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Abstract Background Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda. Methods Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies. Results The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches. Conclusion The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.

Abstract Background Malaria is a leading cause of mortality, particularly in sub-Saharan African children. Prompt and efficacious treatment is important as patients may progress within a few hours to severe and possibly fatal disease. Chlorproguanil-dapsone-artesunate (CDA) was a promising artemisinin-based combination therapy (ACT), but its development was prematurely stopped because of safety concerns secondary to its associated risk of haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The objective of the study was to assess whether CDA treatment and G6PD deficiency are risk factors for a post-treatment haemoglobin drop in African children Methods This case–control study was performed in the context of a larger multicentre randomized clinical trial comparing safety and efficacy of four different ACT in children with uncomplicated malaria. Children, who after treatment experienced a haemoglobin drop ≥2 g/dl (cases) within the first four days (days 0, 1, 2, and 3), were compared with those without an Hb drop (controls). Cases and controls were matched for study site, sex, age and baseline haemoglobin measurements. Data were analysed using a conditional logistic regression model. Results G6PD deficiency prevalence, homo- or hemizygous, was 8.5% (10/117) in cases and 6.8% (16/234) in controls (p = 0.56). The risk of a Hb drop ≥2 g/dl was not associated with either G6PD deficiency (adjusted odds ratio (AOR): 0.81; p = 0.76) or CDA treatment (AOR: 1.28; p = 0.37) alone. However, patients having both risk factors tended to have higher odds (AOR: 11.13; p = 0.25) of experiencing a Hb drop ≥2 g/dl within the first four days after treatment, however this finding was not statistically significant, mainly because G6PD deficient patients treated with CDA were very few. In non-G6PD deficient individuals, the proportion of cases was similar between treatment groups while in G6PD-deficient individuals, haemolytic anaemia occurred more frequently in children treated with CDA (56%) than in those treated with other ACT (29%), though the difference was not significant (p = 0.49). Conclusion The use of CDA for treating uncomplicated malaria may increase the risk of haemolytic anaemia in G6PD-deficient children.

Abstract Background Data on efficacy of artemisinin-based combination therapy (ACT) to treat Plasmodium falciparum during pregnancy in sub-Saharan Africa is scarce. A recent open label, randomized controlled trial in Mbarara, Uganda demonstrated that artemether-lumefantrine (AL) is not inferior to quinine to treat uncomplicated malaria in pregnancy. Haemozoin can persist in the placenta following clearance of parasites, however there is no data whether ACT can influence the amount of haemozoin or the dynamics of haemozoin clearance. Methods Women attending antenatal clinics with weekly screening and positive blood smears by microscopy were eligible to participate in the trial and were followed to delivery. Placental haemozoin deposition and inflammation were assessed by histology. To determine whether AL was associated with increased haemozoin clearance, population haemozoin clearance curves were calculated based on the longitudinal data. Results Of 152 women enrolled in each arm, there were 97 and 98 placental biopsies obtained in the AL and quinine arms, respectively. AL was associated with decreased rates of moderate to high grade haemozoin deposition (13.3% versus 25.8%), which remained significant after correcting for gravidity, time of infection, re-infection, and parasitaemia. The amount of haemozoin proportionately decreased with the duration of time between treatment and delivery and this decline was greater in the AL arm. Haemozoin was not detected in one third of biopsies and the prevalence of inflammation was low, reflecting the efficacy of antenatal care with early detection and prompt treatment of malaria. Conclusions Placental haemozoin deposition was decreased in the AL arm demonstrating a relationship between pharmacological properties of drug to treat antenatal malaria and placental pathology at delivery. Histology may be considered an informative outcome for clinical trials to evaluate malaria control in pregnancy. Trial registration REGISTRY: http://clinicaltrials.gov/ct2/show/NCT00495508

Abstract Background A six-dose antimalarial regimen of artemether-lumefantrine (A/L) may soon become one of the most widely used drug combination in Africa, despite possible constraints with adherence and poor absorption due to inadequate nutrition, and a lack of pharmacokinetic and effectiveness data. Methods Within a trial of supervised versus unsupervised A/L treatment in a stable Ugandan Plasmodium falciparum transmission setting, plasma lumefantrine concentrations were measured in a subset of patients on day 3 (C [lum]day3) and day 7 (C [lum]day7) post-inclusion. Predictors of lumefantrine concentrations were analysed to show how both C [lum]day7 and the weight-adjusted lumefantrine dose affect 28-day recrudescence and re-infection risks. The implications of these novel findings are discussed in terms of the emergence of lumefantrine-resistant strains in Africa. Results C [lum]day3 and C [lum]day7 distributions among 241 supervised and 238 unsupervised patients were positively skewed. Unsupervised treatment and decreasing weight-adjusted lumefantrine dose were negatively associated with C [lum]day3. Unsupervised treatment and decreasing age showed strong negative associations with C [lum]day7. Both models were poorly predictive (R-squared < 0.25). There were no recrudescences in either arm, but decreasing lumefantrine dose per Kg resulted in up to 13-fold higher adjusted risks of re-infection. Re-infections occurred only among patients with C [lum]day7 below 400 ng/mL (p < 0.001). Conclusion Maintaining the present six-dose regimen and ensuring high adherence and intake are essential to maximize the public health benefits of this valuable drug combination.

BackgroundArtesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.MethodsIndividual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites.ResultsForty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P

Plague, caused by the bacterium Yersinia pestis, produced some of the most devastating epidemics in human history; it is endemic to regions of Asia, the Americas, and Africa. Africa accounts [...]

In Europe, evidence for the spread of extended-spectrum [beta]-lactamase (ESBL)-producing Escherichia coli from animals to humans via food is unclear (1). Few studies have been conducted in low- and middle-income [...]

Dengue is endemic to Cambodia; outbreaks are seasonal, occurring during the rainy season (May-October). However, the magnitude of outbreaks varies from year to year. When the epidemic is particularly large, [...]

Problem Evaluation of influenza surveillance systems is poor, especially in Africa. Approach In 2007, the Institut Pasteur de Madagascar and the Malagasy Ministry of Public Health implemented a countrywide system for the prospective syndromic and virological surveillance of influenza-like illnesses. In assessing this system's performance, we identified gaps and ways to promote the best use of resources. We investigated acceptability, data quality, flexibility, representativeness, simplicity, stability, timeliness and usefulness and developed qualitative and/or quantitative indicators for each of these attributes. Local setting Until 2007, the influenza surveillance system In Madagascar was only operational in Antananarivo and the observations made could not be extrapolated to the entire country. Relevant changes By 2014, the system covered 34 sentinel sites across the country. At 12 sites, nasopharyngeal and/or oropharyngeal samples were collected and tested for influenza virus. Between 2009 and 2014,177 718 fever cases were detected, 25 809 (14.5%) of these fever cases were classified as cases of influenza-like illness. Of the 9192 samples from patients with influenza-like illness that were tested for influenza viruses, 3573 (38.9%) tested positive. Data quality for all evaluated indicators was categorized as above 90% and the system also appeared to be strong in terms of its acceptability, simplicity and stability. However, sample collection needed improvement. Lessons learnt The influenza surveillance system In Madagascar performed well and provided reliable and timely data for public health interventions. Given its flexibility and overall moderate cost, this system may become a useful platform for syndromic and laboratory-based surveillance in other low-resource settings. Probleme Evaluation des systemes de surveillance de la grippe est mediocre, en particulier en Afrique. Approche En 2007, l'lnstitut Pasteur de Madagascar et le ministere malgache de la Sante publique ont mis en ceuvre un systeme national de surveillance prospective, syndromique et virologique, des syndromes grippaux. En evaluant les performances de ce systeme, nous avons repere certaines lacunes ainsi que des moyens d'ameliorer l'utilisation des ressources. Nous avons examine l'acceptabilite, la qualite des donnees, la flexibility la representativite, la simplicity la stabilite, l'actualisation et 1'utlllte de ce systeme, et avons developpe des indicateurs qualitatifs et/ou quantitatifs pourchacun de ees aspects. Environnement local Jusqu'en 2007, le systeme de surveillance de la grippe a Madagascar n'etait operationnel qu'a Antananarivo et les observations qui etaient faites ne pouvaient pas etre extrapolees au pays entier. Changements significatifs En 2014, le systeme etait utilise sur 34 sites sentinelles, sur l'ensemble du pays. Des prelevements nasopharynges et/ ou oropharynges ont ete effectues sur 12 sites, avant d'etre soumis a un test pour rechercher le virus de la grippe. Entre 2009 et 2014, 177 718 cas de fievre ont ete detectes, sur lesquels 25 809 (14,5%) ont ete classes comme syndromes grippaux. Sur les 9192 prelevements, effectues sur des patients qui presentaient des syndromes grippaux, sur lesquels on a recherche des virus de la grippe, 3573 (38,9%) se sont reveles positifs. La qualite des donnees, pour tous les indicateurs evalues, a ete classee audessus de 90% et le systeme presentait egalement de bons resultats au niveau de son acceptability de sa simplicite et de sa stabilite. Cependant, la realisation de prelevements devait etre amelioree. Lecons tirees Le systeme de surveillance de la grippe a Madagascar presentait de bons resultats et fournissait des donnees fiables et actualisees pour les interventions de sante publique. Compte tenu de sa flexibilite et de son cout relativement modere, ce systeme pourrait devenir une plate-forme utile pour la surveillance syndromique et en laboratoire dans d'autres pays a faibles ressources. Situacion La evaluacion de los sistemas de vigilancia de la gripe es escasa, sobre todo en Africa. Enfoque En 2007, el Instituto Pasteur de Madagascar y el Ministerio de Salud Publica de Madagascar implementaron un sistema nacional para la futura vigilancia sindromica y epidemiologica de enfermedades similares a la gripe. Al evaluar el rendimiento de este sistema, se identificaron lagunas y formas de fomentar el mejor uso de los recursos. Se investigaron la aceptacion, la calidad de la informacion, la flexibilidad, la representacion, la simplicidad, la estabilidad, el momento y la utilidad, y se desarrollaron indicadores cualitativos y/o cuantitativos para cada uno de estos atributos. Marco regional Hasta 2007, el sistema de vigilancia de Ia gripe en Madagascar operaba unicamente en Antananarivo, y las observaciones realizadas no podian extrapolarse al resto del pais. Cambios importantes En 2014, el sistema abarcaba 34 sitios centinela en todo el pais. En 12 sitios, se recogieron muestras nasofaringeas y/o bucofaringeas, que se sometieron a pruebas del virus de la gripe. Entre 2009 y 2014 se detectaron 177 718 casos de fiebre, 25 809 (14,5%) de los cuales se clasificaron como casos de enfermedades similares a la gripe. De las 9192 muestras de pacientes con enfermedades similares a la gripe sometidos a pruebas del virus de la gripe, 3 573 (38,9%) resultaron positivas. La calidad de los datos para todos los indicadores evaluados se categorizo como superior al 90% y el sistema tambien parecia ser solido en cuanto a su aceptacion, simplicidad y estabilidad. No obstante, la recogida de muestras necesitaba mejorar. Lecciones aprendidas El sistema de vigilancia de la gripe en Madagascar obtuvo buenos resultados y ofrecio informacion fiable y oportuna para las intervenciones de salud publica. Dada su flexibilidad y el coste moderado general, este sistema podria convertirse en una plataforma util para la vigilancia sindromica y en laboratorios en otros entornos con pocos recursos., Introduction The World Health Organization (WHO) recommends that, from no more than two years after implementation, influenza surveillance systems should be periodically and comprehensively evaluated. (1) Such evaluations may enable [...]

