title: Identification of resistance of Plasmodium falciparum to artesunate-mefloquine combination in an area along the Thai-Myanmar border: integration of clinico-parasitological response, systemic drug exposure, and in vitro parasite sensitivity.
abstract: BACKGROUND
  A markedly high failure rate of three-day artesunate-mefloquine was observed in the area along the Thai-Myanmar border.
  
  
  METHODS
  Identification of Plasmodium falciparum isolates with intrinsic resistance to each component of the artesunate-mefloquine combination was analysed with integrated information on clinico-parasitological response, together with systemic drug exposure (area under blood/plasma concentration-time curves (AUC)) of dihydroartemisinin and mefloquine, and in vitro sensitivity of P. falciparum in a total of 17 out of 29 P. falciparum isolates from patients with acute uncomplicated falciparum malaria. Analysis of the contribution of in vitro parasite sensitivity and systemic drug exposure and relationship with pfmdr1 copy number in the group with sensitive response was performed in 21 of 69 cases.
  
  
  RESULTS
  Identification of resistance and/or reduced intrinsic parasitocidal activity of artesunate and/or mefloquine without pharmacokinetic or other host-related factors were confirmed in six cases: one with reduced sensitivity to artesunate alone, two with resistance to mefloquine alone, and three with reduced sensitivity to artesunate combined with resistance to mefloquine. Resistance and/or reduced intrinsic parasitocidal activity of mefloquine/artesunate, together with contribution of pharmacokinetic factor of mefloquine and/or artesunate were identified in seven cases: two with resistance to mefloquine alone, and five with resistance to mefloquine combined with reduced sensitivity to artesunate. Pharmacokinetic factor alone contributed to recrudescence in three cases, all of which had inadequate whole blood mefloquine levels (AUC0-7days). Other host-related factors contributed to recrudescence in one case. Amplification of pfmdr1 (increasing of pfmdr1 copy number) is a related molecular marker of artesunate-mefloquine resistance and seems to be a suitable molecular marker to predict occurrence of recrudescence.
  
