Limits...
Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border.

Na-Bangchang K, Ruengweerayut R, Mahamad P, Ruengweerayut K, Chaijaroenkul W - Malar. J. (2010)

Bottom Line: Parasite clearance time (PCT) and fever clearance time (FCT) were significantly prolonged in patients with treatment failure compared with those with sensitive response [median (95% CI) values for PCT 32.0 (20.0-48.0) vs 24.0 (14.0-32.0) hr and FCT 30.0 (22.0-42.0) vs 26.0 (18.0-36.0) hr; p < 0.005].Although plasma concentration of dihydroartemisinin at 1 hour of treatment was significantly lower in patients with recrudescence compared with sensitive response [mean (95% CI) 456 (215-875) vs 525 (452-599) ng/ml; p < 0.001], the proportion of patients with recrudescence who had relatively low (compared with the lower limit of 95% CI defined in the sensitive group) was significantly smaller than that of the sensitive group.Although pharmacokinetic (ethnic-related) factors including resistance of P. falciparum to mefloquine contribute to some treatment failure following treatment with a three-day combination regimen of artesunate-mefloquine, results suggest that artesunate resistance may be emerging at the Thai-Myanmar border.

View Article: PubMed Central - HTML - PubMed

Affiliation: Graduate Programme in Biomedical Sciences, Thammasat University, Thailand. kesaratmu@yahoo.com

ABSTRACT

Background: Declining in clinical efficacy of artesunate-mefloquine combination has been documented in areas along the eastern border (Thai-Cambodian) of Thailand. In the present study, the clinical efficacy of the three-day combination regimen of artesunate-mefloquine as first-line treatment for acute uncomplicated falciparum malaria in Thailand was monitored in an area along the western border (Thai-Myanmar) of the country.

Methods: A total of 150 Burmese patients (85 males and 65 females) aged between 16 and 50 years who were attending the Mae Tao clinic, Mae-Sot, Tak Province, and presenting with symptomatic acute uncomplicated Plasmodium falciparum malaria were included into the study. Patients were treated initially (day 0) with 4 mg/kg body weight artesunate and 15 mg/kg body weight mefloquine. The dose regimen on day 2 was 4 mg/kg body weight artesunate and 10 mg/kg body weight mefloquine. On day 3, artesunate at the dose of 4 mg/kg body weight was given with 0.6 mg/kg body weight primaquine. Whole blood mefloquine and plasma artesunate and dihydroartemisinin (active plasma metabolite of artesunate) concentrations following treatment were determined by high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LCMS), respectively.

Results: Thirty-four cases had recrudescence during days 7 and 42. Five and 5 cases, respectively had reinfection with P. falciparum and reappearance of Plasmodium vivax in their peripheral blood during follow-up. The Kaplan-Meier estimate of the 42-and 28-day efficacy rates of this combination regimen were 72.58% (95% CI: 63.20-79.07%) and 83.06 (95% CI 76.14-94.40%), respectively. Parasite clearance time (PCT) and fever clearance time (FCT) were significantly prolonged in patients with treatment failure compared with those with sensitive response [median (95% CI) values for PCT 32.0 (20.0-48.0) vs 24.0 (14.0-32.0) hr and FCT 30.0 (22.0-42.0) vs 26.0 (18.0-36.0) hr; p < 0.005]. Whole blood mefloquine concentrations on days 1, 7 and 14 in patients with sensitive and recrudescence response were comparable. Although plasma concentration of dihydroartemisinin at 1 hour of treatment was significantly lower in patients with recrudescence compared with sensitive response [mean (95% CI) 456 (215-875) vs 525 (452-599) ng/ml; p < 0.001], the proportion of patients with recrudescence who had relatively low (compared with the lower limit of 95% CI defined in the sensitive group) was significantly smaller than that of the sensitive group.

Conclusions: Although pharmacokinetic (ethnic-related) factors including resistance of P. falciparum to mefloquine contribute to some treatment failure following treatment with a three-day combination regimen of artesunate-mefloquine, results suggest that artesunate resistance may be emerging at the Thai-Myanmar border.

Show MeSH

Related in: MedlinePlus

Whole blood mefloquine concentrations on day 1 (a), day 7 (b) and day 14 (c) after treatment in patients with sensitive (S) and recrudescence (R) response. Dot lines represent the lower and upper level of 95% CI defined in the sensitive group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2959072&req=5

Figure 2: Whole blood mefloquine concentrations on day 1 (a), day 7 (b) and day 14 (c) after treatment in patients with sensitive (S) and recrudescence (R) response. Dot lines represent the lower and upper level of 95% CI defined in the sensitive group.

Mentions: Whole blood mefloquine concentrations on days 0 (pre-treatment), 1, 7 and 14 of treatment are summarized in Table 2 and Figure 2 and plasma artesunate and dihydroartemisinin at 0 (pre-treatment) 1 and 6 hour after the first dose are summarized in Table 3 and Figure 3. Baseline mefloquine concentrations were detected in 15 (11.36%) cases (11 and 4 cases in the group with sensitive and recrudescence response, respectively) with median (95% CI) of 0 (0-220) ng/ml. No measurable baseline artesunate or dihydroartemisinin was found. Whole blood mefloquine concentrations tended to be lower on days 1, 7, 14 and 21 of treatment in patients with recrudescence response (Table 2). However, due to large inter-individual variability, statistical significance was not reached. Patients who had reappearance of parasitaemia on day 7 (1 case) or day 42 (5 cases) had similar mefloquine concentrations on days 1, 7 and 14. Nevertheless, the proportion of patients in the recrudescence group who had mefloquine concentrations on days 1, 7 and 14 lower than the lower limit of 95% CI for median concentrations defined in the sensitive group (1,377, 738 and 442 ng/ml for days 1, 7 and 14, respectively) was significantly larger than the sensitive group [5 (41.7%) vs 9 (25%), 3 (33.3%) vs 2 (9%) and 5 (50%) vs 5 (23.8%) cases for concentrations on day 1, 7 and 14, respectively] (Figure 2). Plasma aretsunate concentrations at 1 and 6 hours after the first dose were comparable between the group with recrudescence and sensitive response. On the other hand, dihydroartemisinin concentrations at 1 hour of treatment was significantly lower in patients with recrudescence response [mean (95% CI) 456 (215-875) vs 525 (452-599) ng/ml]. For both artesunate and dihydroartemisinin, the proportions of patients in the recrudescence group who had the concentrations at 1 hour after the first dose lower than the lower limit of 95% CI for median concentrations defined in the sensitive group (312 and 445 ng/ml for artesunate and dihydroartemisinin, respectively) was significantly smaller than the sensitive group [8 (26.6%) vs 26 (40%) and 10 (33.3%) vs 30 (46.1%) for artesunate and dihydroartemisinin, respectively] (Figure 3). Among the 34 cases with recrudescence, 12 had adequate blood/plasma concentrations of both mefloquine and dihydroartemisinin. Inadequacy of mefloquine and dihydroartemisinin concentrations was observed in 13 and 10 cases with recrudescence, respectively. Inadequate concentrations of both drugs was found in one case.


Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border.

Na-Bangchang K, Ruengweerayut R, Mahamad P, Ruengweerayut K, Chaijaroenkul W - Malar. J. (2010)

Whole blood mefloquine concentrations on day 1 (a), day 7 (b) and day 14 (c) after treatment in patients with sensitive (S) and recrudescence (R) response. Dot lines represent the lower and upper level of 95% CI defined in the sensitive group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2959072&req=5

Figure 2: Whole blood mefloquine concentrations on day 1 (a), day 7 (b) and day 14 (c) after treatment in patients with sensitive (S) and recrudescence (R) response. Dot lines represent the lower and upper level of 95% CI defined in the sensitive group.
Mentions: Whole blood mefloquine concentrations on days 0 (pre-treatment), 1, 7 and 14 of treatment are summarized in Table 2 and Figure 2 and plasma artesunate and dihydroartemisinin at 0 (pre-treatment) 1 and 6 hour after the first dose are summarized in Table 3 and Figure 3. Baseline mefloquine concentrations were detected in 15 (11.36%) cases (11 and 4 cases in the group with sensitive and recrudescence response, respectively) with median (95% CI) of 0 (0-220) ng/ml. No measurable baseline artesunate or dihydroartemisinin was found. Whole blood mefloquine concentrations tended to be lower on days 1, 7, 14 and 21 of treatment in patients with recrudescence response (Table 2). However, due to large inter-individual variability, statistical significance was not reached. Patients who had reappearance of parasitaemia on day 7 (1 case) or day 42 (5 cases) had similar mefloquine concentrations on days 1, 7 and 14. Nevertheless, the proportion of patients in the recrudescence group who had mefloquine concentrations on days 1, 7 and 14 lower than the lower limit of 95% CI for median concentrations defined in the sensitive group (1,377, 738 and 442 ng/ml for days 1, 7 and 14, respectively) was significantly larger than the sensitive group [5 (41.7%) vs 9 (25%), 3 (33.3%) vs 2 (9%) and 5 (50%) vs 5 (23.8%) cases for concentrations on day 1, 7 and 14, respectively] (Figure 2). Plasma aretsunate concentrations at 1 and 6 hours after the first dose were comparable between the group with recrudescence and sensitive response. On the other hand, dihydroartemisinin concentrations at 1 hour of treatment was significantly lower in patients with recrudescence response [mean (95% CI) 456 (215-875) vs 525 (452-599) ng/ml]. For both artesunate and dihydroartemisinin, the proportions of patients in the recrudescence group who had the concentrations at 1 hour after the first dose lower than the lower limit of 95% CI for median concentrations defined in the sensitive group (312 and 445 ng/ml for artesunate and dihydroartemisinin, respectively) was significantly smaller than the sensitive group [8 (26.6%) vs 26 (40%) and 10 (33.3%) vs 30 (46.1%) for artesunate and dihydroartemisinin, respectively] (Figure 3). Among the 34 cases with recrudescence, 12 had adequate blood/plasma concentrations of both mefloquine and dihydroartemisinin. Inadequacy of mefloquine and dihydroartemisinin concentrations was observed in 13 and 10 cases with recrudescence, respectively. Inadequate concentrations of both drugs was found in one case.