Background The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. Methods and findings A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing Conclusions Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment., Author(s): Frank Kloprogge 1,2,3, Lesley Workman 4,5, Steffen Borrmann 6,7, Mamadou Tékété 7,8, Gilbert Lefèvre 9, Kamal Hamed 10, Patrice Piola 11, Johan Ursing 12,13,14, Poul Erik Kofoed 14,15, Andreas [...]

Background: In Southeast-Asia, where many conditions associated with dissemination of ESBL-producing Enterobacterales (ESBL-E) in the community are met, data from the community are scarce but show high ESBL-E carriage prevalence. Maternal ESBL-E colonization is considered a risk factor for neonatal colonization, which is the first step towards developing neonatal sepsis. Despite this, ESBL-E carriage prevalence and its risk factors during pregnancy or postpartum remain undefined in Southeast-Asia.Objectives: To estimate the prevalence of ESBL-E faecal colonization among peripartum women in the community of an urban and a rural area in Cambodia, to investigate ESBL-E genomic characteristics and to identify associated risk factors.Methods: Epidemiological data and faecal samples from 423 peripartum women were collected in an urban and rural areas in Cambodia (2015-16). Bacterial cultures, antibiotic susceptibility tests and ESBL gene sequencing were performed. Risk factor analysis was conducted using logistic regression.Results: The prevalence of ESBL-E faecal carriage was 79.2% (95% CI 75.0%-82.8%) among which Escherichia coli (n = 315/335, 94.0%) were most frequent. All isolates were multidrug resistant. Among 318 ESBL-E, the genes most frequently detected were blaCTX-M-15 (41.5%), blaCTX-M-55 (24.8%), and blaCTX-M-27 (15.1%). Low income, undernutrition, multiparity, regular consumption of pork, dried meat, and raw vegetables, were associated with ESBL-E faecal carriage.Conclusions: The high prevalence of ESBL-E carriage observed among peripartum women in Southeast-Asia and the identified associated factors underline the urgent need for public health measures to address antimicrobial resistance, including a 'One Health' approach. [ABSTRACT FROM AUTHOR]