Abstract
BackgroundResistance to anti-malarial drugs hampers control efforts and increases the risk of morbidity and mortality from malaria. The efficacy of standard therapies for uncomplicated Plasmodium falciparum and Plasmodium vivax malaria was assessed in Chumkiri, Kampot Province, Cambodia.MethodsOne hundred fifty-one subjects with uncomplicated falciparum malaria received directly observed therapy with 12 mg/kg artesunate (over three days) and 25 mg/kg mefloquine, up to a maximum dose of 600 mg artesunate/1,000 mg mefloquine. One hundred nine subjects with uncomplicated vivax malaria received a total of 25 mg/kg chloroquine, up to a maximum dose of 1,500 mg, over three days. Subjects were followed for 42 days or until recurrent parasitaemia was observed. For P. falciparum infected subjects, PCR genotyping of msp1, msp2, and glurp was used to distinguish treatment failures from new infections. Treatment failure rates at days 28 and 42 were analyzed using both per protocol and Kaplan-Meier survival analysis. Real Time PCR was used to measure the copy number of the pfmdr1 gene and standard 48-hour isotopic hypoxanthine incorporation assays were used to measure IC50 for anti-malarial drugs.ResultsAmong P. falciparum infected subjects, 47.0% were still parasitemic on day 2 and 11.3% on day 3. The PCR corrected treatment failure rates determined by survival analysis at 28 and 42 days were 13.1% and 18.8%, respectively. Treatment failure was associated with increased pfmdr1 copy number, higher initial parasitaemia, higher mefloquine IC50, and longer time to parasite clearance. One P. falciparum isolate, from a treatment failure, had markedly elevated IC50 for both mefloquine (130 nM) and artesunate (6.7 nM). Among P. vivax infected subjects, 42.1% suffered recurrent P. vivax parasitaemia. None acquired new P. falciparum infection.ConclusionThe results suggest that artesunate-mefloquine combination therapy is beginning to fail in southern Cambodia and that resistance is not confined to the provinces at the Thai-Cambodian border. It is unclear whether the treatment failures are due solely to mefloquine resistance or to artesunate resistance as well. The findings of delayed clearance times and elevated artesunate IC50 suggest that artesunate resistance may be emerging on a background of mefloquine resistance.
Highlights
Resistance to anti-malarial drugs hampers control efforts and increases the risk of morbidity and mortality from malaria
In the face of this situation, many countries in the region have adopted artemisinin combination therapies, including artesunate-mefloquine and artemether-lumefantrine. In both Thailand and Cambodia, rising failure rates for mefloquine monotherapy led to introduction of artesunate-mefloquine combination therapy in 1995 and 2000 [4,5], respectively
In 2003, a regimen of 25 mg/kg mefloquine in two divided doses on day 0, and 12 mg/kg oral artesunate divided into two doses on day 0 and day 1, in Trat, Thailand, along the Cambodian border, produced an adequate clinical and parasitological response (ACPR) at day 28 in only 78.6% of 44 patients with uncomplicated P. falciparum malaria; at three other sites in Thailand the same regimen had an efficacy of > 90% [4]
Summary
Resistance to anti-malarial drugs hampers control efforts and increases the risk of morbidity and mortality from malaria. In the face of this situation, many countries in the region have adopted artemisinin combination therapies, including artesunate-mefloquine and artemether-lumefantrine. In 2002 in Pailin, a Cambodian province bordering Trat, a similar regimen produced ACPR at 28 days in 85.7% of subjects [5]; in this study almost one third of patients received less than 12 mg/kg artesunate and 20 mg/kg mefloquine, because blister pack doses were administered according to age rather than to weight. In 2004, using dosing based on weight rather than age, the 42 day ACPR was 79.3% in Pailin [5] Both the Thai and Cambodian studies used directly observed therapy and the Cambodian study used PCR correction for re-infection [7]. These findings suggest that resistance to artesunate-mefloquine may be emerging at the Thai-Cambodian border
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