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Malaria Journal Jul 2013Artesunate/sulphadoxine-pyrimethamine (AS/SP) has been the first-line treatment for falciparum malaria in Sudan since 2004. The impact of this combination on...
Selection of pfdhfr/pfdhps alleles and declining artesunate/sulphadoxine-pyrimethamine efficacy against Plasmodium falciparum eight years after deployment in eastern Sudan.
BACKGROUND
Artesunate/sulphadoxine-pyrimethamine (AS/SP) has been the first-line treatment for falciparum malaria in Sudan since 2004. The impact of this combination on anti-malarial resistance-associated molecular markers has not been investigated. In this study, an evaluation of the efficacy and prevalence of drug resistance alleles (pfcrt, pfmdr1, pfdhfr and pfdhps) eight years after the adoption of AS/SP in eastern Sudan is reported.
METHODS
A 28-day follow-up efficacy trial of AS/SP was conducted in eastern Sudan during the 2012 transmission season. Blood smears were collected from patients on days 0, 1, 2, 3, 7, 14, 21 and 28. Blood spots on filter paper were obtained pre-treatment and on the day the patient was parasite positive by microscopy. Genotyping of alleles was performed by qPCR (pfcrt 72-76 and pfmdr1 copy number) and direct sequencing of pfmdr1, pfdhfr and pfdhps.
RESULTS
Sixty-three patients out of 68 (93%) completed the 28-day follow-up, adequate clinical, and parasitological response occurred in 90.5% and 85.3% of the patients in the per-protocol and intent-to-treat analyses, respectively. PCR corrected per-protocol efficacy was 93.7%. The enrolment prevalence of pfcrt-CVMNK was 30.2% and pfmdr1-N86 was 40.3%. The pfmdr1 haplotype NFD occurred in 32.8% of pre-treatment samples and was significantly higher than previous reports (Fisher's exact p = 0.0001). The pfdhfr-51I/108N combination occurred in all sequenced isolates and 59R was observed in a single individual. pfdhps substitutions 436A, 437G, 540E, 581G and 613S were observed at 7.8, 77.3, 76.9%, 33.8% and 0.0%, respectively. Treatment failures were associated with the pfdhps haplotype SGEGA at these five codons (OR 7.3; 95% CI 0.65 - 368; p = 0.048).
CONCLUSION
The decrease of CQR associated genotypes reflects the formal policy of complete removal of CQ in Sudan. However, the frequency of markers associated with SP failure is increasing in this study area and may be contributing to the treatment efficacy falling below 90%. Further monitoring of AS/SP efficacy and of post-treatment selection of pfdhfr and pfdhps alleles in vivo is required to inform future treatment guidelines.
Topics: Adolescent; Adult; Aged; Artemisinins; Child; Child, Preschool; DNA, Protozoan; Drug Resistance; Female; Gene Dosage; Gene Frequency; Humans; Malaria, Falciparum; Male; Middle Aged; Mutant Proteins; Plasmodium falciparum; Prevalence; Protozoan Proteins; Pyrimethamine; Real-Time Polymerase Chain Reaction; Sequence Analysis, DNA; Sudan; Sulfadoxine; Young Adult
PubMed: 23870667
DOI: 10.1186/1475-2875-12-255 -
Antimicrobial Agents and Chemotherapy Feb 2019Mefloquine was evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first-line drug...
Mefloquine was evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first-line drug sulfadoxine-pyrimethamine (SP). This study determined the pharmacokinetic characteristics of the mefloquine stereoisomers and the metabolite carboxymefloquine (CMQ) when given as IPTp in pregnant women. Also, the relationship between plasma concentrations of the three analytes and cord samples was evaluated, and potential covariates influencing the pharmacokinetic properties were assessed. A population pharmacokinetic analysis was performed with 264 pregnant women from a randomized controlled trial evaluating a single and a split-dose regimen of two 15-mg/kg mefloquine doses at least 1 month apart versus SP-IPTp. Both enantiomers of mefloquine and its carboxy-metabolite (CMQ), measured in plasma and cord samples, were applied for pharmacokinetic modelling using NONMEM 7.3. Both enantiomers and CMQ were described simultaneously by two-compartment models. In the split-dose group, mefloquine bioavailability was significantly increased by 5%. CMQ induced its own metabolism significantly. Maternal and cord blood concentrations were significantly correlated ( = 0.84) at delivery. With the dosing regimens investigated, prophylactic levels are not constantly achieved. A modeling tool for simulation of the pharmacokinetics of alternative mefloquine regimens is presented. This first pharmacokinetic characterization of mefloquine IPTp indicates adequate exposure in both mefloquine regimens; however, concentrations at delivery were below previously suggested threshold levels. Our model can serve as a valuable tool for researchers and clinicians to develop and optimize alternative dosing regimens for IPTp in pregnant women.
