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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 (AUC 0-7days ). 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.

malaria journal

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