Effects of amodiaquine and artesunate on sulphadoxine-pyrimethamine pharmacokinetic parameters in children under five in Mali

<p>Abstract</p> <p>Background</p> <p>Sulphadoxine-pyrimethamine, in combination with artesunate or amodiaquine, is recommended for the treatment of uncomplicated malaria and is being evaluated for intermittent preventive treatment. Yet, limited data is available on pharmacokinetic interactions between these drugs.</p> <p>Methods</p> <p>In a randomized controlled trial, children aged 6-59 months with uncomplicated <it>falciparum </it>malaria, received either one dose of sulphadoxine-pyrimethamine alone (SP), one dose of SP plus three daily doses of amodiaquine (SP+AQ) or one dose of SP plus 3 daily doses of artesunate (SP+AS). Exactly 100 μl of capillary blood was collected onto filter paper before drug administration at day 0 and at days 1, 3, 7, 14, 21 and 28 after drug administration for analysis of sulphadoxine and pyrimethamine pharmacokinetic parameters.</p> <p>Results</p> <p>Fourty, 38 and 31 patients in the SP, SP+AQ and SP+AS arms, respectively were included in this study. The concentrations on day 7 (that are associated with therapeutic efficacy) were similar between the SP, SP+AQ and SP+AS treatment arms for sulphadoxine (median [IQR] 35.25 [27.38-41.70], 34.95 [28.60-40.85] and 33.40 [24.63-44.05] μg/mL) and for pyrimethamine (56.75 [46.40-92.95], 58.75 [43.60-98.60] and 59.60 [42.45-86.63] ng/mL). There were statistically significant differences between the pyrimethamine volumes of distribution (4.65 [3.93-6.40], 4.00 [3.03-5.43] and 5.60 [4.40-7.20] L/kg; <it>p = 0.001</it>) and thus elimination half-life (3.26 [2.74 -3.82], 2.78 [2.24-3.65] and 4.02 [3.05-4.85] days; <it>p < 0.001</it>). This study confirmed the lower SP concentrations previously reported for young children when compared with adult malaria patients.</p> <p>Conclusion</p> <p>Despite slight differences in pyrimethamine volumes of distribution and elimination half-life, these data show similar exposure to SP over the critical initial seven days of treatment and support the current use of SP in combination with either AQ or AS for uncomplicated <it>falciparum </it>malaria treatment in young Malian children.</p

Quinine Treatment Selects the pfnhe-1 ms4760-1 Polymorphism in Malian Patients with Falciparum Malaria

Background. The mechanism of Plasmodium falciparum resistance to quinine is not known. In vitro quantitative trait loci mapping suggests involvement of a predicted P. falciparum sodium-hydrogen exchanger (pfnhe-1) on chromosome 13. Methods. We conducted prospective quinine efficacy studies in 2 villages, Kolle and Faladie, Mali. Cases of clinical malaria requiring intravenous therapy were treated with standard doses of quinine and followed for 28 days. Treatment outcomes were classified using modified World Health Organization protocols. Molecular markers of parasite polymorphisms were used to distinguish recrudescent parasites from new infections. The prevalence of pfnhe-1 ms4760-1 among parasites before versus after quinine treatment was determined by direct sequencing. Results. Overall, 163 patients were enrolled and successfully followed. Without molecular correction, the mean adequate clinical and parasitological response (ACPR) was 50.3% (n = 163). After polymerase chain reaction correction to account for new infections, the corrected ACPR was 100%. The prevalence of ms4760-1 increased significantly, from 26.2% (n = 107) before quinine treatment to 46.3% (n = 54) after therapy (P = .01). In a control sulfadoxine-pyrimethamine study, the prevalence of ms4760-1 was similar before and after treatment. Conclusions. This study supports a role for pfnhe-1 in decreased susceptibility of P. falciparum to quinine in the field.Howard Hughes Medical Institute [55005502]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; European and Developing Countries Clinical Trials Partnership [EDCTP IP_07_31060_002]info:eu-repo/semantics/publishedVersio

Increase in EPI vaccines coverage after implementation of intermittent preventive treatment of malaria in infant with Sulfadoxine -pyrimethamine in the district of Kolokani, Mali: Results from a cluster randomized control trial

