfadoxine/pyrimethamine in Uganda: correlation with polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes.

Jelı́nek, Tomáš; Kilian, Albert; Kabagambe, G.; Sonnenburg, Frank von

doi:10.4269/ajtmh.1999.61.463

Cited by 47 publications

(32 citation statements)

References 21 publications

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“…Since the identification of molecular markers for SP resistance, numerous field studies have assessed the correlation between genetic mutations and treatment failure. A number of studies have attributed SP treatment failure to infection with parasites having at least a double mutation in DHFR coupled with a single mutation in the DHPS gene (1,5,7,15,20). The model results presented here are in agreement with these findings.…”

Section: Vol 48 2004 Evolution Of P Falciparum Drug Resistance 2119supporting

confidence: 82%

Evolution of Resistance to Sulfadoxine-Pyrimethamine in Plasmodium falciparum

Gatton

Martin

Cheng³

2004

Antimicrob Agents Chemother

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The development of resistance to sulfadoxine-pyrimethamine by Plasmodium parasites is a major problem for the effective treatment of malaria, especially P. falciparum malaria. Although the molecular basis for parasite resistance is known, the factors promoting the development and transmission of these resistant parasites are less clear. This paper reports the results of a quantitative comparison of factors previously hypothesized as important for the development of drug resistance, drug dosage, time of treatment, and drug elimination half-life, with an in-host dynamics model of P. falciparum malaria in a malaria-naïve host. The results indicate that the development of drug resistance can be categorized into three stages. The first is the selection of existing parasites with genetic mutations in the dihydrofolate reductase or dihydropteroate synthetase gene. This selection is driven by the long half-life of the sulfadoxine-pyrimethamine combination. The second stage involves the selection of parasites with allelic types of higher resistance within the host during an infection. The timing of treatment relative to initiation of a specific anti-P. falciparum EMP1 immune response is an important factor during this stage, as is the treatment dosage. During the third stage, clinical treatment failure becomes prevalent as the parasites develop sufficient resistance mutations to survive therapeutic doses of the drug combination. Therefore, the model output reaffirms the importance of correct treatment of confirmed malaria cases in slowing the development of parasite resistance to sulfadoxine-pyrimethamine.Drug resistance is becoming an increasingly important factor in the effective treatment of malaria. High levels of resistance to chloroquine have forced some countries to switch their first-line drug to sulfadoxine-pyrimethamine (SP, trade name Fansidar). However, resistance to this drug combination is developing fast, with treatment failure being reported in Africa, Asia, Indonesia, and South America (5,7,16,20,31).Pyrimethamine and sulfadoxine act synergistically to inhibit two enzymes important in the parasite's folate biosynthetic pathway, dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) (13). Point mutations in the DHFR and DHPS genes confer resistance to pyrimethamine and sulfadoxine, respectively, with decreasing in vitro Plasmodium falciparum susceptibility related to the number of mutations in each gene (6,30,34). The same mutations have been linked to treatment failure in the clinical setting (5,7,20,33); the presence of mutations in DHFR appear to be more important in causing treatment failure than DHPS mutations (5). Although the molecular basis for SP resistance is understood, the factors promoting the development and transmission of these mutants are less clear.It has been suggested that drug pharmacokinetics (12), overusage of drugs (28), cross-resistance between drugs (14), and inadequate treatment through inappropriate prescription or administration, noncompliance, or poor absorption...

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Section: Vol 48 2004 Evolution Of P Falciparum Drug Resistance 2119supporting

confidence: 82%

Evolution of Resistance to Sulfadoxine-Pyrimethamine in Plasmodium falciparum

Gatton

Martin

Cheng³

2004

Antimicrob Agents Chemother

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“…7 Triple mutant alleles of dhfr are now common in Tanzania, Kenya, and Uganda, where PYR/ SDX has been used for some time. 7,24 The quadruple mutant allele has not been reported previously from Africa, but it has been present in South East Asia and South America for many years, and in these regions, neither PYR/SDX nor chlorproguanil/dapsone is clinically effective. 25 Concerning dhps, only the Ala 436 was detected in 3 isolates.…”

Section: Discussionmentioning

confidence: 99%

Pyrimethamine/sulfadoxine combination in the treatment of uncomplicated falciparum malaria: relation between dihydropteroate synthase/dihydrofolate reductase genotypes, sulfadoxine plasma levels, and treatment outcome.

