Escalating Plasmodium falciparum antifolate drug resistance mutations in Macha, rural Zambia

Mkulama, Mtawa; Chishimba, Sandra; Sikalima, Jay; Rouse, Petrica; Thuma, Philip E.; Mharakurwa, Sungano

doi:10.1186/1475-2875-7-87

Cited by 16 publications

(9 citation statements)

References 11 publications

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“…The results showed a complex mixture of pfdhfr/pfdhps haplotypes in Luanda as already reported in other six provinces of Angola [ 25 , 26 ]. The 164L mutation was not disclosed, corroborating the findings of other nearby African countries [ 27 - 29 ]. The pfdhfr 50R SNP herein found confers an increased level of resistance to pyrimethamine and this mutation is characteristic from South-American isolates [ 30 ] and, it was found only once in Africa, when Kenyan isolates were evaluated [ 31 ].…”

Section: Discussionsupporting

confidence: 85%

Molecular markers of antifolate resistance in Plasmodium falciparum isolates from Luanda, Angola

Gama

Pereira-Carvalho

Kosi

et al. 2011

Malar J

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BackgroundPlasmodium falciparum malaria remains a leading health problem in Africa and its control is seriously challenged by drug resistance. Although resistance to the sulphadoxine-pyrimethamine (SP) is widespread, this combination remains an important component of malaria control programmes as intermittent preventive therapy (IPT) for pregnant women and children. In Angola, resistance patterns have been poorly characterized, and IPT has been employed for pregnant women since 2006. The aim of this study was to assess the prevalence of key antifolate resistance mediating polymorphisms in the pfdhfr and pfdhps genes in P. falciparum samples from Angola.MethodsPlasmodium falciparum samples collected in Luanda, in 2007, were genotyped by amplification and DNA forward and reverse sequencing of the pfdhfr and pfdhps genes.ResultsThe most prevalent polymorphisms identified were pfdhfr 108N (100%), 51I (93%), 59R (57%) and pfdhps 437G (93%). Resistance-mediating polymorphisms in pfdhps less commonly observed in West Africa were also identified (540E in 10%, 581G in 7% of samples).ConclusionThis study documents an important prevalence of 4 P. falciparum polymorphisms that predicts an antifolate resistance in Luanda. Further, some samples presented additional mutations associated to high-level resistance. These results suggest that the use of SP for IPT may no longer be warranted in Angola.

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Section: Discussionsupporting

confidence: 85%

Molecular markers of antifolate resistance in Plasmodium falciparum isolates from Luanda, Angola

Gama

Pereira-Carvalho

Kosi

et al. 2011

Malar J

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“…SP has been in use for over two decades in Zambia and due to drug pressure parasite resistance is expected to be high as is evident from trends analysis in populations were SP has been used for even shorter periods of time. Data from southern Zambia showed that by 2006, the prevalence of dhfr and dhps mutants had escalated rapidly since 1988, and that the quintuple ( dhfr triple + dhps double) mutant associated with highest levels of SP clinical failure was starting to be seen (6.5%) [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

High prevalence of dhfr and dhps molecular markers in Plasmodium falciparum in pregnant women of Nchelenge district, Northern Zambia

Siame

Mharakurwa

Chipeta

et al. 2015

Malar J

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BackgroundSulphadoxine-pyrimethamine (SP) is the recommended drug for intermittent preventive treatment in pregnancy (IPTp) in most African countries, including Zambia. However, malaria is still one of the leading causes of morbidity and mortality in pregnant women despite reports of greater than 50% of women taking at least two doses of SP in IPTp. Studies have shown that resistance to SP is associated with mutations in the dhfr and dhps gene of Plasmodium falciparum. This study examined the prevalence of dhfr and dhps polymorphisms in P. falciparum found in pregnant women of Nchelenge district.MethodThis cross-sectional study was conducted in 2013 in Nchelenge, a holoendemic area with malaria prevalence estimated at 50% throughout the year. Three rural health centres were randomly selected and a census survey carried out at each health centre. A questionnaire was administered and malaria testing done using RDT and microscopy, with collection of a dried blood spot. A chelex extraction was done to extract parasite DNA from dried blood spots followed by nested PCR and enzyme restriction digestion.ResultsOf the enrolled participants (n = 375), the median age of the women was 23. The prevalence of malaria by PCR was 22%. The PCR positive samples examined (n = 72) showed a high prevalence of dhfr triple (Asn-108 + Arg-59 + Ile-59) mutant (68%) and dhps double (Gly -437 + Glu-540) mutant (21%). The quintuple haplotype was found in 17% with 2 samples with an additional Gly-581mutation. In addition 6% mutations at Val-16 were found and none found at Thr-108 respectively, these both confer resistance to cycloguanil. Multivariate analysis showed that there was an association between malaria and women aged 30-34 years old p < 0.05(AOR: 0.36) at 95% CI.ConclusionThis study showed a high number of mutations in the dhfr and dhps genes. The high malaria endemicity in the general population of this area may have contributed to the high prevalence of resistant parasites in pregnant women, suggesting a need to examine the efficacy of SP given that it is the only approved drug for IPTp in Zambia.

