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PubMed | Institute of Tropical Medicine, Institute Pasteur Of Madagascar, Ghent University, University of Mahajanga and Clinical Research Unit of Nanoro IRSS CRUN
Type: Journal Article | Journal: mSphere | Year: 2016

Burkholderia pseudomallei, an environmental bacterium that causes the deadly disease melioidosis, is endemic in northern Australia and Southeast Asia. An increasing number of melioidosis cases are being reported in other tropical regions, including Africa and the Indian Ocean islands. B.pseudomallei first emerged in Australia, with subsequent rare dissemination event(s) to Southeast Asia; however, its dispersal to other regions is not yet well understood. We used large-scale comparative genomics to investigate the origins of three B.pseudomallei isolates from Madagascar and two from Burkina Faso. Phylogenomic reconstruction demonstrates that these African B.pseudomallei isolates group into a single novel clade that resides within the more ancestral Asian clade. Intriguingly, South American strains reside within the African clade, suggesting more recent dissemination from West Africa to the Americas. Anthropogenic factors likely assisted in B.pseudomallei dissemination to Africa, possibly during migration of the Austronesian peoples from Indonesian Borneo to Madagascar ~2,000years ago, with subsequent genetic diversity driven by mutation and recombination. Our study provides new insights into global patterns of B.pseudomallei dissemination and adds to the growing body of evidence of melioidosis endemicity in Africa. Our findings have important implications for melioidosis diagnosis and management in Africa. IMPORTANCE Sporadic melioidosis cases have been reported in the African mainland and Indian Ocean islands, but until recently, these regions were not considered areas where B.pseudomallei is endemic. Given the high mortality rate of melioidosis, it is crucial that this disease be recognized and suspected in all regions of endemicity. Previous work has shown that B.pseudomallei originated in Australia, with subsequent introduction into Asia; however, the precise origin of B.pseudomallei in other tropical regions remains poorly understood. Using whole-genome sequencing, we characterized B.pseudomallei isolates from Madagascar and Burkina Faso. Next, we compared these strains to a global collection of B.pseudomallei isolates to identify their evolutionary origins. We found that African B.pseudomallei strains likely originated from Asia and were closely related to South American strains, reflecting a relatively recent shared evolutionary history. We also identified substantial genetic diversity among African strains, suggesting long-term B.pseudomallei endemicity in this region.


Tahita M.C.,Institute Of Recherche En Science Of La Sante Direction Regionale Of Louest Irss Dro | Tahita M.C.,Clinical Research Unit of Nanoro IRSS CRUN | Tahita M.C.,Institute of Tropical Medicine | Tahita M.C.,University of Antwerp | And 20 more authors.
Malaria Journal | Year: 2015

Background: Ex vivo assays are usually carried out on parasite isolates collected from patients with uncomplicated Plasmodium falciparum malaria, from which pregnant women are usually excluded as they are often asymptomatic and with relatively low parasite densities. Nevertheless, P. falciparum parasites infecting pregnant women selectively sequester in the placenta and may have a different drug sensitivity profile compared to those infecting other patients. The drug sensitivity profile of P. falciparum isolates from infected pregnant women recruited in a treatment efficacy trial conducted in Burkina Faso was determined in an ex vivo study. Methods: The study was conducted between October 2010 and December 2012. Plasmodium falciparum isolates were collected before treatment and at the time of any recurrent infection whose parasite density was at least 100/μl. A histidine-rich protein-2 assay was used to assess their susceptibility to a panel of seven anti-malarial drugs. The concentration of anti-malarial drug inhibiting 50% of the parasite maturation to schizonts (IC50) for each drug was determined with the IC Estimator version 1.2. Results: The prevalence of resistant isolates was 23.5% for chloroquine, 9.2% for mefloquine, 8.0% for monodesethylamodiaquine, and 4.4% for quinine. Dihydroartemisinin, mefloquine, lumefantrine, and monodesethylamodiaquine had the lowest mean IC50 ranging between 1.1 and 1.5 nM respectively. The geometric mean IC50 of the tested drugs did not differ between chloroquine-sensitive and resistant parasites, with the exception of quinine, for which the IC50 was higher for chloroquine-resistant isolates. The pairwise comparison between the IC50 of the tested drugs showed a positive and significant correlation between dihydroartemisinin and both mefloquine and chloroquine, between chloroquine and lumefantrine and between monodesethylamodiaquine and mefloquine. Conclusion: These ex vivo results suggest that treatment with the currently available artemisinin-based combinations is efficacious for the treatment of malaria in pregnancy in Burkina Faso. Trial registration: ClinicalTrials.gov ID: NCT00852423 © 2015 Tahita et al.


