title: Genetic markers of resistance to pyrimethamine and sulfonamides in Plasmodium falciparum parasites compared with the resistance patterns in isolates of Escherichia coli from the same children in Guinea-Bissau.
abstract: The antifolate drugs sulphadoxine and pyrimethamine are used for treatment of chloroquine-resistant Plasmodium falciparum in Africa. Resistance to pyrimethamine has been associated with point mutations in the dhfr-gene and resistance to sulphadoxine with mutations in the dhps-gene. There is concern that the use of the antifolates trimethoprim and sulphamethoxazole for treatment of other infectious diseases will result in the selection of malaria parasites with mutations in these genes. In Guinea-Bissau, where sulfonamide and trimethoprim-containing drugs have been used extensively, we decided to assess the prevalence of mutations in the dhfr-and dhps-gene in P. falciparum isolated from children suffering from acute malaria and to assess the resistance patterns to trimethoprim/sulphamethoxazole in Escherichia coli isolated from the same patients. A thick film and a blood sample for polymerase chain reaction (PCR) were obtained from 100 children attending the Bandim Health Centre in Bissau with symptoms compatible with malaria. Furthermore, a stool sample was collected from the same children and cultured for E. coli. Of the cultured E. coli, 67% were resistant both to sulfonamides and trimethoprim, 4% to sulfonamides alone, 3% to trimethoprim alone while 26% were fully sensitive to both drugs. PCR was successfully performed in 97 blood samples. Of these, 41% had triple mutations at the dhfr-gene (at codons 51, 59 and 108), and 15% had triple mutations plus mutation at codon 437 in the dhps-gene. Only 45% harboured the wild-type dhfr-gene. Thus both bacterial resistance and mutations in the parasitic genes were common, but not linked in the individual child. As sulphadoxine-pyrimethamine has only been used as a second line treatment for chloroquine resistant malaria in Guinea-Bissau for a few years, it is worrying to find a high prevalence of mutations in the parasitic genes coding for resistance to these drugs. Therefore, restricting the use of sulphadoxine-pyrimethamine for the treatment of chloroquine resistant malaria might not be sufficient to prevent the development of resistance in the parasites as long as antifolate drugs are used extensively.
authors.affiliation: Projecto de Saúde de Bandim, Guinea-Bissau. pekofoed@dadlnet.dk
authors.forename: Poul-Erik
authors.initials: PE
authors.lastname: Kofoed
authors.forename: Michael
authors.initials: M
authors.lastname: Alfrangis
authors.forename: Anja
authors.initials: A
authors.lastname: Poulsen
authors.forename: Amabelia
authors.initials: A
authors.lastname: Rodrigues
authors.forename: Susanne Borum
authors.initials: SB
authors.lastname: Gjedde
authors.forename: Anita
authors.initials: A
authors.lastname: Rønn
authors.forename: Lars
authors.initials: L
authors.lastname: Rombo
mesh_terms: D000293:Adolescent; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D004351:Drug Resistance; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000453:epidemiology; D005260:Female; D005819:Genetic Markers; D006169:Guinea-Bissau / Q000453:epidemiology; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000235:genetics* / Q000469:parasitology; D008297:Male; D009154:Mutation / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D011739:Pyrimethamine / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000627:therapeutic use*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D005819:Genetic Markers; C001205:fanasil, pyrimethamine drug combination; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D013413:Sulfadoxine; D011739:Pyrimethamine