Topics: Adolescent; Adult; Antimalarials; Drug Combinations; Female; Humans; Malaria; Mefloquine; Pharmacokinetics; Plasmodium falciparum; Pregnancy; Pyrimethamine; Sulfadoxine; Young Adult
PubMed: 30455233
DOI: 10.1128/AAC.01113-18 -
The Journal of Biological Chemistry Sep 2018The genomes of the malaria-causing parasites encode a protein fused of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS)...
The genomes of the malaria-causing parasites encode a protein fused of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS) domains that catalyze sequential reactions in the folate biosynthetic pathway. Whereas higher organisms derive folate from their diet and lack the enzymes for its synthesis, most eubacteria and a number of lower eukaryotes including malaria parasites synthesize tetrahydrofolate via DHPS. () and () HPPK-DHPSs are currently targets of drugs like sulfadoxine (SDX). The SDX effectiveness as an antimalarial drug is increasingly diminished by the rise and spread of drug-resistant mutations. Here, we present the crystal structure of HPPK-DHPS in complex with four substrates/analogs, revealing the bifunctional HPPK-DHPS architecture in an unprecedented state of enzymatic activation. SDX's effect on HPPK-DHPS is due to 4-amino benzoic acid (ABA) mimicry, and the HPPK-DHPS structure sheds light on the SDX-binding cavity, as well as on mutations that effect SDX potency. We mapped five dominant drug resistance mutations in HPPK-DHPS: S382A, A383G, K512E/D, A553G, and V585A, most of which occur individually or in clusters proximal to the ABA-binding site. We found that these resistance mutations subtly alter the intricate enzyme/ABA/SDX interactions such that DHPS affinity for ABA is diminished only moderately, but its affinity for SDX is changed substantially. In conclusion, the HPPK-DHPS structure rationalizes and unravels the structural bases for SDX resistance mutations and highlights architectural features in HPPK-DHPSs from malaria parasites that can form the basis for developing next-generation anti-folate agents to combat malaria parasites.
Topics: Amino Acids; Crystallography, X-Ray; Dihydropteroate Synthase; Diphosphotransferases; Drug Resistance; Humans; Malaria, Vivax; Mutation; Plasmodium falciparum; Plasmodium vivax; Sulfadoxine; Tetrahydrofolates
PubMed: 30104413
DOI: 10.1074/jbc.RA118.004558 -
Parasitology Oct 2011Intermittent preventive treatment of infants (IPTi) with sulphadoxine pyrimethamine (SP) is recommended as an additional malaria control intervention in high... (Review)
Review
Intermittent preventive treatment of infants (IPTi) with sulphadoxine pyrimethamine (SP) is recommended as an additional malaria control intervention in high transmission areas of sub-Saharan Africa, provided its protective efficacy is not compromised by SP resistance. A significant obstacle in implementing SP-IPTi, is in establishing the degree of resistance in an area. Since SP monotherapy is discontinued, no contemporary measures of in vivo efficacy can be made, so the World Health Organisation has recommended a cut-off based upon molecular markers, stating that SP-IPTi should not be implemented when the prevalence of the dhps 540E mutation among infections exceeds 50%. We created a geo-referenced database of SP resistance markers in Africa from published literature. By selecting surveys of malaria infected blood samples conducted since 2004 we have mapped the contemporary prevalence of dhps 540E. Additional maps are freely available in interactive form at http://www.drugresistancemaps.org/ipti/. Eight countries in East Africa are classified as unsuitable for SP-IPTi when data are considered at a national level. Fourteen countries in Central and West Africa were classified as suitable while seven countries had no available contemporary data to guide policy. There are clear deficiencies in molecular surveillance data coverage. We discuss requirements for ongoing surveillance of SP resistance markers in support of the use of SP-IPTi.
