High levels of sulphadoxine-pyrimethamine resistance Pfdhfr-Pfdhps quintuple mutations: a cross sectional survey of six regions in Tanzania

Matondo, Sungwa; Temba, Godfrey S.; Kavishe, Adelaida A; Kauki, Julius; Kalinga, Akili; Zwetselaar, Marco van; Reyburn, Hugh; Kavishe, Reginald A.

doi:10.1186/1475-2875-13-152

Cited by 45 publications

(46 citation statements)

References 37 publications

(43 reference statements)

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“…The overall prevalence of single SNPs and as well, the resulting triple 86-184-1246 haplotype YFY haplotype was highest in Tanga. Interestingly, this coincides with highest prevalence of SP resistance markers also documented in Tanga region [25,28,29]. The haplotype YFY is linked to AQ and CQ resistance [21].…”

Section: Discussionmentioning

confidence: 67%

Surveillance of artemether-lumefantrine associated Plasmodium falciparum multidrug resistance protein-1 gene polymorphisms in Tanzania

Kavishe

Paulo

Kaaya

et al. 2014

Malar J

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BackgroundResistance to anti-malarials is a major public health problem worldwide. After deployment of artemisinin-based combination therapy (ACT) there have been reports of reduced sensitivity to ACT by malaria parasites in South-East Asia. In Tanzania, artemether-lumefantrine (ALu) is the recommended first-line drug in treatment of uncomplicated malaria. This study surveyed the distribution of the Plasmodium falciparum multidrug resistance protein-1 single nucleotide polymorphisms (SNPs) associated with increased parasite tolerance to ALu, in Tanzania.MethodsA total of 687 Plasmodium falciparum positive dried blood spots on filter paper and rapid diagnostic test strips collected by finger pricks from patients attending health facilities in six regions of Tanzania mainland between June 2010 and August 2011 were used. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to detect Pfmdr1 SNPs N86Y, Y184F and D1246Y.ResultsThere were variations in the distribution of Pfmdr1 polymorphisms among regions. Tanga region had exceptionally high prevalence of mutant alleles, while Mbeya had the highest prevalence of wild type alleles. The haplotype YFY was exclusively most prevalent in Tanga (29.6%) whereas the NYD haplotype was the most prevalent in all other regions. Excluding Tanga and Mbeya, four, most common Pfmdr1 haplotypes did not vary between the remaining four regions (χ2 = 2.3, p = 0.512). The NFD haplotype was the second most prevalent haplotype in all regions, ranging from 17% - 26%.ConclusionThis is the first country-wide survey on Pfmdr1 mutations associated with ACT resistance. Distribution of individual Pfmdr1 mutations at codons 86, 184 and 1246 varies throughout Tanzanian regions. There is a general homogeneity in distribution of common Pfmdr1 haplotypes reflecting strict implementation of ALu policy in Tanzania with overall prevalence of NFD haplotype ranging from 17 to 26% among other haplotypes. With continuation of ALu as first-line drug this haplotype is expected to keep rising, thus there is need for continued pharmacovigilance studies to monitor any delayed parasite clearance by the drug.

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Section: Discussionmentioning

confidence: 67%

Surveillance of artemether-lumefantrine associated Plasmodium falciparum multidrug resistance protein-1 gene polymorphisms in Tanzania

Kavishe

Paulo

Kaaya

et al. 2014

Malar J

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“…Mutations at codon 613S have been documented in Africa (13). In Tanzania, the prevalence of a triple Pfdhfr mutation was recently found to be Ͼ84% in all regions, whereas prevalence of the Pfdhps double mutation ranged from as low as 43.8 to 95% (14). Recently, studies in some countries of East Africa have observed the emergence of the Pfdhps 581G mutation with quintuple mutants, resulting in sextuple mutants (15).…”

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confidence: 99%

Prevalence of Plasmodium falciparum Resistance Markers to Sulfadoxine-Pyrimethamine among Pregnant Women Receiving Intermittent Preventive Treatment for Malaria in Uganda