Tahita M.C.,Institute Of Recherche En Science Of La Sante Irss | Tahita M.C.,Clinical Research Unit of Nanoro IRSS CRUN | Tahita M.C.,Center Muraz | Tahita M.C.,Institute of Tropical Medicine | And 18 more authors.
PLoS ONE | Year: 2015

Background. The emergence and spread of drug resistance represents one of the biggest challenges for malaria control in endemic regions. Sulfadoxine-pyrimethamine (SP) is currently deployed as intermittent preventive treatment in pregnancy (IPTp) to prevent the adverse effects of malaria on the mother and her offspring. Nevertheless, its efficacy is threatened by SP resistance which can be estimated by the prevalence of dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) mutations. This was measured among pregnant women in the health district of Nanoro, Burkina Faso. Methods. From June to December 2010, two hundred and fifty six pregnant women in the second and third trimester, attending antenatal care with microscopically confirmed malaria infection were invited to participate, regardless of malaria symptoms. A blood sample was collected on filter paper and analyzed by PCR-RFLP for the alleles 51, 59, 108, 164 in the pfdhfr gene and 437, 540 in the pfdhps gene. Results. The genes were successfully genotyped in all but one sample (99.6%; 255/256) for dhfr and in 90.2% (231/256) for dhps. The dhfr C59R and S108N mutations were the most common, with a prevalence of 61.2%(156/255) and 55.7%(142/255), respectively; 12.2%(31/255) samples had also the dhfr N51I mutation while the I164L mutation was absent. The dhps A437G mutation was found in 34.2%(79/231) isolates, but none of them carried the codon K540E. The prevalence of the dhfr double mutations NRNI and the triple mutations IRNI was 35.7% (91/255) and 11.4% (29/255), respectively. Conclusion. Though the mutations in the pfdhfr and pfdhps genes were relatively common, the prevalence of the triple pfdhfr mutation was very low, indicating that SP as IPTp is still efficacious in Burkina Faso. © 2015 Tahita et al.


Tinto H.,Center Muraz | Tinto H.,Institute Of Recherche En Science Of La Sante Direction Regionale Of Louest | Tinto H.,Clinical Research Unit of Nanoro IRSS CRUN | Bonkian L.N.,Center Muraz | And 18 more authors.
Malaria Journal | Year: 2014

Background: The recent reports on the decreasing susceptibility of Plasmodium falciparum to artemisinin derivatives along the Thailand and Myanmar border are worrying. Indeed it may spread to India and then Africa, repeating the same pattern observed for chloroquine resistance. Therefore, it is essential to start monitoring P. falciparum sensitivity to artemisinin derivatives and its partner drugs in Africa. Efficacy of AL and ASAQ were tested by carrying out an in vivo drug efficacy test, with an ex vivo study against six anti-malarial drugs nested into it. Results of the latter are reported here. Methods. Plasmodium falciparum ex-vivo susceptibility to chloroquine (CQ), quinine (Q), lumefantrine (Lum), monodesethylamodiaquine (MDA), piperaquine (PPQ) and dihydroartemisinin (DHA) was investigated in children (6 months - 15 years) with a parasitaemia of at least ≥4,000/μl. The modified isotopic microtest technique was used. The results of cellular proliferation were analysed using ICEstimator software to determine the 50% inhibitory concentration (IC50) values. Results: DHA was the most potent among the 6 drugs tested, with IC50 values ranging from 0.8 nM to 0.9 nM (Geometric mean IC50 = 0.8 nM; 95% CI [0.8 - 0.9]). High IC50 values ranged between 0.8 nM to 166.1 nM were reported for lumefantrine (Geometric mean IC50 = 25.1 nM; 95% CI [22.4 - 28.2]). MDA and Q IC50s were significantly higher in CQ-resistant than in CQ-sensitive isolates (P = 0.0001). However, the opposite occurred for Lum and DHA (P < 0.001). No difference was observed for PPQ. Conclusion: Artemisinin derivatives are still very efficacious in Burkina Faso and DHA-PPQ seems a valuable alternative ACT. The high lumefantrine IC50 found in this study is worrying as it may indicate a decreasing efficacy of one of the first-line treatments. This should be further investigated and monitored over time with large in vivo and ex vivo studies that will include also plasma drug measurements. © 2014 Tinto et al.; licensee BioMed Central Ltd.


