Abstract. The factors affecting the development of patent Plasmodium falciparum gametocytemia were assessed in 5,682 patients entered prospectively into a series of antimalarial drug trials conducted in an area of low and seasonal transmission on the western border of Thailand. Of the 4,565 patients with admission thick smear assessments, 110 (2.4%) had gametocytemia. During the follow-up period 170 (3%) of all patients developed patent gametocytemia, which in 89% had developed by day 14 following treatment. In a multiple logistic regression model five factors were found to be independent risk factors at presentation for the development or persistence of gametocytemia during follow up; patent gametocytemia on admission (adjusted odds ratio [AOR] ϭ 7.8, 95% confidence interval [CI] ϭ 3.7-16, P Ͻ 0.001), anemia (hematocrit Ͻ30%) (AOR ϭ 3.9, 95% CI ϭ 2.3-6.5, P Ͻ 0.001), no coincident P. vivax malaria (AOR ϭ 3.5, 95% CI ϭ 1.04-11.5, P Ͻ 0.04), presentation with a recrudescent infection (AOR ϭ 2.3, 95% CI ϭ 1.3-4.1, P Ͻ 0.004), and a history of illness longer than two days (AOR ϭ 3.3, 95% CI ϭ 1.7-6.6, P Ͻ 0.001). Patients whose infections responded slowly to treatment or recrudesced subsequently were also more likely to carry gametocytes than those who responded rapidly or were cured (relative risks ϭ 1.9, 95% CI ϭ 1.3-2.7 and 2.8, 95% CI ϭ 2.0-4.0, respectively; P Ͻ 0.001). These data provide further evidence of important epidemiologic interactions between P. falciparum and P. vivax, and drug resistance and transmission potential.The life cycle of Plasmodium falciparum is dependent upon the production of viable sexual stages of the parasite and their appearance in sufficient numbers in the peripheral blood of the human host. These gametocytes can then be transmitted to a feeding anopheline mosquito and on to a new human host, thus completing the life cycle of the malaria parasite. In contrast to the treatment of the three other species of human malaria, most of the antimalarial drugs used to treat the asexual stages of P. falciparum malaria have little or no effects on the viability of mature gametocytes. The rate of production of gametocytes is influenced considerably by host factors, notably immunity, 1 and this may have significant epidemiologic consequences. Integrated malaria control programs that aim to reduce malaria transmission are often based on identifying those individuals most likely to transmit malaria. We investigated the factors that influence the production of gametocytes following uncomplicated falciparum malaria in an area where there is a high prevalence of multidrug resistance, and a relatively low level of transmission and consequent background immunity. METHODSStudy site. The study took place between 1990 and 1995 in patients living in a camp for displaced person of the Karen ethnic minority situated in an area of malarious hill forest on the western border of Thailand. During the five-year period, a series of 18 antimalarial drug studies were conducted to determine the optimum treatment of ...

Following a marked decline in the efficacy in vivo of mefloquine between 1990 and 1994, a combination of artesunate (4 mg/kg/d for 3 d) and mefloquine (25 mg/kg) has been used as first line treatment of uncomplicated falciparum malaria in camps for displaced persons located along the north-western border of Thailand. Antimalarial drug susceptibility of fresh isolates of Plasmodium falciparum from this population was evaluated using a radioisotope microdilution assay between 1995 and 1999. In total, 268 isolates were collected, of which 189 were from primary infections and 79 from recrudescent infections. The geometric mean 50% inhibitory concentration (IC50) values from primary infections were: dihydroartemisinin 1.2 ng/mL, artesunate 1.6 ng/mL, artemether 4.8 ng/mL, atovaquone 0.4 ng/mL, lumefantrine 32 ng/mL, chloroquine 149 ng/mL, quinine 354 ng/mL, mefloquine 27 ng/mL and halofantrine 4.1 ng/mL. A significant positive correlation was found between the susceptibility in vitro to artesunate and quinine (r = 0.43, P < 0.001), mefloquine (r = 0.46, P < 0.001), and halofantrine (r = 0.51, P < 0.001). These levels of resistance in vitro are among the highest reported and confirm continuing high level multidrug resistance in this area. Despite intensive use of the combination between 1995 and 1999 there has been a significant improvement in mefloquine sensitivity (P < 0.001) and artesunate sensitivity (P < 0.001). This supports observations in vivo that the combination of artesunate and mefloquine has reversed the previous decline in mefloquine sensitivity.