Mbonye

Birungi

Yanow

et al. 2015

Antimicrob Agents Chemother

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The aim of this study was to assess the prevalence of mutations in Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes among pregnant women using sulfadoxine-pyrimethamine (SP) as an intermittent preventive treatment (IPTp). A molecular epidemiological study of P. falciparum parasite resistance markers to SP was conducted from August 2010 to February 2012 in Mukono district in central Uganda. DNA was extracted from 413 P. falciparum-positive samples. Real-time PCR, followed by melting curve analysis, was used to characterize point mutations in the Pfdhfr and Pfdhps genes that are associated with SP resistance. The prevalence of the single-nucleotide mutations in Pfdhfr at codons 51I, 59R, and 108N and in Pfdhps at codons 437G and 540E was high (>98%), reaching 100% fixation after one dose of SP, while the prevalence of 581G was 3.3% at baseline, reaching 12.5% after one dose of SP. At baseline, the prevalence of Pfdhfr and Pfdhps quintuple mutations was 89%, whereas the sextuple mutations (including 581G) were not prevalent (3.9%), reaching 16.7% after one dose of SP. However, the numbers of infections at follow-up visits were small, and hence there was insufficient statistical power to test whether there was a true rise in the prevalence of this allele. The overall high frequency of Pfdhfr and Pfdhps quintuple mutations throughout pregnancy excluded further analyses of possible associations between certain haplotypes and the risk of lower birth weight and anemia. However, women infected with P. falciparum had 1.3-g/dl-lower hemoglobin levels (P ‫؍‬ 0.001) and delivered babies with a 400-g-lower birth weight (P ‫؍‬ 0.001) compared to nonparasitemic women. Despite this, 44 women who were P. falciparum positive at baseline became negative after one or two doses of SP (i.e., 50.5%), implying that SP-IPTp still has some efficacy. P. falciparum resistance markers to SP are high in this population, whereas P. falciparum infection was associated with poor birth outcomes. Malaria in pregnancy is a major public health problem in areas where malaria is endemic (1, 2). The current policy in Uganda for treating malaria in pregnancy in the first trimester is to give quinine (10 mg/kg). During the second and third trimesters, the following artemesinin-based combination therapy is recommended: Coartem (artemether [20 mg] and lumefantrine [120 mg]) at four tablets twice a day for 3 days. For malaria prevention, the policy recommendation is at least two doses of sulfadoxinepyrimethamine (SP) as an intermittent preventive treatment of malaria in pregnancy (IPTp) (3). Recently, the World Health Organization (WHO) issued new guidelines on IPTp for countries in areas of moderate to high transmission: IPTp with SP is now recommended for all pregnant women at each scheduled antenatal care (ANC) visit, and each SP dose should be given at least monthly (4). This recommendation is based on evidence that three or more doses of SP as IPTp are more beneficial in reducing the risk of low-birth-w...

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“…To this end, a number of bepotastine-based sulphonamides were synthesized, as both these compound classes are known to efficiently inhibit parasitic development. 7,8 Subsequently, these compounds were tested to establish their inhibitory potential on the asexual stages of human malaria parasite. To prioritize potential antimalarial scaffolds within the synthesized library, we conducted preliminary screening experiments, based on which the ten most active molecules were selected for detailed analyses.…”

Section: Discussionmentioning

confidence: 99%

“…In combination with pyrimethamine, folic acid antagonists such as sulfadoxine were widely used for malaria treatment; however resistance against this combination has been reported extensively. 7 Histamine-1 receptor antagonists like bepotastine were shown to be effective against the proliferation of Plasmodia both in vitro and in vivo. Thus, we designed and evaluated novel chemical scaffolds, which combine the structural features of both sulphonamides and bepotastine, against the asexual developmental stages of P. falciparum.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization and in vitro evaluation of novel enantiomerically-pure sulphonamide antimalarials

et al. 2015

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Malaria parasites are currently gaining drug-resistance rapidly, across countries and continents. Hence, the discovery and development of novel chemical scaffolds, with superior antimalarial activity remain an important priority, for the developing world. Our report describes the development, characterization and evaluation of novel bepotastine-based sulphonamide antimalarials inhibiting asexual stage development of Plasmodium falciparum parasites in vitro. The screening results showed potent inhibitory activity of a number of novel sulphonamides against P. falciparum at low micromolar concentrations, in particular in late-stage parasite development. Based on computational studies we hypothesize N-myristoyltransferase as the target of the compounds developed here. Our results demonstrate the value of novel bepotastine-based sulphonamide compounds for targeting the asexual developmental stages of P. falciparum.

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High levels of sulphadoxine-pyrimethamine resistance Pfdhfr-Pfdhps quintuple mutations: a cross sectional survey of six regions in Tanzania

Cited by 45 publications

References 37 publications

Surveillance of artemether-lumefantrine associated Plasmodium falciparum multidrug resistance protein-1 gene polymorphisms in Tanzania

Surveillance of artemether-lumefantrine associated Plasmodium falciparum multidrug resistance protein-1 gene polymorphisms in Tanzania

Prevalence of Plasmodium falciparum Resistance Markers to Sulfadoxine-Pyrimethamine among Pregnant Women Receiving Intermittent Preventive Treatment for Malaria in Uganda

Synthesis, characterization and in vitro evaluation of novel enantiomerically-pure sulphonamide antimalarials

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