Khalil

Alifrangis²,

Rønn³

et al. 2002

Am J Trop Med Hyg

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Abstract. Several in vitro studies have shown the correlation between mutations in dhfr and dhps genes and resistance to pyrimethamine/sulfadoxine (PYR/SDX) combination, but the in vivo correlates of these mutations with PYR/ SDX efficacy have not been investigated fully. We assessed PYR/SDX efficacy in relation to the frequency of dhfr and dhps mutations in 37 Plasmodium falciparum isolates sampled before treatment. Plasma levels of SDX measured at days 0, 3, 7, and 14 ascertained drug absorption. Point mutations were detected only at codons 51 and 108 of dhfr and codon 436 of dhps. The frequency of dhfr 51/108 and dhps 436 mutations was 79% and 8%. The plasma levels of SDX indicated adequate drug absorption by all patients. The presence of Ile 51and Asn 108 mutations among parasites that cleared after treatment indicates that these mutations alone are insufficient to cause in vivo resistance. In all recrudescent parasites, however, the presence of Ile 51/Asn 108 dhfr mutations was coupled with the dhps Ala 436. The findings suggest that the presence of Ile 51/Asn 108 dhfr mutations and Ala 436 dhps confers decreased susceptibility of P. falciparum to PYR/SDX in areas of low endemicity.

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“…We found that women who used IPTp harbored a significantly higher fraction of parasites with the resistance allele, suggesting selection for more highly drug-resistant parasites. This step in selection may have clinical relevance, since in vivo studies have demonstrated associations between treatment failure in children and the mutant allele at DHPS codon 581 (9,10).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Harrington

Mutabingwa

Muehlenbachs

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

188

244

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Intermittent preventive treatment in pregnancy (IPTp) is used to prevent Plasmodium falciparum malaria. However, parasites resistant to the IPTp drug sulfadoxine-pyrimethamine (SP) have emerged worldwide, and infections with mixed resistant and susceptible parasites are exacerbated by pyrimethamine in mice. In a prospective delivery cohort in Muheza, Tanzania, we examined the effects of SP IPTp on parasite resistance alleles, parasite diversity, level of parasitemia, and inflammation in the placenta. IPTp use was associated with an increased fraction of parasites carrying the resistance allele at DHPS codon 581, an increase in the level of parasitemia, and more intense placental inflammation. The lowest mean level of parasite diversity and highest mean level of parasitemia occurred in women after recent IPTp use. These findings support a model of parasite release and facilitation, whereby the most highly resistant parasites out-compete less fit parasite populations and overgrow under drug pressure. Use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance.evolution of drug resistance ͉ intermittent preventive treatment in pregnancy ͉ malaria drug resistance ͉ pregnancy malaria M alaria during pregnancy causes both maternal and fetal morbidity and mortality, including the deaths of an estimated 100,000 infants each year because of malaria-related low birth weight. The World Health Organization recommends that women living in sub-Saharan Africa receive at least two doses of intermittent preventive treatment (IPTp) with sulfadoxinepyrimethamine (SP) to prevent malaria and improve pregnancy outcomes (1-5) and this advice is widely followed. However, the rapid spread of SP-resistant parasites might undermine the efficacy of SP-IPTp, although it still confers benefits in areas with low to moderate levels of drug resistance (6). The effect of SP IPTp in areas where resistant parasites are more widespread has not been studied.Pyrimethamine and sulfadoxine target the parasite proteins DHFR and DHPS, respectively, and increasing resistance is conferred by ordered accumulating point mutations, of which DHPS codon 581 is one of the final to occur (7). 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). In contrast, IPTp use was not related to increased prevalence of resistance alleles at the same study site (14). Modeling studies have proposed that IPTp is less likely to contribute to accumulating drug resistance as...

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Plasmodium falciparum resistance to sulfadoxine/pyrimethamine in Uganda: correlation with polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes.

Cited by 47 publications

References 21 publications

Evolution of Resistance to Sulfadoxine-Pyrimethamine in Plasmodium falciparum

Evolution of Resistance to Sulfadoxine-Pyrimethamine in Plasmodium falciparum

Pyrimethamine/sulfadoxine combination in the treatment of uncomplicated falciparum malaria: relation between dihydropteroate synthase/dihydrofolate reductase genotypes, sulfadoxine plasma levels, and treatment outcome.

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

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