title: Whole-Genome Sequencing to Evaluate the Resistance Landscape Following Antimalarial Treatment Failure With Fosmidomycin-Clindamycin.
abstract: Novel antimalarial therapies are needed in the face of emerging resistance to artemisinin combination therapies. A previous study found a high cure rate in Mozambican children with uncomplicated Plasmodium falciparum malaria 7 days after combination treatment with fosmidomycin-clindamycin. However, 28-day cure rates were low (45.9%), owing to parasite recrudescence. We sought to identify any genetic changes underlying parasite recrudescence. To this end, we used a selective whole-genome amplification method to amplify parasite genomes from blood spot DNA samples. Parasite genomes from pretreatment and postrecrudescence samples were subjected to whole-genome sequencing to identify nucleotide variants. Our data did not support the existence of a genetic change responsible for recrudescence following fosmidomycin-clindamycin treatment. Additionally, we found that previously described resistance alleles for these drugs do not represent biomarkers of recrudescence. Future studies should continue to optimize fosmidomycin combinations for use as antimalarial therapies.
authors.affiliation: Department of Pediatrics.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Guggisberg
authors.affiliation: Department of Medicine Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Sesh A
authors.initials: SA
authors.lastname: Sundararaman
authors.affiliation: Centro de Investigação em Saúde de Manhiça, Mozambique Barcelona Institute for Global Health, Barcelona Center for International Health Research, Hospital Clínic-Universitat de Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lanaspa
authors.affiliation: Centro de Investigação em Saúde de Manhiça, Mozambique Barcelona Institute for Global Health, Barcelona Center for International Health Research, Hospital Clínic-Universitat de Barcelona, Spain.
authors.forename: Cinta
authors.initials: C
authors.lastname: Moraleda
authors.affiliation: Centro de Investigação em Saúde de Manhiça, Mozambique Barcelona Institute for Global Health, Barcelona Center for International Health Research, Hospital Clínic-Universitat de Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: González
authors.affiliation: Centro de Investigação em Saúde de Manhiça, Mozambique Barcelona Institute for Global Health, Barcelona Center for International Health Research, Hospital Clínic-Universitat de Barcelona, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Mayor
authors.affiliation: Barcelona Institute for Global Health, Barcelona Center for International Health Research, Hospital Clínic-Universitat de Barcelona, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Cisteró
authors.affiliation: Jomaa Pharma, Hamburg.
authors.forename: David
authors.initials: D
authors.lastname: Hutchinson
authors.affiliation: Institut für Tropenmedizin, University of Tübingen, Germany Centre de Recherches Médicales de Lambaréné, Gabon.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.affiliation: Department of Medicine Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Centro de Investigação em Saúde de Manhiça, Mozambique.
authors.forename: Quique
authors.initials: Q
authors.lastname: Bassat
authors.affiliation: Department of Pediatrics Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Audrey R
authors.initials: AR
authors.lastname: Odom
mesh_terms: D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D002675:Child, Preschool; D002981:Clindamycin / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004351:Drug Resistance; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018503:Genome, Protozoan; D023281:Genomics / Q000379:methods*; D005838:Genotype; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D009073:Mozambique; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D017422:Sequence Analysis, DNA / Q000379:methods; D017211:Treatment Failure
chemical_list: D000962:Antimalarials; D005578:Fosfomycin; D002981:Clindamycin; C024640:fosmidomycin
keywords: Malaria; Plasmodium; clindamycin; fosmidomycin; recrudescence; whole genome amplification