Topics: Africa; Antimalarials; Dihydropteroate Synthase; Drug Combinations; Drug Resistance; Humans; Infant; Malaria; Mutation; Plasmodium; Prevalence; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase
PubMed: 21835078
DOI: 10.1017/S0031182011000746 -
PloS One 2009Malaria in pregnancy is serious, and drug resistance in Africa is spreading. Drugs have greater risks in pregnancy and determining the safety and efficacy of drugs in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Malaria in pregnancy is serious, and drug resistance in Africa is spreading. Drugs have greater risks in pregnancy and determining the safety and efficacy of drugs in pregnancy is therefore a priority. This study set out to determine the efficacy and safety of several antimalarial drugs and combinations in pregnant women with uncomplicated malaria.
METHODS
Pregnant women with non-severe, slide proven, falciparum malaria were randomised to one of 4 regimes: sulfadoxine-pyrimethamine [SP]; chlorproguanil-dapsone [CD]; SP+amodiaquine [SP+AQ] or amodiaquine+artesunate [AQ+AS]. Randomisation was on a 1ratio2ratio2ratio2 ratio. Women were admitted for treatment, and followed at days 7, 14, 21, 28 after the start of treatment, at delivery and 6 weeks after delivery to determine adverse events, clinical and parasitological outcomes. Primary outcome was parasitological failure by day 28.
RESULTS
1433 pregnant women were screened, of whom 272 met entry criteria and were randomised; 28 to SP, 81 to CD, 80 to SP+AQ and 83 to AQ+AS. Follow-up to day 28 post treatment was 251/272 (92%), and to 6 weeks following delivery 91%. By day 28 parasitological failure rates were 4/26 (15%, 95%CI 4-35) in the SP, 18/77 (23%, 95%CI 14-34) in the CD, 1/73 (1% 95%CI 7-0.001) in the SP+AQ and 7/75 (9% 95%CI 4-18) in the AQ+AS arms respectively. After correction by molecular markers for reinfection the parasitological failure rates at day 28 were 18% for CD, 1% for SP+AQ and 4.5% for AQ+AS. There were two maternal deaths during the trial. There was no apparent excess of stillbirths or adverse birth outcomes in any arm. Parasitological responses were strikingly better in pregnant women than in children treated with the same drugs at this site.
CONCLUSIONS
Failure rates with monotherapy were unacceptably high. The two combinations tested were efficacious and appeared safe. It should not be assumed that efficacy in pregnancy is the same as in children.
TRIAL REGISTRATION
ClinicalTrials.gov NCT00146731.
Topics: Adult; Amodiaquine; Artemisinins; Artesunate; Dapsone; Drug Combinations; Drug Therapy, Combination; Female; Humans; Malaria; Pregnancy; Pregnancy Complications, Parasitic; Proguanil; Pyrimethamine; Sulfadoxine; Tanzania; Young Adult
PubMed: 19352498
DOI: 10.1371/journal.pone.0005138 -
Antimicrobial Agents and Chemotherapy Apr 2023Sulfadoxine-pyrimethamine (SP) is used for prevention of malaria in pregnant women in Angola. We sequenced the Plasmodium falciparum dihydrofolate reductase () and...
Sulfadoxine-pyrimethamine (SP) is used for prevention of malaria in pregnant women in Angola. We sequenced the Plasmodium falciparum dihydrofolate reductase () and dihydropteroate synthase () genes, implicated in SP resistance, in samples collected during a 2019 study of artemisinin-based combination therapy efficacy in Benguela, Lunda Sul, and Zaire provinces. A total of 90 day 0 and day of failure samples were individually sequenced, while 508 day 0 samples from participants without recurrent parasitemia were pooled after DNA extraction into 61 pools. The N51I, C59R, and S108N mutations and A437G mutations were present at high proportions in all provinces (weighted allele frequencies, 62% to 100%). The K540E mutation was present at lower proportions (10% to 14%). The A581G mutation was only observed in Zaire, at a 4.6% estimated prevalence. The I431V and A613S mutations were also only observed in Zaire, at a prevalence of 2.8% to 2.9%. The most common (27% to 66%) reconstructed haplotype in all three provinces was the canonical quadruple mutant. The canonical quintuple mutant was absent in Lunda Sul and Benguela and present in 7.9% of samples in Zaire. A single canonical sextuple (2.6%) mutant was observed in Zaire Province. Proportions of the K540E and A581G mutations were well below the World Health Organization thresholds for meaningful SP resistance (prevalence of 95% for K540E and 10% for A581G). Samples from therapeutic efficacy studies represent a convenient source of samples for monitoring SP resistance markers.