The efficacy of chloroquine (25 mg base/kg over 3 days) in Plasmodium vivax malaria was evaluated in 1995/96 in 342 patients living in an endemic area on the western border of Thailand. Clearance of fever and parasites was obtained within 2 days in > 95% of the patients, and all were aparasitaemic by day 4. Reappearance of P. vivax occurred in 1 patient on day 21 and in 8 by day 28, giving a 28-day cure rate of 97% [95% confidence interval (CI) 95-99%]. By day 63, the relapse/re-infection rate was 63% (95% CI 57-69%). Most reappearances of parasitaemia (85%; 121/143) were symptomatic. These patients were retreated either with chloroquine alone (n = 70) or with chloroquine and primaquine (0.25 mg/kg daily for 14 days) (n = 43). Only 1 patient (in the chloroquine-only group) had prolonged parasite clearance (D8) and he developed recurrent P. vivax by day 21 suggesting possible recrudescence. The addition of primaquine to chloroquine reduced the risk of having a third vivax episode within 2 months by 96% (95% CI 83-99%). This resulted in a significantly higher haematocrit at day 42 despite a greater decrease in haematocrit during the first week of treatment with chloroquine-primaquine (P = 0.04). Chloroquine remains highly effective on the western border of Thailand and the use of strictly supervised primaquine effectively prevents relapse. The introduction of primaquine on a large scale in an endemic area still requires a long-term risk-benefit assessment which must take into account potential toxicity, low compliance and reductions in the incidence and severity of P. falciparum infections by co-existent P. vivax.

BackgroundAchieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the ‘therapeutic’ day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations.MethodsThe WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data.ResultsOf 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (<3 years), among whom underweight-for-age children had 23 % (95 % CI −1 to 41 %) lower concentrations than adequately nourished children of the same age and 53 % (95 % CI 37 to 65 %) lower concentrations than adults. Day 7 lumefantrine concentrations were 44 % (95 % CI 38 to 49 %) lower following unsupervised treatment. The highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng/ml were associated with >98 % cure rates (if parasitemia <135,000/μL).ConclusionsCurrent artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0456-7) contains supplementary material, which is available to authorized users.

Abstract. The artemisinin derivatives are now used widely in areas with multidrug-resistant Plasmodium falciparum malaria such as Southeast Asia, but concerns remain over their potential for neurotoxicity. Mice, rats, dogs, and monkeys treated with high doses of intramuscular artemether or arteether develop an unusual pattern of focal damage to brain stem nuclei (particularly those involved in auditory processing). To investigate whether a similar toxic effect occurs in patients treated with these compounds, clinical neurologic evaluation, audiometry and early latency auditory evoked responses were measured in a single-blind comparison of 79 patients who had been treated with Ն2 courses of oral artemether or artesunate within the previous 3 years, and 79 age-and sex-matched controls living in a malaria-endemic area on the northwestern border of Thailand. There were no consistent differences in any of these test results between the cases and controls. This study failed to detect any evidence of significant neurotoxicity in patients treated previously with oral artemether or artesunate for acute malaria.Artemisinin derivatives are now used widely for the treatment of Plasmodium falciparum malaria in Southeast Asia. On the western border of Thailand where P. falciparum has developed resistance to nearly all antimalarials, the combination of mefloquine and artesunate was introduced in 1994 as a first-line treatment. 1 More than 3,000 patients with uncomplicated falciparum malaria have been recruited subsequently in prospective studies to optimize antimalarial treatment. Detailed prospective follow-up of these patients, including simple neurologic examinations, has failed to identify any serious adverse effects associated with the 2 most widely used compounds, oral artesunate or artemether. 2 However, animal studies have raised concerns about the potential neurotoxicity of some of the artemisinin derivatives. [3][4][5][6][7][8] These studies showed that rodents, dogs, and monkeys treated with intramuscular arteether or artemether (the 2 oil-soluble derivatives) develop dose-dependent damage to certain brain stem nuclei. Neurologic findings included gait disturbance, loss of spinal, brain stem, and pain responses, and, eventually, death. Pathologic changes in these experimental animals were found even in the absence of any detectable neurobehavioural symptoms. 4,5 The neuropathologic lesions were unusual in that they were confined to the neuronal cells of certain brain stem nuclei, whereas adjacent nuclei were often unaffected. The nuclei affected included those in the auditory relay. 6,7 Despite the lack of reported toxicity in extensive clinical studies to date, 2,9 it remains possible that the artemisinin compounds produce a similar pattern of neurotoxicity in humans. To assess possible toxic effects on the brain stem in patients treated with repeated courses of artemether or artesunate, brain stem auditory evoked responses (BAERs) were measured in a case-control study. These have been used 10 to detect neurotoxici...

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Angiostrongylus cantonensis is the most common cause of eosinophilic meningitis. Although a rare condition among travelers, increased travel and global transportation of food products may result in more cases across non-endemic, developed countries in the future. We here describe two men with headache and painful skin after visiting the Philippines as presenting symptoms. Subsequently, confusion and focal neurologic symptoms developed. Both had increased serum eosinophils; however, CSF eosinophilia was only demonstrated after repeated lumbar puncture. In the CSF of both, Angiostrongylus spp. DNA was detected. Both were treated with albendazole combined with corticosteroids, after which symptoms improved.

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