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      Antimalarial Drug Resistance: A Threat to Malaria Elimination

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          Abstract

          Increasing antimalarial drug resistance once again threatens effective antimalarial drug treatment, malaria control, and elimination. Artemisinin combination therapies (ACTs) are first-line treatment for uncomplicated falciparum malaria in all endemic countries, yet partial resistance to artemisinins has emerged in the Greater Mekong Subregion. Concomitant emergence of partner drug resistance is now causing high ACT treatment failure rates in several areas. Genetic markers for artemisinin resistance and several of the partner drugs have been established, greatly facilitating surveillance. Single point mutations in the gene coding for the Kelch propeller domain of the K13 protein strongly correlate with artemisinin resistance. Novel regimens and strategies using existing antimalarial drugs will be needed until novel compounds can be deployed. Elimination of artemisinin resistance will imply elimination of all falciparum malaria from the same areas. In vivax malaria, chloroquine resistance is an increasing problem.

          Abstract

          Resistance to antimalarial drugs (e.g., artemisinins) is an increasing problem, but molecular markers have helped with surveillance. Novel regimens and strategies will be needed until new drugs can be deployed.

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          Jaime Sepúlveda, Robert Aune, Kayla Wishall … (1999)
          Article 0 comments Cited 2060 times – based on 0 reviews     Review now
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            Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study

            Aung Pyae Phyo, Aung Phyo, Standwell Nkhoma … (2012)
            Summary Background Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand–Myanmar (Burma) border. Methods In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. Findings 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5–2·7) in 2001, to 3·7 h (3·6–3·8) in 2010, compared with a mean of 5·5 h (5·2–5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. Interpretation Genetically determined artemisinin resistance in P falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2–6 years. Funding The Wellcome Trust and National Institutes of Health.
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              Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique.

              R E Desjardins, C. J. Canfield, J D Haynes … (1979)
              A rapid, semiautomated microdilution method was developed for measuring the activity of potential antimalarial drugs against cultured intraerythrocytic asexual forms of the human malaria parasite Plasmodium falciparum. Microtitration plates were used to prepare serial dilutions of the compounds to be tested. Parasites, obtained from continuous stock cultures, were subcultured in these plates for 42 h. Inhibition of uptake of a radiolabeled nucleic acid precursor by the parasites served as the indicator of antimalarial activity. Results of repeated measurements of activity with chloroquine, quinine, and the investigational new drug mefloquine demonstrated that the method is sensitive and precise. Several additional antimalarial drugs and compounds of interest were tested in vitro, and the results were consistent with available in vivo data. The use of P. falciparum isolates with known susceptibility to antimalarial drugs also permitted evaluation of the cross-resistance potential of each compound tested. The applications and expectations of this new test system within a drug development program are discussed.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cold Spring Harb Perspect Med
                Journal ID (iso-abbrev): Cold Spring Harb Perspect Med
                Journal ID (publisher-id): cshperspectmed
                Journal ID (hwp): cshperspectmed
                Title: Cold Spring Harbor Perspectives in Medicine
                Publisher: Cold Spring Harbor Laboratory Press (Cold Spring Harbor, New York )
                ISSN (Electronic): 2157-1422
                Publication date (Print): July 2017
                Volume: 7
                Issue: 7
                Electronic Location Identifier: a025619
                Affiliations
                [1 ]Malaria Molecular Epidemiology Unit, Institut Pasteur in Cambodia, Phnom Penh 12201, Cambodia
                [2 ]Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 73170, Thailand
                Author notes
                Article
                Accession ID: PMC5495053 Pmcid ID: PMC5495053 Pmc-uid ID: 5495053 Publisher ID: a025619
                DOI: 10.1101/cshperspect.a025619
                PMC ID: 5495053
                PubMed ID: 28289248
                SO-VID: a105f03a-a6cd-4790-ad71-261fb1bac8bb
                Copyright © Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved
                History
                Page count
                Pages: 24
                Categories
                Subject: 107
                Subject: Perspectives

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