Topics: Child; Female; Humans; Pregnancy; Plasmodium falciparum; Antimalarials; Malaria, Falciparum; Angola; Pyrimethamine; Sulfadoxine; Drug Combinations; Tetrahydrofolate Dehydrogenase; Drug Resistance
PubMed: 36916920
DOI: 10.1128/aac.01601-22 -
International Journal of Environmental... Oct 2022A significant gap exists between high rates of antenatal care attendance and low uptake of intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine...
A significant gap exists between high rates of antenatal care attendance and low uptake of intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) in Senegal. This study aims to investigate whether IPTp-SP is delivered per Senegal's national guidelines and to identify factors affecting the delivery of IPTp-SP at antenatal care visits. A secondary analysis was conducted using the 2014 and 2016 Senegal's Service Provision Assessment. The study sample consists of 1076 antenatal care across 369 health facilities. Multiple logit regression models were used to estimate the probability of receiving IPTp-SP during the antenatal care visit based on prior receipt of IPTp-SP and gestational age during the current pregnancy. At an antenatal care visit, the probability of receiving IPTp-SP is 84% (95% CI = [83%, 86%]) among women with no IPTp-SP history and 85% (95% CI = [79%, 92%]) among women with one prior dose. Women who visit a facility in the top quintile of the proportion of IPTp trained staff have a nearly 4-fold higher odds of receiving IPTp compared to those who visit a facility in the bottom quintile (95% CI = [1.54, 9.80]). The dose and timing of IPTp-SP provided in antenatal care settings in Senegal did not always conform with the national guideline. More training for providers and patient engagement is warranted to improve the uptake of IPTp-SP in antenatal care visits.
Topics: Antimalarials; Cross-Sectional Studies; Drug Combinations; Female; Humans; Malaria; Male; Pregnancy; Pregnancy Complications, Parasitic; Prenatal Care; Pyrimethamine; Senegal; Sulfadoxine
PubMed: 36232166
DOI: 10.3390/ijerph191912866 -
Malaria Journal Apr 2020Malaria in pregnancy increases the risk of deleterious maternal and birth outcomes. The use of ≥ 3 doses of sulfadoxine-pyrimethamine (SP) for intermittent...
BACKGROUND
Malaria in pregnancy increases the risk of deleterious maternal and birth outcomes. The use of ≥ 3 doses of sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria (IPTp-SP) is recommended for preventing the consequences of malaria during pregnancy. This study assessed the effect of IPTp-SP for prevention of malaria during pregnancy in low transmission settings.
METHODS
A cross-sectional study that involved consecutively selected 1161 pregnant women was conducted at Mwananyamala regional referral hospital in Dar es Salaam. Assessment of the uptake of IPTp-SP was done by extracting information from antenatal clinic cards. Maternal venous blood, cord blood, placental blood and placental biopsy were collected for assessment of anaemia and malaria. High performance liquid chromatography with ultraviolet detection (HPLC-UV) was used to detect and quantify sulfadoxine (SDX). Dried blood spots (DBS) of placental blood were collected for determination of sub-microscopic malaria using polymerase chain reaction (PCR).
RESULTS
In total, 397 (34.2%) pregnant women reported to have used sub-optimal doses (≤ 2) while 764 (65.8%) used optimal doses (≥ 3) of IPTp-SP at the time of delivery. The prevalence of placental malaria as determined by histology was 3.6%. Submicroscopic placental malaria was detected in 1.4% of the study participants. Women with peripheral malaria had six times risk of maternal anaemia than those who were malaria negative (aOR, 5.83; 95% CI 1.10-30.92; p = 0.04). The geometric mean plasma SDX concentration was 10.76 ± 2.51 μg/mL. Sub-optimal IPTp-SP dose was not associated with placental malaria, premature delivery and fetal anaemia. The use of ≤ 2 doses of IPTp-SP increased the risk of maternal anaemia by 1.36-fold compared to ≥ 3 doses (aOR, 1.36; 95% CI 1.04-1.79; p = 0.02).
CONCLUSION
The use of < 2 doses of IPTp-SP increased the risk of maternal anaemia. However, sub-optimal doses (≤ 2 doses) were not associated with increased the risk of malaria parasitaemia, fetal anaemia and preterm delivery among pregnant women in low malaria transmission setting. The use of optimal doses (≥ 3 doses) of IPTp-SP and complementary interventions should continue even in areas with low malaria transmission.
Topics: Adult; Antimalarials; Cross-Sectional Studies; Drug Combinations; Endemic Diseases; Female; Humans; Malaria; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Sulfadoxine; Tanzania; Young Adult
PubMed: 32306955
DOI: 10.1186/s12936-020-03234-4 -
BMC Infectious Diseases May 2021While the use of sulphadoxine pyrimethamine (SP) is effective in preventing malaria infection during pregnancy, there are challenges limiting its uptake in Nigeria. This...
