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: Ann M Guggisberg, Sesh A Sundararaman, Miguel Lanaspa, Cinta Moraleda, Raquel González, Alfredo Mayor, Pau Cisteró, David Hutchinson, Peter G Kremsner, Beatrice H Hahn, Quique Bassat, Audrey R Odom
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 214 Issue 7 Pg. 1085-91 (10 01 2016) ISSN: 1537-6613 [Electronic] United States
• PMID: 27443612 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected].

Chemical References

• Antimalarials
• Fosfomycin
• Clindamycin
• fosmidomycin

Topics

• Antimalarials (pharmacology, therapeutic use)
• Child, Preschool
• Clindamycin (pharmacology, therapeutic use)
• Clinical Trials as Topic
• Drug Resistance
• Fosfomycin (analogs & derivatives, pharmacology, therapeutic use)
• Genome, Protozoan
• Genomics (methods)
• Genotype
• Humans
• Infant
• Malaria, Falciparum (drug therapy, parasitology)
• Mozambique
• Plasmodium falciparum (drug effects, genetics, isolation & purification)
• Sequence Analysis, DNA (methods)
• Treatment Failure