  
  CONCLUSIONS
  Despite the evidence of a low level of a decline in sensitivity of P. falciparum isolates to artemisinins in areas along the Thai-Myanmar border, artemisinin-based combination therapy (ACT) would be expected to remain the key anti-malarial drug for treatment of multidrug resistance P. falciparum. Continued monitoring and active surveillance of clinical efficacy of ACT, including identification of true artemisinin resistant parasites, is required for appropriate implementation of malaria control policy in this area.
authors.affiliation: International College of Medicine, Thammasat University, Klongluang, Pathumthanee, Thailand. kesaratmu@yahoo.com
authors.forename: Kesara
authors.initials: K
authors.lastname: Na-Bangchang
authors.forename: Phunuch
authors.initials: P
authors.lastname: Muhamad
authors.forename: Ronnatrai
authors.initials: R
authors.lastname: Ruaengweerayut
authors.forename: Wanna
authors.initials: W
authors.lastname: Chaijaroenkul
authors.forename: Juntra
authors.initials: J
authors.lastname: Karbwang
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use; D000077332:Artesunate; D016054:DNA, Protozoan / Q000235:genetics; D004338:Drug Combinations; D005260:Female; D018628:Gene Dosage; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology* / Q000473:pathology; D008297:Male; D015767:Mefloquine / Q000494:pharmacology* / Q000627:therapeutic use; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D002052:Myanmar; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D013785:Thailand; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D016054:DNA, Protozoan; D004338:Drug Combinations; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513498:Mdr1 protein, Plasmodium falciparum
references.citation: Mem Inst Oswaldo Cruz. 1999 Nov-Dec;94(6):803-9
references.pmid: 10585659
references.citation: Trop Med Int Health. 2006 Dec;11(12):1800-7
references.pmid: 17176344
references.citation: Malar J. 2006 Jan 18;5:1
references.pmid: 16420686
references.citation: Antimicrob Agents Chemother. 1999 Dec;43(12):2943-9
references.pmid: 10582887
references.citation: Antimicrob Agents Chemother. 2004 May;48(5):1807-10
references.pmid: 15105139
references.citation: PLoS One. 2012;7(5):e30927
references.pmid: 22701513
references.citation: Nature. 1990 May 17;345(6272):255-8
references.pmid: 2185424
references.citation: Mol Microbiol. 2000 May;36(4):955-61
references.pmid: 10844681
references.citation: J Infect Dis. 2010 Feb 15;201(4):570-9
references.pmid: 20085495
references.citation: Nat Rev Microbiol. 2010 Apr;8(4):272-80
references.pmid: 20208550
references.citation: N Engl J Med. 2008 Dec 11;359(24):2619-20
references.pmid: 19064625
references.citation: Trans R Soc Trop Med Hyg. 2003 Mar-Apr;97(2):226-8
references.pmid: 14584382
references.citation: Emerg Infect Dis. 2008 May;14(5):716-9
references.pmid: 18439351
references.citation: Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1143-7
references.pmid: 8302844
references.citation: Lancet. 2012 May 26;379(9830):1960-6
references.pmid: 22484134
references.citation: Exp Parasitol. 1992 Sep;75(2):207-12
references.pmid: 1516668
references.citation: Malar J. 2011 Sep 18;10:268
references.pmid: 21923936
references.citation: Wien Klin Wochenschr. 2010 Oct;122 Suppl 3:52-6
references.pmid: 20924699
references.citation: Am J Trop Med Hyg. 2008 Nov;79(5):662-9
references.pmid: 18981500
references.citation: Antimicrob Agents Chemother. 2003 Aug;47(8):2418-23
references.pmid: 12878499
references.citation: N Engl J Med. 2009 Jul 30;361(5):540-1
references.pmid: 19641219
references.citation: Trop Med Int Health. 2006 Sep;11(9):1360-6
references.pmid: 16930257
references.citation: Lancet. 2005 Dec 3;366(9501):1960-3
references.pmid: 16325698
references.citation: Malar J. 2009 May 04;8:89
references.pmid: 19413906
references.citation: Fundam Clin Pharmacol. 2009 Aug;23(4):387-409
references.pmid: 19709319
references.citation: Lancet. 1978 Jan 7;1(8054):22-3
references.pmid: 74500
references.citation: Lancet. 2004 Jul 31-Aug 6;364(9432):438-447
references.pmid: 15288742
references.citation: Am J Trop Med Hyg. 2011 Sep;85(3):568-72
references.pmid: 21896824
references.citation: Malar J. 2012 Aug 28;11:300
references.pmid: 22929621
references.citation: PLoS One. 2009;4(2):e4551
references.pmid: 19234601
references.citation: Southeast Asian J Trop Med Public Health. 1989 Mar;20(1):55-60
references.pmid: 2788925
references.citation: Am J Trop Med Hyg. 1999 Dec;61(6):978-85
references.pmid: 10674682
references.citation: Mol Microbiol. 2005 Aug;57(4):913-26
references.pmid: 16091034
references.citation: Trop Med Int Health. 2006 Feb;11(2):211-9
references.pmid: 16451346
references.citation: N Engl J Med. 2009 Jul 30;361(5):455-67
references.pmid: 19641202
references.citation: Malar J. 2011 Nov 10;10:339
references.pmid: 22074219
references.citation: Malar J. 2009 Feb 20;8:31
references.pmid: 19228438
references.citation: Malar J. 2010 Oct 08;9:273
references.pmid: 20929590
references.citation: Southeast Asian J Trop Med Public Health. 2008 Nov;39(6):963-77
references.pmid: 19062683
references.citation: Acta Trop. 2011 Oct-Nov;120(1-2):130-5
references.pmid: 21777558
references.citation: Clin Infect Dis. 2010 Dec 1;51(11):e82-9
references.pmid: 21028985
references.citation: Parasitol Today. 1993 Aug;9(8):303-5
references.pmid: 15463789
references.citation: Southeast Asian J Trop Med Public Health. 1993 Jun;24(2):221-5
references.pmid: 8266221
references.citation: Science. 1976 Aug 20;193(4254):673-5
references.pmid: 781840
references.citation: J Infect Dis. 2006 Aug 15;194(4):528-35
references.pmid: 16845638