Tahita M.C.,Institute Of Recherche En Science Of La Sante | Tahita M.C.,Clinical Research Unit of Nanoro IRSS CRUN | Tahita M.C.,Institute of Tropical Medicine | Tahita M.C.,University of Antwerp | And 21 more authors.
Malaria Journal | Year: 2015

Background: Ex vivo assays are usually carried out on parasite isolates collected from patients with uncomplicated Plasmodium falciparum malaria, from which pregnant women are usually excluded as they are often asymptomatic and with relatively low parasite densities. Nevertheless, P. falciparum parasites infecting pregnant women selectively sequester in the placenta and may have a different drug sensitivity profile compared to those infecting other patients. The drug sensitivity profile of P. falciparum isolates from infected pregnant women recruited in a treatment efficacy trial conducted in Burkina Faso was determined in an ex vivo study. Methods: The study was conducted between October 2010 and December 2012. Plasmodium falciparum isolates were collected before treatment and at the time of any recurrent infection whose parasite density was at least 100/μl. A histidine-rich protein-2 assay was used to assess their susceptibility to a panel of seven anti-malarial drugs. The concentration of anti-malarial drug inhibiting 50% of the parasite maturation to schizonts (IC50) for each drug was determined with the IC Estimator version 1.2. Results: The prevalence of resistant isolates was 23.5% for chloroquine, 9.2% for mefloquine, 8.0% for monodesethylamodiaquine, and 4.4% for quinine. Dihydroartemisinin, mefloquine, lumefantrine, and monodesethylamodiaquine had the lowest mean IC50 ranging between 1.1 and 1.5 nM respectively. The geometric mean IC50 of the tested drugs did not differ between chloroquine-sensitive and resistant parasites, with the exception of quinine, for which the IC50 was higher for chloroquine-resistant isolates. The pairwise comparison between the IC50 of the tested drugs showed a positive and significant correlation between dihydroartemisinin and both mefloquine and chloroquine, between chloroquine and lumefantrine and between monodesethylamodiaquine and mefloquine. Conclusion: These ex vivo results suggest that treatment with the currently available artemisinin-based combinations is efficacious for the treatment of malaria in pregnancy in Burkina Faso. Trial registration: ClinicalTrials.gov ID: NCT00852423 © 2015 Tahita et al.


PubMed | Institute Of Recherche En Science Of La Sante Direction Regionale Of Louest Irss Dro, Clinical Research Unit of Nanoro IRSS CRUN, Institute Superieur Des Science Of La Sante Inssa, Institute of Tropical Medicine and 2 more.
Type: Journal Article | Journal: PloS one | Year: 2015

The emergence and spread of drug resistance represents one of the biggest challenges for malaria control in endemic regions. Sulfadoxine-pyrimethamine (SP) is currently deployed as intermittent preventive treatment in pregnancy (IPTp) to prevent the adverse effects of malaria on the mother and her offspring. Nevertheless, its efficacy is threatened by SP resistance which can be estimated by the prevalence of dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) mutations. This was measured among pregnant women in the health district of Nanoro, Burkina Faso.From June to December 2010, two hundred and fifty six pregnant women in the second and third trimester, attending antenatal care with microscopically confirmed malaria infection were invited to participate, regardless of malaria symptoms. A blood sample was collected on filter paper and analyzed by PCR-RFLP for the alleles 51, 59, 108, 164 in the pfdhfr gene and 437, 540 in the pfdhps gene.The genes were successfully genotyped in all but one sample (99.6%; 255/256) for dhfr and in 90.2% (231/256) for dhps. The dhfr C59R and S108N mutations were the most common, with a prevalence of 61.2% (156/255) and 55.7% (142/255), respectively; 12.2% (31/255) samples had also the dhfr N51I mutation while the I164L mutation was absent. The dhps A437G mutation was found in 34.2% (79/231) isolates, but none of them carried the codon K540E. The prevalence of the dhfr double mutations NRNI and the triple mutations IRNI was 35.7% (91/255) and 11.4% (29/255), respectively.Though the mutations in the pfdhfr and pfdhps genes were relatively common, the prevalence of the triple pfdhfr mutation was very low, indicating that SP as IPTp is still efficacious in Burkina Faso.


