In vitro activity of antimalarials against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon

The in vitro activity of nine antimalarials was determined against 119 fresh clinical isolates of #Plasmodium falciparum$ obtained from symptomatic indigenous patients in Yaounde, Cameroun, using the isotopic semimicrotest. Seventy-four parasites were resistant to chloroquine (mean 50% inhibitory concentration [IC50] 337 nM) ; 45 were chloroquine-sensitive (mean IC50 35.6 nM). Twenty-five of 58 chloroquine-resistant parasites were resistant to monodesethylamodiaquine, the biologically active metabolite of amodiaquine. None of the chloroquine-sensitive isolates was resistant to monodesethylamodiaquine (IC50 17.3 nM). Pyronaridine, quinine, mefloquine, halofantrine, and artemether were highly active against the chloroquine-sensitive and the chloroquine-resistant isolates. Of the 43 isolates tested, 25 were sensitive to both pyrimethamine and cycloguanil, the biologically active metabolite of proguanil. The in vitro responses of chloroquine and monodesethylamodiaquine, chloroquine and quinine, quinine and mefloquine, mefloquine and halofantrine, artemether and mefloquine or halofantrine, and pyrimethamine and cycloguanil were significantly correlated. The present study suggests that chloroquine resistance is highly prevalent in vitro in Yaounde and that the alternative drugs are generally highly active against the chloroquine-resistant parasites. (Résumé d'auteur

Evaluation of community-based systems for the surveillance of day three-positive Plasmodium falciparum cases in Western Cambodia.

BACKGROUND: Delayed clearance of Plasmodium falciparum parasites is used as an operational indicator of potential artemisinin resistance. Effective community-based systems to detect P. falciparum cases remaining positive 72 hours after initiating treatment would be valuable for guiding case follow-up in areas of known resistance risk and for detecting areas of emerging resistance. METHODS: Systems incorporating existing networks of village malaria workers (VMWs) to monitor day three-positive P. falciparum cases were piloted in three provinces in western Cambodia. Quantitative and qualitative data were used to evaluate the wider feasibility and sustainability of community-based surveillance of day three-positive P. falciparum cases. RESULTS: Of 294 day-3 blood slides obtained across all sites (from 297 day-0 positives), 63 were positive for P. falciparum, an overall day-3 positivity rate of 21%. There were significant variations in the systems implemented by different partners. Full engagement of VMWs and health centre staff is critical. VMWs are responsible for a range of individual tasks including preparing blood slides on day-0, completing forms, administering directly observed therapy (DOT) on days 0-2, obtaining follow-up slides on day-3 and transporting slides and paperwork to their supervising health centre. When suitably motivated, unsalaried VMWs are willing and able to produce good quality blood smears and achieve very high rates of DOT and day-3 follow-up. CONCLUSIONS: Community-based surveillance of day-3 P. falciparum cases is feasible, but highly intensive, and as such needs strong and continuous support, particularly supervision and training. The purpose and role of community-based day-3 surveillance should be assessed in the light of resource requirements; scaling-up would need to be systematic and targeted, based on clearly defined epidemiological criteria. To be truly comprehensive, the system would need to be extended beyond VMWs to other public and private health providers

Artemisinin resistance in Plasmodium falciparum malaria.

BACKGROUND: Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance. METHODS: In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance. RESULTS: We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. CONCLUSIONS: P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.

Artemisinin-Resistant Malaria: Research Challenges, Opportunities, and Public Health Implications

Artemisinin-based combination therapies are the most effective drugs to treat Plasmodium falciparum malaria. Reduced sensitivity to artemisinin monotherapy, coupled with the emergence of parasite resistance to all partner drugs, threaten to place millions of patients at risk of inadequate treatment of malaria. Recognizing the significance and immediacy of this possibility, the Fogarty International Center and the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health convened a conference in November 2010 to bring together the diverse array of stakeholders responding to the growing threat of artemisinin resistance, including scientists from malarious countries in peril. This conference encouraged and enabled experts to share their recent unpublished data from studies that may improve our understanding of artemisinin resistance. Conference sessions addressed research priorities to forestall artemisinin resistance and fostered collaborations between field- and laboratory-based researchers and international programs, with the aim of translating new scientific evidence into public health solutions. Inspired by this conference, this review summarizes novel findings and perspectives on artemisinin resistance, approaches for translating research data into relevant public health information, and opportunities for interdisciplinary collaboration to combat artemisinin resistance