BACKGROUND
While the use of sulphadoxine pyrimethamine (SP) is effective in preventing malaria infection during pregnancy, there are challenges limiting its uptake in Nigeria. This study aimed at exploring the barriers to IPTp usage among pregnant women in Kano state - Nigeria.
METHODS
This is a qualitative study. The purposive sampling strategy was used for identification and selection of 14 key informants for interviews. In addition, six focus group discussions (FGDs) were conducted with pregnant women (3 FGDs) and married men (3 FGDs). The conventional content analysis method was used to interpret meaning from the content of the data. MAXQDA 10 software was used for data management and analysis.
RESULTS
Poor policy implementation, poor antenatal care attendance, inadequate access to intermittent preventive treatment at the community levels, lack of sustainable funding, and poor community engagement emerged as major barriers to IPTp use in Nigeria.
CONCLUSION
While the political will to allocate sufficient financial resources could help improve service delivery and IPTp usage among pregnant women, community participation is critical to sustain the gains.
Topics: Adolescent; Adult; Antimalarials; Delivery of Health Care; Drug Combinations; Female; Focus Groups; Humans; Malaria; Male; Nigeria; Pregnancy; Pregnancy Complications, Parasitic; Pyrimethamine; Qualitative Research; Sulfadoxine; Young Adult
PubMed: 33985434
DOI: 10.1186/s12879-021-06135-2 -
Malaria Journal Jul 2014Anti-malarial drug resistance in Plasmodium falciparum in India has historically travelled from northeast India along the Myanmar border. The treatment policy for P....
BACKGROUND
Anti-malarial drug resistance in Plasmodium falciparum in India has historically travelled from northeast India along the Myanmar border. The treatment policy for P. falciparum in the region was, therefore, changed from chloroquine to artesunate (AS) plus sulphadoxine-pyrimethamine (SP) in selected areas in 2005 and in 2008 it became the first-line treatment. Recognizing that resistance to the partner drug can limit the useful life of this combination therapy, routine in vivo and molecular monitoring of anti-malarial drug efficacy through sentinel sites was initiated in 2009.
METHODS
Between May and October 2012, 190 subjects with acute uncomplicated falciparum malaria were enrolled in therapeutic efficacy studies in the states of Arunachal Pradesh, Tripura, and Mizoram. Clinical and parasitological assessments were conducted over 42 days of follow-up. Multivariate analysis was used to determine risk factors associated with treatment failure. Genotyping was done to distinguish re-infection from recrudescence as well as to determine the prevalence of molecular markers of antifolate resistance among isolates.
RESULTS
A total of 169 patients completed 42 days of follow-up at three sites. The crude and PCR-corrected Kaplan-Meier survival estimates of AS + SP were 60.8% (95% CI: 48.0-71.4) and 76.6% (95% CI: 64.1-85.2) in Gomati, Tripura; 74.6% (95% CI: 62.0-83.6) and 81.7% (95% CI: 69.4-89.5) in Lunglei, Mizoram; and, 59.5% (95% CI: 42.0-73.2) and 82.3% (95% CI: 64.6-91.6) in Changlang, Arunachal Pradesh. Most patients with P. falciparum cleared parasitaemia within 24 hours of treatment, but eight, including three patients who failed treatment, remained parasitaemic on day 3. Risk factors associated with treatment failure included age < five years, fever at the time of enrolment and AS under dosing. No adverse events were reported. Presence of dhfr plus dhps quintuple mutation was observed predominantly in treatment failure samples.
CONCLUSION
AS + SP treatment failure was widespread in northeast India and exceeded the threshold for changing drug policy. Based on these results, in January 2013 the expert committee of the National Vector Borne Disease Control Programme formulated the first subnational drug policy for India and selected artemether plus lumefantrine as the new first-line treatment in the northeast. Continued monitoring of anti-malarial drug efficacy is essential for effective malaria control.
Topics: Adolescent; Adult; Antimalarials; Artemisinins; Artesunate; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Female; Humans; India; Kaplan-Meier Estimate; Malaria, Falciparum; Male; Plasmodium falciparum; Pyrimethamine; Risk Factors; Sulfadoxine; Treatment Failure
PubMed: 25052385
DOI: 10.1186/1475-2875-13-284