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“…Resistance to type 1 antifolates (pyrimethamine, chlorproguanil, trimethoprim) has been associated with amino acid substitutions in the Pfdhfr gene while resistance to type II antifolates (sulfonamides: sulfadoxine and dapsone) are associated with mutations in P . falciparum dihydropteroate synthase ( Pfdhps ) gene [ 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Assessment of Markers of Antimalarial Drug Resistance in Plasmodium falciparum Isolates from Pregnant Women in Lagos, Nigeria

et al. 2016

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BackgroundThe use of antimalarial drugs for prevention and treatment is a major strategy in the prevention of malaria in pregnancy. Although sulphadoxine-pyrimethamine (SP) is currently recommended for intermittent preventive treatment of malaria during pregnancy in Nigeria, previously used drugs for prophylaxis such as chloroquine (CQ) and pyrimethamine are accessible as they are purchased over the counter. This study describes the markers of absence or presence of resistance to quinoline (Pfcrt and Pfmdr 1) and type 1 antifolate antimalarial medicines (Pfdhfr).MethodsPlasmodium falciparum-positive dried blood spots from pregnant women attending antenatal clinics for the first time during current pregnancy were investigated for the presence of mutations at codons 72–76 of Plasmodium falciparum chloroquine resistance transporter (Pfcrt) gene by real time polymerase chain reaction (PCR) using haplotype-specific probes. PCR followed by sequence analysis was used to identify mutations at codons 86, 184, 1034, 1042 and 1246 of P. falciparum multi-drug resistance-1 (Pfmdr1) gene; and codons 16, 50, 51, 59, 108, 140 and 164 of Pfdhfr gene.ResultsTwo haplotypes of Pfcrt (n = 54) were observed: CVMNK 13(24.2%) and CVIET 41 (75.9%) of the samples. The SVMNT haplotype was absent in this population. The Pfmdr1 (n = 28) haplotypes were NYSND 15(53.6%), YYSND 5(17.9%), NFSND 6(21.4%) and YFSND 2(7.1%). The Pfdhfr (n = 15) were ACNCSVI 4(26.7%), and ACICNSVI 1(6.7%) and ACIRNVI 10 (66.7%). The rate of occurrence of Pfcrt 76T, Pfdhfr108N, Pfmdr186Yand184F were 75.9%, 73.3%, 25% and 28.1% respectively. The Pfmdr1 86Y was associated with low parasitaemia (median = 71 parasites/μl, P = 0.024) while Pfcrt 76T was associated with young maternal age (mean 24.1 ± 4.5 years; P = 0.006). The median parasitaemia were similar (P>0.05) in wild and mutant strains of Pfcrt 76, Pfmdr1 184 and Pfdhfr 108. There was no association between gravidity or gestational age of the women and presence of mutations in the Pfcrt, Pfmdr1 or Pfdhfr genes (P>0.05).ConclusionMarkers of resistance to chloroquine and pyrimethamine were high, whereas cycloguanil-resistance marker was not present in the studied population. The low level of mutations in the Pfmdr1gene indicates likely efficacy of amodiaquine against malaria in pregnancy.

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Escalating Plasmodium falciparum antifolate drug resistance mutations in Macha, rural Zambia

Cited by 16 publications

References 11 publications

Molecular markers of antifolate resistance in Plasmodium falciparum isolates from Luanda, Angola

Molecular markers of antifolate resistance in Plasmodium falciparum isolates from Luanda, Angola

High prevalence of dhfr and dhps molecular markers in Plasmodium falciparum in pregnant women of Nchelenge district, Northern Zambia

Assessment of Markers of Antimalarial Drug Resistance in Plasmodium falciparum Isolates from Pregnant Women in Lagos, Nigeria

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