RECRUDESCENCE IN ARTESUNATE-TREATED PATIENTS WITH FALCIPARUM MALARIA IS DEPENDENT ON PARASITE BURDEN NOT ON PARASITE FACTORS

WANIDA ITTARAT Departments of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC; Hospital for Tropical Disease, Faculty of Tropical Medicine/Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI; Department of Experimental Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand

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AMY L. PICKARD Departments of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC; Hospital for Tropical Disease, Faculty of Tropical Medicine/Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI; Department of Experimental Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand

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PANTHIP RATTANASINGANCHAN Departments of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC; Hospital for Tropical Disease, Faculty of Tropical Medicine/Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI; Department of Experimental Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand

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POLRAT WILAIRATANA Departments of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC; Hospital for Tropical Disease, Faculty of Tropical Medicine/Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI; Department of Experimental Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand

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SORNCHAI LOOAREESUWAN Departments of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC; Hospital for Tropical Disease, Faculty of Tropical Medicine/Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI; Department of Experimental Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand

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KATHRYN EMERY Departments of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC; Hospital for Tropical Disease, Faculty of Tropical Medicine/Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI; Department of Experimental Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand

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JONATHAN LOW Departments of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC; Hospital for Tropical Disease, Faculty of Tropical Medicine/Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI; Department of Experimental Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand

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RACHANEE UDOMSANGPETCH Departments of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC; Hospital for Tropical Disease, Faculty of Tropical Medicine/Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI; Department of Experimental Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand

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STEVEN R. MESHNICK Departments of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC; Hospital for Tropical Disease, Faculty of Tropical Medicine/Mahidol University, Bangkok, Thailand; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI; Department of Experimental Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand

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Artemisinin derivatives are first-line antimalarial drugs in Thailand. No firm evidence of clinically relevant artemisinin resistance exists. When used as monotherapy, artesunate has been associated with a high treatment failure (recrudescence) rate, which could be due to low-level artemisinin resistance. To understand the causes of recrudescence, we retrospectively studied a cohort of 104 malaria patients treated with artesunate monotherapy, 32 of whom recrudesced. There was no difference in in vitro artesunate sensitivities between 6 nonrecrudescent isolates and 16 paired admission and recrudescent isolates. Paired admission and recrudescent isolates from 10 patients were genotyped; only 3 had pfmdr1 mutations. Patients with admission parasitemias >10,000 per μl had a 9-fold higher likelihood of recrudescence (adjusted odds ratio) compared with patients with lower parasitemias. This study suggests (1) recrudescence after treatment with artesunate is not the result of inherent parasite resistance, and (2) admission parasitemia may be useful in choosing therapeutic options.

Author Notes

Reprint requests: Steven R. Meshnick, Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill NC 27599-7435, Telephone: 919-966-7414, Fax: 919-966-2089, E-mail: meshnick@unc.edu
  • 1

    White NJ, Nosten F, Looareesuwan S, Watkins WM, Marsh K, Snow RW, Kokwaro G, Ouma J, Hien TT, Molyneux ME, Taylor TE, Newbold CI, Ruebush TK, 2nd, Danis M, Greenwood BM, Anderson RM, Olliaro P , 1999. Averting a malaria disaster. Lancet 353 :1965–1967.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    World Health Organization, 1988. The Use of Artemisinin and Its Derivatives as Antimalarial Drugs: Report of a Joint CTD/ DMP/TDR Informal Consultation. Geneva: WHO.

    • PubMed
    • Export Citation
  • 3

    Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR, 2002. Epidemiology of drug-resistant malaria. Lancet Infect Dis 2 :209–218.

  • 4

    Sahr F, Willoughby VR, Gbakima AA, Bockarie MJ, 2001. Apparent drug failure following artesunate treatment of Plasmodium falciparum malaria in Freetown, Sierra Leone: four case reports. Ann Trop Med Parasitol 95 :445–449.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Luxemburger C, AB, Silamut K, Nosten F, van Vugt M, Gimenez F, Chongsuphajaisiddhi T, White NJ, 1998. Two patients with falciparum malaria and poor in vivo responses to artesunate. Trans R Soc Trop Med Hyg 92 :668–669.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Karnad DC, Kanbur A, Kamtekar KD, Kshirsagar NA, 2000. Probable resistance to parenteral artemether in Plasmodium falciparum: case reports from Mumbai (Bombay), India. Ann Trop Med Parasitol 94 :519–520.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Walker DJ, Pitsch JL, Peng MM, Robinson BL, Peters W, Bhisutthibhan J, Meshnick SR, 2000. Mechanisms of artemisinin resistance in the rodent malaria pathogen Plasmodium yoelii. Antimicrob Agents Chemother 44 :344–347.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Price RN, Nosten F, Luxemburger C, ter Kuile FO, Paiphun L, Chongsuphajaisiddhi T, White NJ, 1996. Effects of artemisinin derivatives on malaria transmissibility. Lancet 347 :1654–1658.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Nzila AM, Nduati E, Mberu EK, Hopkins Sibley C, Monks SA, Winstanley PA, Watkins WM, 2000. Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate Pyrimethamine/Sulfadoxine compared with the shorter-acting chlorproguanil/dapsone on Kenyan Plasmodium falciparum. J Infect Dis 181 :2023–2028.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Meshnick SR, Taylor TE, Kamchonwongpaisan S, 1996. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol Rev 60 :301–315.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    White NJ, 1997. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother 41 :1413–1422.

