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The treatment of malaria in glucose-6-phosphate dehydrogenase deficient patients in Sabah

Khoo KK

Ann Trop Med Parasitol, 1981 Dec;75(6):591-5.
PMID: 7325735 DOI: 10.1080/00034983.1981.11687489

One hundred and nine (9·8%) out of 1103 malaria patients examined in Sabah were deficient in glucose-6-phosphate dehydrogenase (G6PD). Sixty-nine of these G6PD-deficient patients were randomly allocated to one of three treatment regimes with (a) chloroquine, (b) chloroquine and primaquine or (c) sulfadoxine-pyrimethamine (Fansidar). No haemolysis was observed in group (a); except for a single mild case, no haemolysis was seen in group (c). However, in the primaquine group (23 patients), haemolysis occurred in seven of the 16 patients who had complete G6PD deficiency. Of these seven, five required blood transfusion and the other two developed acute renal failure, one requiring peritoneal dialysis. In the Fansidar group (c), four of the 22 patients took more than 15 days to clear the parasitaemia. Chloroquine resistance to falciparum infection was common in the patients given this anti-malarial.
Study site: Queen Elizabeth Hospital, Kola Kinabalu, Sabah, Malaysia

Matched MeSH terms: Sulfadoxine/therapeutic use
Clinical efficacy of sulfadoxine-pyrimethamine in the treatment of falciparum malaria in Sabah, Malaysia

Tan HS, Tan PE

Ann Acad Med Singap, 1984 Apr;13(2):170-4.
PMID: 6388486

One hundred and ten consecutive patients with falciparum malaria were treated with Fansidar and primaquine. Of the 61 patients who were followed up at one week, 4 (6.6%) failed to clear their parasitaemia (1 R III and 3 R II treatment failures). Of the subsequent 40 patients who were seen again at one month, another 3 (7.5%) had recrudesced (R I treatment failure). A total of 7 patients thus experienced some form of treatment failure in the cohort of 40 who completed the one month follow up. Only 1 of these 7 patients (with R III treatment failure) failed to respond to repeat Fansidar treatment, and may be the only one with true Fansidar resistance. The overall treatment failure rate of 17.5% (95% confidence interval: 6-29%) in the cohort who completed the study is consistent with the known clinical efficacy of Fansidar. These results suggest no significant Fansidar resistance in falciparum malaria found in Sabah.

Matched MeSH terms: Sulfadoxine/therapeutic use*
Application of a multi-faceted approach for the assessment of treatment response in falciparum malaria: a study from Malaysian Borneo

Cox-Singh J, Lu HY, Davis TM, Ilett KF, Hackett LP, Matusop A, et al.

Int J Parasitol, 2003 Nov;33(13):1545-52.
PMID: 14572517

Thirty-two patients reporting to the Lundu District Hospital, Sarawak, Malaysian Borneo, with uncomplicated falciparum malaria were recruited into a multifaceted study to assess treatment response. Following combined chloroquine and sulphadoxine/pyrimethamine treatment the patients were followed for 28 days according to the World Health Organisation in vivo drug response protocol. The in vivo study revealed that 13 (41%) of the patients had a sensitive response to treatment, five (16%) cleared asexual stage parasites but had persistent gametocytes, 11 (34%) had RI type resistance and three (9%) had RII type resistance requiring quinine intervention before day 7 for parasite clearance. Although clinically insignificant, patients with persistent gametocytes, surviving chloroquine and sulphadoxine/pyrimethamine treatment during maturation, were placed in the reduced response to treatment group for analysis. Allelic typing detected 100% prevalence of the pfcrt K76T marker associated with chloroquine resistance and 78% prevalence of the pfdhfr NRNL haplotype associated with sulphadoxine/pyrimethamine treatment failure. High serum chloroquine levels and pfdhfr haplotypes with

Matched MeSH terms: Sulfadoxine/therapeutic use
Fulltext Increased prevalence of pfdhfr and pfdhps mutations associated with sulfadoxine-pyrimethamine resistance in Plasmodium falciparum isolates from Jazan Region, Southwestern Saudi Arabia: important implications for malaria treatment policy

Madkhali AM, Al-Mekhlafi HM, Atroosh WM, Ghzwani AH, Zain KA, Abdulhaq AA, et al.