<p>Abstract</p> <p>Background</p> <p>Even though the efficacy of Intermittent Preventive Treatment in infants (IPTi) with Sulfadoxine-Pyrimethamine (SP) against clinical disease and the absence of its interaction with routine vaccines of the Expanded Immunization Programme (EPI) have been established, there are still some concerns regarding the addition of IPTi, which may increase the work burden and disrupt the routine EPI services especially in Africa where the target immunization coverage remains to be met. However IPTi may also increase the adherence of the community to EPI services and improve EPI coverage, once the benefice of strategy is perceived.</p> <p>Methods</p> <p>To assess the impact of IPTi implementation on the coverage of EPI vaccines, 22 health areas of the district of Kolokani were randomized at a 1:1 ratio to either receive IPTi-SP or to serve as a control. The EPI vaccines coverage was assessed using cross-sectional surveys at baseline in November 2006 and after one year of IPTi pilot-implementation in December 2007.</p> <p>Results</p> <p>At baseline, the proportion of children of 9-23 months who were completely vaccinated (defined as children who received BGG, 3 doses of DTP/Polio, measles and yellow fever vaccines) was 36.7% (95% CI 25.3% -48.0%). After one year of implementation of IPTi-SP using routine health services, the proportion of children completely vaccinated rose to 53.8% in the non intervention zone and 69.5% in the IPTi intervention zone (P <0.001).</p> <p>The proportion of children in the target age groups who received IPTi with each of the 3 vaccinations DTP2, DTP3 and Measles, were 89.2% (95% CI 85.9%-92.0%), 91.0% (95% CI 87.6% -93.7%) and 77.4% (95% CI 70.7%-83.2%) respectively. The corresponding figures in non intervention zone were 2.3% (95% CI 0.9% -4.7%), 2.6% (95% CI 1.0% -5.6%) and 1.7% (95% CI 0.4% - 4.9%).</p> <p>Conclusion</p> <p>This study shows that high coverage of the IPTi can be obtained when the strategy is implemented using routine health services and implementation results in a significant increase in coverage of EPI vaccines in the district of Kolokani, Mali.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00766662">NCT00766662</a></p

Overall and Gender-Specific Effects of Intermittent Preventive Treatment of Malaria with Artemisinin-Based Combination Therapies among Schoolchildren in Mali: A Three-Group Open Label Randomized Controlled Trial.

Intermittent preventive treatment of malaria among schoolchildren (IPTsc) reduces clinical malaria, asymptomatic parasitemia, and anemia. The effects of IPTsc by gender have not been studied longitudinally. We investigated overall IPTsc efficacy and conducted a secondary analysis to explore gender-specific differences. We enrolled schoolchildren aged 6-13 years in an open-label, rolling-cohort randomized controlled trial between September 2007 and February 2013 in Kolle, Mali. Annually, schoolchildren received two full-treatment courses of sulfadoxine-pyrimethamine (SP) plus artesunate, or amodiaquine (AQ) plus artesunate, or no malaria treatment as control. We used mixed-effects generalized linear models to estimate differences in treatment outcomes across groups with interaction terms to explore gender-specific differences associated with Plasmodium falciparum infection, hemoglobin, and grade point averages (GPA) based on standardized testing. Overall, 305 students contributed 4,564 observations. Compared with the control, SP plus artesunate and AQ plus artesunate reduced the odds of P. falciparum infection (odds ratio [OR]: 0.33, 95% CI: 0.26-0.43; OR: 0.46, 95% CI: 0.36-0.59). We found strong evidence of increased mean hemoglobin concentrations (g/dL) in the SP plus artesunate group versus control (difference +0.37, 95% CI: 0.13-0.58). Collectively, schoolchildren given AQ plus artesunate had higher mean GPA (difference +0.36, 95% CI: 0.02-0.69) relative to control. Schoolgirls, compared with schoolboys, given SP plus artesunate had greater improvement in GPA (+0.50, 95% CI: -0.02 to 1.02 versus -0.27, 95% CI: -0.71 to 0.16); interaction P = 0.048, respectively. The IPTsc decreases P. falciparum infections in schoolchildren. Treatment regimens that include longer-acting drugs may be more effective at decreasing malaria-related anemia and improving educational outcomes as observed among girls in this setting

Host candidate gene polymorphisms and clearance of drug-resistant Plasmodium falciparum parasites

Resistance to anti-malarial drugs is a widespread problem for control programmes for this devastating disease. Molecular tests are available for many anti-malarial drugs and are useful tools for the surveillance of drug resistance. However, the correlation of treatment outcome and molecular tests with particular parasite markers is not perfect, due in part to individuals who are able to clear genotypically drug-resistant parasites. This study aimed to identify molecular markers in the human genome that correlate with the clearance of malaria parasites after drug treatment, despite the drug resistance profile of the protozoan as predicted by molecular approaches

Population Pharmacokinetic properties of Sulfadoxine and Pyrimethamine: A pooled analysis to Inform Optimal Dosing in African Children with Uncomplicated Malaria.

Sulfadoxine/pyrimethamine with amodiaquine is recommended by the World Health Organization as seasonal malaria chemoprevention for children between 3 to 59 months in the sub-Sahel regions of Africa. Sub-optimal dosing in children may lead to treatment failure and increased resistance. Pooled individual patient data from four previously published trials on the pharmacokinetics of sulfadoxine and pyrimethamine in 415 paediatric and 386 adult patients were analysed using nonlinear mixed effects modelling to evaluate the current dosing regimen and, if needed, propose an optimised dosing regimen in children under five years old. The population pharmacokinetics of sulfadoxine and pyrimethamine were both best described by a one-compartment disposition model, with first-order absorption and elimination. Body weight, age and nutrition status (measured as weight-for-age z-scores) were found to be significant covariates. Allometric scaling with total body weight and maturation of clearance in children using post-gestational age improved the model fit. Underweight-for-age children were found to have 15.3% and 26.7% lower bioavailability of sulfadoxine and pyrimethamine, respectively, for each z-score unit below minus 2. Under current dosing recommendations, simulation predicted that the median day 7 concentration was below the 25 percentile of a typical adult patient (50 kg) for sulfadoxine for patients in 8-9, 19-24, 46-49 and 74-79 kg weight bands, and for pyrimethamine for the weight-bands 8-9, 14-24 and 42-49 kg. An evidence-based dosing regimen was constructed that would achieve sulfadoxine and pyrimethamine exposure in young children and underweight-for-age young children that was similar to that currently seen in a typical adult. [Abstract copyright: Copyright © 2018 de Kock et al.

Characterization of new races of Xanthomonas oryzae pv. oryzae in Mali informs resistance gene deployment

Bacterial leaf blight caused by Xanthomonas oryzae pv. oryzae represents a severe threat to rice cultivation in Mali. Characterizing the pathotypic diversity of bacterial populations is key to the management of pathogen-resistant varieties. Forty-one X. oryzae pv. oryzae isolates were collected between 2010 and 2013 in the major rice growing regions in Mali. All isolates were virulent on the susceptible rice variety Azucena; evaluation of the isolates on 12 near isogenic rice lines, each carrying a single resistance gene, identified six new races (A4 to A9) and confirmed race A3 that was previously reported in Mali. Races A5 and A6, isolated in Office du Niger and Selingue, were the most prevalent races in Mali. Race A9 was the most virulent, circumventing all of the resistance genes tested. Xa3 controlled six of seven races (i.e., 89% of the isolates tested). The expansion of race A9 represents a major risk to rice cultivation and highlights the urgent need to identify a local source of resistance. We selected 14 isolates of X. oryzae pv. oryzae representative of the most prevalent races to evaluate 29 rice varieties grown by farmers in Mali. Six isolates showed a high level of resistance to X. oryzae pv. oryzae and were then screened with a larger collection of isolates. Based on the interactions among the six varieties and the X. oryzae pv. oryzae isolates, we characterized eight different pathotypes (P1 to P8). Two rice varieties, SK20-28 and Gigante, effectively controlled all of the isolates tested. The low association observed among races and pathotypes of X. oryzae pv. oryzae suggests that the resistance observed in the local rice varieties does not simply rely on single known Xa genes. X. oryzae pv. oryzae is pathogenically and geographically diverse. Both the races of X. oryzae pv. oryzae characterized in this study and the identification of sources of resistance in local rice varieties provide useful information to inform the design of effective breeding programs for resistance to bacterial leaf blight in Mali