PubMed | University of Antwerp, Center Muraz, Institute Of Recherche En Science Of La Sante Direction Regionale Of Louest Irss Dro, Institute of Tropical Medicine and Clinical Research Unit of Nanoro IRSS CRUN
Type: | Journal: Malaria journal | Year: 2015

Ex vivo assays are usually carried out on parasite isolates collected from patients with uncomplicated Plasmodium falciparum malaria, from which pregnant women are usually excluded as they are often asymptomatic and with relatively low parasite densities. Nevertheless, P. falciparum parasites infecting pregnant women selectively sequester in the placenta and may have a different drug sensitivity profile compared to those infecting other patients. The drug sensitivity profile of P. falciparum isolates from infected pregnant women recruited in a treatment efficacy trial conducted in Burkina Faso was determined in an ex vivo study.The study was conducted between October 2010 and December 2012. Plasmodium falciparum isolates were collected before treatment and at the time of any recurrent infection whose parasite density was at least 100/l. A histidine-rich protein-2 assay was used to assess their susceptibility to a panel of seven anti-malarial drugs. The concentration of anti-malarial drug inhibiting 50% of the parasite maturation to schizonts (IC(50)) for each drug was determined with the IC Estimator version 1.2.The prevalence of resistant isolates was 23.5% for chloroquine, 9.2% for mefloquine, 8.0% for monodesethylamodiaquine, and 4.4% for quinine. Dihydroartemisinin, mefloquine, lumefantrine, and monodesethylamodiaquine had the lowest mean IC(50) ranging between 1.1 and 1.5 nM respectively. The geometric mean IC(50) of the tested drugs did not differ between chloroquine-sensitive and resistant parasites, with the exception of quinine, for which the IC(50) was higher for chloroquine-resistant isolates. The pairwise comparison between the IC(50) of the tested drugs showed a positive and significant correlation between dihydroartemisinin and both mefloquine and chloroquine, between chloroquine and lumefantrine and between monodesethylamodiaquine and mefloquine.These ex vivo results suggest that treatment with the currently available artemisinin-based combinations is efficacious for the treatment of malaria in pregnancy in Burkina Faso.ClinicalTrials.gov ID: NCT00852423.


Tinto H.,Center Muraz | Tinto H.,Institute Of Recherche En Science Of La Sante Direction Regionale Irss Dro | Tinto H.,Clinical Research Unit of Nanoro IRSS CRUN | Valea I.,Center Muraz | And 20 more authors.
Malaria Journal | Year: 2014

Background: The opportunities for developing new drugs and vaccines for malaria control look brighter now than ten years ago. However, there are few places in sub-Saharan Africa with the necessary infrastructure and expertise to support such research in compliance to international standards of clinical research (ICH-GCP). The Clinical Research Unit of Nanoro (CRUN) was founded in 2008 to provide a much-needed GCP-compliant clinical trial platform for an imminent large-scale Phase 3 malaria vaccine trial. A dynamic approach was used that entailed developing the required infrastructure and human resources, while engaging local communities in the process as key stakeholders. This provided a better understanding and ownership of the research activities by the local population. Case description. Within five years (2008-2013), the CRUN set up a fully and well-equipped GCP-compliant clinical trial research facility, which enabled to attract 25 grants. The research team grew from ten health workers prior to 2008 to 254 in 2013. A Health and Demographic Surveillance System (HDSS), which covers a total population of about 60,000 people in 24 villages was set up in the district. The local community contributed to the development of the facility through the leadership of the king and the mayor of Nanoro. As a result of their active advocacy, the government extended the national electrical grid to the new research center, and later to the entire village. This produced a positive impact on the community's quality of life. The quality of health care improved substantially, due to the creation of more elaborate clinical laboratory services and the acquisition of state-of-the-art equipment. Conclusion: Involving the community in the key steps of establishing the centre provided the foundation for what was to become the CRUN success story. This experience demonstrates that when clinical trials research sites are carefully developed and implemented, they can have a positive and powerful impact on local communities in resource-poor settings, well beyond the task of generating expected study data. © 2014 Tinto et al.; licensee BioMed Central Ltd.

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