Malar J, 2020 Dec 02;19(1):446.
PMID: 33267841 DOI: 10.1186/s12936-020-03524-x

BACKGROUND: Despite significant progress in eliminating malaria from the Kingdom of Saudi Arabia, the disease is still endemic in the southwestern region of the country. Artesunate plus sulfadoxine-pyrimethamine (AS + SP) has been used in Saudi Arabia since 2007 as a first-line treatment for uncomplicated Plasmodium falciparum malaria. This study aimed to investigate the prevalence of mutations associated with resistance to artemisinin and sulfadoxine-pyrimethamine (SP) resistance in P. falciparum parasites circulating in Jazan region, southwestern Saudi Arabia.
METHODS: A total of 151 P. falciparum isolates were collected between April 2018 and March 2019 from 12 of the governorates in Jazan region. Genomic DNA was extracted from dried blood spots and amplified using nested PCR. Polymorphisms in the propeller domain of the P. falciparum k13 (pfkelch13) gene and point mutations in the P. falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes were identified by sequencing.
RESULTS: No mutations in the pfkelch13 propeller domain were found in any of the 151 isolates. However, point mutations in the pfdhfr and pfdhps genes were detected in 90.7% (137/151) of the isolates. The pfdhfr double mutations N51I + S108N (i.e. ACICNI haplotype) and triple mutations N51I + C59R + S108N (i.e. ACIRNI haplotype) were detected in 47% and 37.8% of the isolates, respectively. Moreover, the pfdhps single mutation at codon A437G and double mutations A437G + K540E (i.e. SGEAAI haplotype) were observed in 4.6% and 51.7% of the isolates, respectively. Interestingly, 23.8%, 25.1 and 12.6% of the isolates had quintuple, quadruple and triple mutated combined pfdhfr-pfdhps genotypes, respectively. Furthermore, significant associations were found between the prevalence of mutant haplotypes and the age, gender and nationality of the patients (P

Matched MeSH terms: Sulfadoxine/pharmacology*
Molecular markers associated with resistance to commonly used antimalarial drugs among Plasmodium falciparum isolates from a malaria-endemic area in Taiz governorate-Yemen during the transmission season

Alareqi LMQ, Mahdy MAK, Lau YL, Fong MY, Abdul-Ghani R, Mahmud R

Acta Trop, 2016 Oct;162:174-179.
PMID: 27343362 DOI: 10.1016/j.actatropica.2016.06.016

Since 2005, artesunate (AS) plus sulfadoxine/pyrimethamine (SP) combination has been adopted as the first-line treatment for uncomplicated malaria in Yemen in response to the high level of Plasmodium falciparum resistance to chloroquine (CQ). Therefore, the aim of the present study was to determine the frequency distribution of molecular markers associated with resistance to CQ and AS plus SP combination among P. falciparum isolates from a malaria-endemic area in Taiz governorate, Yemen. Fifty P. falciparum isolates were collected during a cross-sectional study in Mawza district, Taiz, in the period from October 2013 to April 2014. The isolates were investigated for drug resistance-associated molecular markers in five genes, including P. falciparum CQ resistance transporter (pfcrt) 76T and P. falciparum multidrug resistance 1 (pfmdr1) 86Y as markers of resistance to CQ, mutations in the Kelch 13 (K13) propeller domain for resistance to AS, and P. falciparum dihydrofolate reductase (pfdhfr) and P. falciparum dihydropteroate synthase (pfdhps) genes for resistance to SP. Nested polymerase chain reaction was used to amplify target genes in DNA extracts of the isolates followed by restriction fragment length polymorphism for detecting 76T and 86Y mutations in pfcrt and pfmdr1, respectively, and by DNA sequencing for detecting mutations in K13, pfdhfr and pfdhps. All the investigated isolates from Mawza district were harboring the pfcrt 76T mutant and the pfmdr1 N86 wild-type alleles. The pfdhfr 51I/108N double mutant allele was found in 2.2% (1/45) of the isolates; however, no mutations were detected at codons 436, 437, 540, 581 and 613 of pfdhps. All P. falciparum isolates that were successfully sequenced (n=47) showed the K13 Y493, R539, I543 and C580 wild-type alleles. In conclusion, the pfcrt 76T mutant allele is fixed in the study area about six years after the official withdrawal of CQ, possibly indicating its over-the-counter availability and continued use as a self-medication in the study area. However, the almost predominant wild-type alleles of the genes associated with resistance to AS and SP among P. falciparum isolates in the present study indicates the sustained efficacy of the currently adopted first-line treatment of AS plus SP in the study area.

Matched MeSH terms: Sulfadoxine/pharmacology
Fulltext Molecular characterization of Plasmodium falciparum antifolate resistance markers in Thailand between 2008 and 2016

Sugaram R, Suwannasin K, Kunasol C, Mathema VB, Day NPJ, Sudathip P, et al.

