title: Dihydrofolate reductase I164L mutations in Plasmodium falciparum isolates: clinical outcome of 14 Kenyan adults infected with parasites harbouring the I164L mutation.
abstract: Recently, Plasmodium falciparum bearing dihydrofolate reductase (DHFR) I164L was isolated from Africa. Quadruple mutations containing I164L confer high-level resistance to antifolate antimalarials. We prospectively measured the effect of co-trimoxazole (CTX) prophylaxis on P. falciparum antifolate resistance development among HIV-infected persons. HIV-positive patients with CD4 cell count < 350 cells/microl (n=692) received CTX; HIV-positive patients with CD4 cell count > or = 350 cells/microl (n=336) and HIV-negative patients (n=132) received multivitamins. Malaria microscopy-positive samples (n=413) and selected microscopy-negative/PCR-positive samples (n=76) were analysed for DHFR mutations at baseline and during six months follow up. We identified I164L in 14 patients. Seven were malaria microscopy-positive: two failed sulfadoxine-pyrimethamine (SP). Among seven microscopy-negative/PCR-positive patients, none developed patent infections with I164L. I164L was not associated with high-level SP resistance or poor outcome among adults living where malaria is highly endemic. Surveillance to monitor spread of I164L is critical, especially among children and pregnant women, who are potentially a source for I164L amplification.
authors.affiliation: Centers for Disease Control and Prevention, Division of Parasitic Diseases, Malaria Branch, Atlanta, GA, USA. mhamel@ke.cdc.gov
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Hamel
authors.forename: Amanda
authors.initials: A
authors.lastname: Poe
authors.forename: Peter
authors.initials: P
authors.lastname: Bloland
authors.forename: Andrea
authors.initials: A
authors.lastname: McCollum
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhou
authors.forename: Ya Ping
authors.initials: YP
authors.lastname: Shi
authors.forename: Peter
authors.initials: P
authors.lastname: Ouma
authors.forename: Kephas
authors.initials: K
authors.lastname: Otieno
authors.forename: John
authors.initials: J
authors.lastname: Vulule
authors.forename: Ananias
authors.initials: A
authors.lastname: Escalante
authors.forename: Venkatachalam
authors.initials: V
authors.lastname: Udhayakumar
authors.forename: Laurence
authors.initials: L
authors.lastname: Slutsker
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D011446:Prospective Studies; D011739:Pyrimethamine / Q000627:therapeutic use; D013413:Sulfadoxine / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine