Two patients with falciparum malaria and poor in vivo responses to artesunate

Luxemburger, Christine; Brockman, Al; Silamut, Kamolrat; Nosten, François; Vugt, M. van; Gimenez, François; Chongsuphajaisiddhi, T; White, Nicholas J.

doi:10.1016/s0035-9203(98)90807-0

Cited by 41 publications

(18 citation statements)

References 7 publications

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“…Slow parasite clearance after treatment with artemisinin derivatives was observed infrequently soon after they were introduced in Asia. 34 Detection of persistently dormant yet drug-sensitive parasites and splenic hypofunction are possible explanations. 35 Another factor is the initial doses of artemisinin derivatives, which vary considerably among different artemisinin-based combination therapies and range from 1.6 mg of artemether per kilogram in artemether–lumefantrine to 2.5 mg of dihydroartemisinin per kilogram in dihydroartemisinin–piperaquine to 4 mg of artesunate per kilogram in other artemisinin-based combination therapies.…”

Section: Discussionmentioning

confidence: 99%

Spread of Artemisinin Resistance in Plasmodium falciparum Malaria

et al. 2014

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BACKGROUND Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand–Cambodia border. Slowly clearing in fections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the “propeller” region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.)

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Section: Discussionmentioning

confidence: 99%

Spread of Artemisinin Resistance in Plasmodium falciparum Malaria

et al. 2014

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“…More recently, it has been suggested that the view that combinations will protect artemisinins is overly optimistic, and reports of treatment failures and reduced in vitro drug susceptibility have begun to emerge [19][20][21][22]. In vitro data on artemisinin susceptibility from Senegal, Cambodia, and French Guiana suggest reduced drug susceptibility as a consequence of uncontrolled use of artemisinin derivatives [17].…”

Section: Discussionmentioning

confidence: 99%

Artemisinin Resistance in Cambodia: A Clinical Trial Designed to Address an Emerging Problem in Southeast Asia

et al. 2010

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“…19 Poor therapeutic responses have been found with both five-day and seven-day treatment courses of artesunate monotherapy for uncomplicated falciparum malaria in multidrug-resistant areas of Indonesia 20 and Thailand. 21 This high recrudescence rate results from the rapid elimination of the drug. 19,22 The presence of sulfadoxine-pyrimethamine in the blood at effective concentrations during four asexual cycles (Ͼ 6 days) is likely to ensure elimination of residual parasites after the very rapid and substantial reduction of initial parasite biomass with artesunate.…”

Section: Discussionmentioning

confidence: 99%

Therapy of uncomplicated falciparum malaria: a randomized trial comparing artesunate plus sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine alone in Irian Jaya, Indonesia.

Tjitra¹,

Suprianto²,

Currie³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

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Abstract. Combining artesunate with existing antimalarial drugs may improve cure rates, delay emergence of resistance, and reduce transmission. We performed a randomized comparative trial to quantify the effect of adding artesunate to sulfadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria in Indonesia. Using a modified 1997 World Health Organization protocol for assessment of therapeutic efficacy of antimalarial drugs, 105 patients (stratified by age/ethnic group) were randomized: 53 received artesunate orally, 4 mg/kg of body weight, a single daily dose for three days, plus sulfadoxine-pyrimethamine orally (1.25 mg of pyrimethamine/kg of body weight), a single dose on day 0, and 52 patients received sulfadoxine-pyrimethamine alone. Six from the combination group were withdrawn from analysis, as were six of the sulfadoxine-pyrimethamine group. Treatment failure rates on day 14 were 0% in the artesunate plus sulfadoxine-pyrimethamine group and 8.7% in the sulfadoxine-pyrimethamine group (P ϭ 0.12). Treatment failure rates on day 28 were 4.4% and 15.2%, respectively (P ϭ 0.16). Relative risk of treatment failure at 28 days was 0.3 (95% confidence interval [CI] ϭ 0.1-1.3). Mean fever clearance time (1.3 versus 1.7 days) and mean parasite clearance time (1.4 versus 2.0 days) were both faster in the artesunate plus sulfadoxinepyrimethamine group than in the sulfadoxine-pyrimethamine group (P ϭ 0.08 and P Ͻ 0.0001, respectively). Only 20 (39.2%) of 51 patients treated with artesunate plus sulfadoxine-pyrimethamine were still parasitemic on day 1 compared with 45 (86.5%) of 52 patients treated with sulfadoxine-pyrimethamine alone (P ϭ 0.000001, relative risk [RR] ϭ 0.4, 95% CI ϭ 0.3-0.6). Gametocyte carriage was lower following artesunate plus sulfadoxine-pyrimethamine than following sulfadoxine-pyrimethamine (RR ϭ 0.5, 95% CI ϭ 0.2-1.0 on day 7 and RR ϭ 0.5, 95% CI ϭ 0.2-1

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Two patients with falciparum malaria and poor in vivo responses to artesunate

Cited by 41 publications

References 7 publications

Spread of Artemisinin Resistance in Plasmodium falciparum Malaria

Spread of Artemisinin Resistance in Plasmodium falciparum Malaria

Artemisinin Resistance in Cambodia: A Clinical Trial Designed to Address an Emerging Problem in Southeast Asia

Therapy of uncomplicated falciparum malaria: a randomized trial comparing artesunate plus sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine alone in Irian Jaya, Indonesia.

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