  • 12

    Trager W, Jensen JB, 1976. Human malaria parasites in continuous culture. Science 193 :673–675.

  • 13

    Desjardins RE, Canfield CJ, Haynes JD, Chulay JD, 1979. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother 16 :710–718.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Pujades A, Lewis M, Salvati AM, Miwa S, Fujii H, Zarza R, Alvarez R, Rull E, Corrons JL, 1999. Evaluation of the blue formazan spot test for screening glucose 6 phosphate dehydrogenase deficiency. Int J Hematol 69 :234–236.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Adagu IS, Dias F, Pinheiro L, Rombo L, do Rosario V, Warhurst DC, 1996. Guinea Bissau: association of chloroquine resistance of Plasmodium falciparum with the Tyr86 allele of the multiple drug-resistance gene Pfmdr1. Trans R Soc Trop Med Hyg 90 :90–91.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Grobusch MP, Adagu IS, Kremsner PG, Warhurst DC, 1998. Plasmodium falciparum: in vitro chloroquine susceptibility and allele-specific PCR detection of Pfmdr1 Asn86Tyr polymorphism in Lambarene, Gabon. Parasitology 116 :211–217.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Lane BR, Ast JC, Hossler PA, Mindell DP, Bartlett MS, Smith JW, Meshnick SR, 1997. Dihydropteroate synthase polymorphisms in Pneumocystis carinii. J Infect Dis 175 :482–485.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    McElroy PD, ter Kuile FO, Lal AA, Bloland PB, Hawley WA, Oloo AJ, Monto AS, Meshnick SR, Nahlen BL, 2000. Effect of Plasmodium falciparum parasitemia density on hemoglobin concentrations among full-term, normal birth weight children in western Kenya, IV. The Asembo Bay Cohort Project. Am J Trop Med Hyg 62 :504–512.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Duraisingh MT, Roper C, Walliker D, Warhurst DC, 2000. Increased sensitivity to the antimalarials mefloquine and artemisinin is conferred by mutations in the pfmdr1 gene of Plasmodium falciparum. Mol Microbiol 36 :955–961.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF, 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403 :906–909.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Price R, Cassar C, Brockman A, Duraisingh M, van Vugt M, White NJ, Nosten F, Krishna S, 1999. The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the Western border of Thailand. Antimicrob Agents Chemother 12 :2943–2949.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Sokhna CS, Rogier C, Dieye A, Trape JF, 2000. Host factors affecting the delay of reappearance of Plasmodium falciparum after radical treatment among a semi-immune population exposed to intense perennial transmission. Am J Trop Med Hyg 62 :266–270.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    ter Kuile FO, Luxemburger C, Nosten F, Thwai KL, Chongsuphajaisiddhi T, White NJ, 1995. Predictors of mefloquine treatment failure: a prospective study of 1590 patients with uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg 89 :660–664.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Giao PT, Binh TQ, Kager PA, Long HP, Van Thang N, Van Nam N, de Vries PJ, 2001. Artemisinin for treatment of uncomplicated falciparum malaria: is there a place for monotherapy? Am J Trop Med Hyg 65 :690–695.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Wongsrichanalai C, Wimonwattrawatee T, Sookto P, Laoboon-chai A, Heppner DG, Kyle DE, Wernsdorfer WH, 1999. In vitro sensitivity of Plasmodium falciparum to artesunate in Thailand. Bull World Health Organ 77 :392–398.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Brockman A, Price RN, van Vugt M, Heppner DG, Walsh D, Sookto P, Wimonwattrawatee T, Looareesuwan S, White NJ, Nosten F, 2000. Plasmodium falciparum antimalarial drug susceptibility on the north-western border of Thailand during five years of extensive use of artesunate-mefloquine. Trans R Soc Trop Med Hyg 94 :537–544.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Nakazawa S, Kanbara H, Aikawa M, 1995. Plasmodium-falciparum—recrudescence of parasites in culture. Exp Parasitol 81 :556–563.

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