Malar J, 2020 Mar 04;19(1):107.
PMID: 32127009 DOI: 10.1186/s12936-020-03176-x

BACKGROUND: Resistance to anti-malarials is a major threat to the control and elimination of malaria. Sulfadoxine-pyrimethamine (SP) anti-malarial treatment was used as a national policy for treatment of uncomplicated falciparum malaria in Thailand from 1973 to 1990. In order to determine whether withdrawal of this antifolate drug has led to restoration of SP sensitivity, the prevalence of genetic markers of SP resistance was assessed in historical Thai samples.
METHODS: Plasmodium falciparum DNA was collected from the Thailand-Myanmar, Thailand-Malaysia and Thailand-Cambodia borders during 2008-2016 (N = 233). Semi-nested PCR and nucleotide sequencing were used to assess mutations in Plasmodium falciparum dihydrofolate reductase (pfdhfr), P. falciparum dihydropteroate synthase (pfdhps). Gene amplification of Plasmodium falcipaurm GTP cyclohydrolase-1 (pfgch1) was assessed by quantitative real-time PCR. The association between pfdhfr/pfdhps mutations and pfgch1 copy numbers were evaluated.
RESULTS: Mutations in pfdhfr/pfdhsp and pfgch1 copy number fluctuated overtime through the study period. Altogether, 14 unique pfdhfr-pdfhps haplotypes collectively containing quadruple to octuple mutations were identified. High variation in pfdhfr-pfdhps haplotypes and a high proportion of pfgch1 multiple copy number (51% (73/146)) were observed on the Thailand-Myanmar border compared to other parts of Thailand. Overall, the prevalence of septuple mutations was observed for pfdhfr-pfdhps haplotypes. In particular, the prevalence of pfdhfr-pfdhps, septuple mutation was observed in the Thailand-Myanmar (50%, 73/146) and Thailand-Cambodia (65%, 26/40) border. In Thailand-Malaysia border, majority of the pfdhfr-pfdhps haplotypes transaction from quadruple (90%, 9/10) to quintuple (65%, 24/37) during 2008-2016. Within the pfdhfr-pfdhps haplotypes, during 2008-2013 the pfdhps A/S436F mutation was observed only in Thailand-Myanmar border (9%, 10/107), while it was not identified later. In general, significant correlation was observed between the prevalence of pfdhfr I164L (ϕ = 0.213, p-value = 0.001) or pfdhps K540E/N (ϕ = 0.399, p-value ≤ 0.001) mutations and pfgch1 gene amplification.
CONCLUSIONS: Despite withdrawal of SP as anti-malarial treatment for 17 years, the border regions of Thailand continue to display high prevalence of antifolate and anti-sulfonamide resistance markers in falciparum malaria. Significant association between pfgch1 amplification and pfdhfr (I164L) or pfdhps (K540E) resistance markers were observed, suggesting a compensatory mutation.

Matched MeSH terms: Sulfadoxine/pharmacology*
Fulltext Artemisinin combination therapy fails even in the absence of Plasmodium falciparum kelch13 gene polymorphism in Central India

Das S, Kar A, Manna S, Mandal S, Mandal S, Das S, et al.

Sci Rep, 2021 05 11;11(1):9946.
PMID: 33976269 DOI: 10.1038/s41598-021-89295-0

Artemisinin is the frontline fast-acting anti-malarial against P. falciparum. Emergence and spread of resistant parasite in eastern-India poses a threat to national malaria control programs. Therefore, the objective of our study is to evaluate the artesunate-sulfadoxine-pyrimethamine efficacy in Central India. 180 monoclonal P. falciparum-infected patients received standard ASSP therapy during August 2015-January 2017, soon after diagnosis and monitored over next 42-days. Artemisinin-resistance was assessed through in-vivo parasite clearance half-life (PC1/2), ex-vivo ring-stage survivability (RSA), and genome analysis of kelch13 and other candidate gene (pfcrt, pfmdr1, pfatpase 6, pfdhfr and pfdhps). Of 180 P. falciparum positive patients, 9.5% showed increased PC1/2 (> 5.5 h), among them eleven isolates (6.1%) showed reduced sensitivity to RSA. In 4.4% of cases, parasites were not cleared by 72 h and showed prolonged PC1/2(5.6 h) (P

Matched MeSH terms: Sulfadoxine/therapeutic use
Fulltext Tracking origins and spread of sulfadoxine-resistant Plasmodium falciparum dhps alleles in Thailand

Alam MT, Vinayak S, Congpuong K, Wongsrichanalai C, Satimai W, Slutsker L, et al.

Antimicrob Agents Chemother, 2011 Jan;55(1):155-64.
PMID: 20956597 DOI: 10.1128/AAC.00691-10

The emergence and spread of drug-resistant Plasmodium falciparum have been a major impediment for the control of malaria worldwide. Earlier studies have shown that similar to chloroquine (CQ) resistance, high levels of pyrimethamine resistance in P. falciparum originated independently 4 to 5 times globally, including one origin at the Thailand-Cambodia border. In this study we describe the origins and spread of sulfadoxine-resistance-conferring dihydropteroate synthase (dhps) alleles in Thailand. The dhps mutations and flanking microsatellite loci were genotyped for P. falciparum isolates collected from 11 Thai provinces along the Burma, Cambodia, and Malaysia borders. Results indicated that resistant dhps alleles were fixed in Thailand, predominantly being the SGEGA, AGEAA, and SGNGA triple mutants and the AGKAA double mutant (mutated codons are underlined). These alleles had different geographical distributions. The SGEGA alleles were found mostly at the Burma border, while the SGNGA alleles occurred mainly at the Cambodia border and nearby provinces. Microsatellite data suggested that there were two major genetic lineages of the triple mutants in Thailand, one common for SGEGA/SGNGA alleles and another one independent for AGEAA. Importantly, the newly reported SGNGA alleles possibly originated at the Thailand-Cambodia border. All parasites in the Yala province (Malaysia border) had AGKAA alleles with almost identical flanking microsatellites haplotypes. They were also identical at putatively neutral loci on chromosomes 2 and 3, suggesting a clonal nature of the parasite population in Yala. In summary, this study suggests multiple and independent origins of resistant dhps alleles in Thailand.

Matched MeSH terms: Sulfadoxine