Bottom Line: Parasite clearance time (PCT) and fever clearance time (FCT) were significantly prolonged in patients with treatment failure compared with those with sensitive response [median (95% CI) values for PCT 32.0 (20.0-48.0) vs 24.0 (14.0-32.0) hr and FCT 30.0 (22.0-42.0) vs 26.0 (18.0-36.0) hr; p < 0.005].Although plasma concentration of dihydroartemisinin at 1 hour of treatment was significantly lower in patients with recrudescence compared with sensitive response [mean (95% CI) 456 (215-875) vs 525 (452-599) ng/ml; p < 0.001], the proportion of patients with recrudescence who had relatively low (compared with the lower limit of 95% CI defined in the sensitive group) was significantly smaller than that of the sensitive group.Although pharmacokinetic (ethnic-related) factors including resistance of P. falciparum to mefloquine contribute to some treatment failure following treatment with a three-day combination regimen of artesunate-mefloquine, results suggest that artesunate resistance may be emerging at the Thai-Myanmar border.

View Article: PubMed Central - HTML - PubMed

Affiliation: Graduate Programme in Biomedical Sciences, Thammasat University, Thailand. kesaratmu@yahoo.com

ABSTRACT

Background: Declining in clinical efficacy of artesunate-mefloquine combination has been documented in areas along the eastern border (Thai-Cambodian) of Thailand. In the present study, the clinical efficacy of the three-day combination regimen of artesunate-mefloquine as first-line treatment for acute uncomplicated falciparum malaria in Thailand was monitored in an area along the western border (Thai-Myanmar) of the country.

Methods: A total of 150 Burmese patients (85 males and 65 females) aged between 16 and 50 years who were attending the Mae Tao clinic, Mae-Sot, Tak Province, and presenting with symptomatic acute uncomplicated Plasmodium falciparum malaria were included into the study. Patients were treated initially (day 0) with 4 mg/kg body weight artesunate and 15 mg/kg body weight mefloquine. The dose regimen on day 2 was 4 mg/kg body weight artesunate and 10 mg/kg body weight mefloquine. On day 3, artesunate at the dose of 4 mg/kg body weight was given with 0.6 mg/kg body weight primaquine. Whole blood mefloquine and plasma artesunate and dihydroartemisinin (active plasma metabolite of artesunate) concentrations following treatment were determined by high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LCMS), respectively.

Results: Thirty-four cases had recrudescence during days 7 and 42. Five and 5 cases, respectively had reinfection with P. falciparum and reappearance of Plasmodium vivax in their peripheral blood during follow-up. The Kaplan-Meier estimate of the 42-and 28-day efficacy rates of this combination regimen were 72.58% (95% CI: 63.20-79.07%) and 83.06 (95% CI 76.14-94.40%), respectively. Parasite clearance time (PCT) and fever clearance time (FCT) were significantly prolonged in patients with treatment failure compared with those with sensitive response [median (95% CI) values for PCT 32.0 (20.0-48.0) vs 24.0 (14.0-32.0) hr and FCT 30.0 (22.0-42.0) vs 26.0 (18.0-36.0) hr; p < 0.005]. Whole blood mefloquine concentrations on days 1, 7 and 14 in patients with sensitive and recrudescence response were comparable. Although plasma concentration of dihydroartemisinin at 1 hour of treatment was significantly lower in patients with recrudescence compared with sensitive response [mean (95% CI) 456 (215-875) vs 525 (452-599) ng/ml; p < 0.001], the proportion of patients with recrudescence who had relatively low (compared with the lower limit of 95% CI defined in the sensitive group) was significantly smaller than that of the sensitive group.

Conclusions: Although pharmacokinetic (ethnic-related) factors including resistance of P. falciparum to mefloquine contribute to some treatment failure following treatment with a three-day combination regimen of artesunate-mefloquine, results suggest that artesunate resistance may be emerging at the Thai-Myanmar border.

Show MeSH
Related in: MedlinePlus