Treatment of uncomplicated multidrug-resistant falciparum malaria with artesunate-atovaquone-proguanil
ABSTRACT In an open-label trial carried out on the northwest border of Thailand, 1596 patients with uncomplicated multidrug-resistant falciparum malaria were randomly assigned to receive atovaquone-proguanil, atovaquone-proguanil-artesunate, or artesunate-mefloquine and were followed up for 42 days. All 3 regimens were highly effective and well tolerated. Fever duration and parasite clearance times were significantly shorter among patients who received artesunate (P<.001). Polymerase chain reaction genotyping confirmed that recrudescence occurred in 13 patients who received artesunate-mefloquine (2.4%), 5 who received atovaquone-proguanil-artesunate (0.9%), and 15 who received atovaquone-proguanil (2.8%). Adding artesunate to atovaquone-proguanil reduced the risk of failure 3-fold (95% confidence interval [CI], 1.1-8.2) and subsequent gametocyte carriage 21-fold (95% CI, 14-30). Gastrointestinal complaints in the first 48 h after initiation of treatment were more common among artesunate recipients, but after day 2, dizziness, sleep disturbance, nausea, vomiting, and anorexia were more common among mefloquine recipients (P< or =.014). Artesunate-atovaquone-proguanil is a highly effective and well-tolerated treatment for multidrug-resistant falciparum malaria.
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ABSTRACT: Artemisinin-based combination therapies (ACTs) are recommended for the treatment of acute uncomplicated falciparum malaria in many malaria-endemic countries. Despite the emergence of artemisinin resistance, few alternative non-ACTs, including atovaquone-proguanil, are currently available. Plasmodium falciparum-infected Cameroonian children a parts per thousand currency sign5 years old (n = 338) were randomly assigned to artesunate-amodiaquine, atovaquone-proguanil, or artesunate-atovaquone-proguanil treatment groups and followed for 28 days, according to the standard World Health Organization protocol. In vitro response to atovaquone and cytochrome b sequence of clinical isolates were determined. Eight late failures and 16 failures (8 late and 8 early failures) were observed after artesunate-amodiaquine and atovaquone-proguanil therapies, respectively. Most late failures were due to reinfections. Artesunate-atovaquone-proguanil was not associated with any failure. After correction by genotyping, per-protocol analysis showed no difference in the efficacy of 3 drugs. However, the proportion of atovaquone-proguanil-treated patients with positive smears on day 3 was much higher (36.0%; P < .05) than that of the artesunate-amodiaquine (2.9%) and artesunate-atovaquone-proguanil (1.0%) groups. In vitro response and cytochrome b sequence did not indicate atovaquone resistance. Atovaquone-proguanil was characterized by a slow blood schizontocidal action and resulted in early treatment failure in a few patients. Artesunate-atovaquone-proguanil was a highly effective alternative treatment. UMIN000003813.The Journal of Infectious Diseases 06/2014; 210(12). DOI:10.1093/infdis/jiu341 · 5.78 Impact Factor
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ABSTRACT: Introduction: Chemotherapy of malaria has become a rapidly changing field. Less than two decades ago, treatment regimens were increasingly bound to fail due to emerging drug resistance against 4-aminoquinolines and sulfa compounds. By now, artemisinin-based combination therapies (ACTs) constitute the standard of care for uncomplicated falciparum malaria and are increasingly also taken into consideration for the treatment of non-falciparum malaria. Areas covered: This narrative review provides an overview of the state-of-art antimalarial drug therapy, highlights the global portfolio of current Phase III/IV clinical trials and summarizes current developments. Expert opinion: Malaria chemotherapy remains a dynamic field, with novel drugs and drug combinations continuing to emerge in order to outpace the development of large-scale drug resistance against the currently most important drug class, the artemisinin derivatives. More randomized controlled studies are urgently needed especially for the treatment of malaria in first trimester pregnant women. ACTs should be used for the treatment of imported malaria more consequently. Gaining sufficient efficacy and safety information on ACT use for non-falciparum species including Plasmodium ovale and malariae should be a research priority. Continuous investment into malaria drug development is a vital factor to combat artemisinin resistance and successfully improve malaria control toward the ultimate goal of elimination.Expert Opinion on Pharmacotherapy 08/2014; 15(15). DOI:10.1517/14656566.2014.944499 · 3.09 Impact Factor
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ABSTRACT: The usefulness of atovaquone-proguanil (AP) as antimalarial treatment is compromised by the emergence of atovaquone resistance during therapy. However, the origin of the parasite mitochondrial DNA (mtDNA) mutation conferring atovaquone resistance remains elusive. Here, we report a patient-based stochastic model that tracks the intra-host emergence of mutations in the multi-copy mtDNA during the few erythrocytic parasite cycles leading to the malaria febrile episode. The effect of mtDNA copy number, mutation rate, mutation cost and total parasite load on the mutant parasite load per patient was evaluated. Computer simulations showed that almost any infected patient carried, after 4 to 7 erythrocytic cycles, de novo mutant parasites at low-frequency, with varied frequencies of parasites carrying varied numbers of mutant mtDNA copies. A large inter-patient variability in the size of this mutant reservoir was found, explained by the different parameters tested but also by the relaxed replication and partitioning of mtDNA copies during mitosis. We also report seven clinical cases in which AP-resistant infections were treated by AP. These provided evidences that parasiticidal drug concentrations against AP-resistant parasites were transiently obtained within days following treatment initiation. Altogether, these results suggest that each patient carries new mtDNA mutant parasites emerging before treatment and that are destroyed by high starting drug concentrations; however, because the size of this mutant reservoir is highly variable from patients to patients, we propose that some patients fail to eliminate all the mutant parasites, repeatedly producing de novo AP treatment failures.Antimicrobial Agents and Chemotherapy 05/2014; 58(8). DOI:10.1128/AAC.02550-13 · 4.45 Impact Factor