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Briolant S.,Institute Of Recherche Biomedicale Des Armees | Briolant S.,French National Institute for Agricultural Research | Wurtz N.,Institute Of Recherche Biomedicale Des Armees | Zettor A.,Institute Of Recherche Biomedicale Des Armees | And 6 more authors.
Journal of Infectious Diseases | Year: 2010

Background. Doxycycline is used in combination with quinine for malaria treatment or alone for malaria chemoprophylaxis. However, the occurrence of malaria after doxycycline chemoprophylaxis has been reported. Identification of genetic determinants that contribute to the susceptibility of Plasmodium falciparum to doxycycline will be important for the detection and surveillance of doxycycline resistance. Methods. Sequence analysis of 11 genes (pftufA, pfEF-TS, pfmdt, pftetQ, pfrps3, pfrps7, pfrps8, pfrps9, pfrps11, pfrpsl4, and pfrps17) and evaluation of pfmdt and pftetQ copy numbers by quantitative real-time polymerase chain reaction were conducted in 90 African P falciparum isolates that were obtained from 14 countries and that belonged to phenotypic groups differing in their doxycycline median inhibitory concentrations. Results. We found that pfmdt copy number of >1 (adjusted odds ratio [OR], 7.09 [95% confidence interval {CI}, 1.58-31.82]; P = .011), pftetQ copy number of >1 (adjusted OR, 5.23 [95% CI, 1.06-25.77]; P = .042), and KYNNNN amino acid motif repeats of <3 (adjusted OR, 3.00 [95% CI, 1.02-8.86]; P = .046) were independently associated with decreased susceptibility to doxycycline. Conclusions. Our findings suggest that pfmdt and pftetQ copy numbers and pftetQ sequence polymorphisms are potential molecular markers of decreased in vitro susceptibility to doxycycline in African P falciparum isolates. © 2009 by the Infectious Diseases Society of America. All rights reserved.

Pascual A.,Institute Of Recherche Biomedicale Des Armees Antenne Of Marseille | Basco L.K.,Unite de Recherche sur les Maladies Infectieuses et Tropicales Emergentes | Baret E.,Institute Of Recherche Biomedicale Des Armees Antenne Of Marseille | Amalvict R.,Institute Of Recherche Biomedicale Des Armees Antenne Of Marseille | And 4 more authors.
Malaria Journal | Year: 2011

Background: The aim of this study was to evaluate the cultivation system in which the proper atmospheric conditions for growing Plasmodium falciparum parasites were maintained in a sealed bag. The Genbag® system associated with the atmospheric generators for capnophilic bacteria Genbag CO2® was used for in vitro susceptibility test of nine standard anti-malarial drugs and compared to standard incubator conditions. Methods. The susceptibility of 36 pre-identified parasite strains from a wide panel of countries was assessed for nine standard anti-malarial drugs (chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone and pyrimethamine) by the standard 42-hour 3H-hypoxanthine uptake inhibition method using the Genbag CO2® system and compared to controlled incubator conditions (5% CO2and 10% O2). Results: The counts per minute values in the control wells in incubator atmospheric conditions (5% CO2and 10% O2) were significantly higher than those of Genbag® conditions (2738 cpm vs 2282 cpm, p < 0.0001). The geometric mean IC50estimated under the incubator atmospheric conditions was significantly lower for atovaquone (1.2 vs 2.1 nM, p = 0.0011) and higher for the quinolines: chloroquine (127 vs 94 nM, p < 0.0001), quinine (580 vs 439 nM, p < 0.0001), monodesethylamodiaquine (41.4 vs 31.8 nM, p < 0.0001), mefloquine (57.5 vs 49.7 nM, p = 0.0011) and lumefantrine (23.8 vs 21.2 nM, p = 0.0044). There was no significant difference of IC 50between the 2 conditions for dihydroartemisinin, doxycycline and pyrimethamine. To reduce this difference in term of anti-malarial susceptibility, a specific cut-off was estimated for each drug under Genbag® conditions by regression. The cut-off was estimated at 77 nM for chloroquine (vs 100 nM in 10% O2), 611 nM for quinine (vs 800 nM), 30 nM for mefloquine (vs 30 nM), 61 nM for monodesethylamodiaquine (vs 80 nM) and 1729 nM for pyrimethamine (vs 2000 nM). Conclusions: The atmospheric generators for capnophilic bacteria Genbag CO2® is an appropriate technology that can be transferred to the field for epidemiological surveys of drug-resistant malaria. The present data suggest the importance of the gas mixture on in vitro microtest results for anti-malarial drugs and the importance of determining the microtest conditions before comparing and analysing the data from different laboratories and concluding on malaria resistance. © 2011 Pascual et al; licensee BioMed Central Ltd.

Fall B.,Laboratoire Detude Of La Chimiosensibilite Du Paludisme | Camara C.,Service des Urgences | Fall M.,Service de Reanimation medicale | Nakoulima A.,Service de pediatrie | And 8 more authors.
Malaria Journal | Year: 2015

Background: In 2006, the Senegalese National Malaria Control Programme recommended artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. Since the introduction of ACT, there have been very few reports on the level of Plasmodium falciparum resistance to anti-malarial drugs. An ex vivo susceptibility study was conducted on local isolates obtained from the Hôpital Principal de Dakar (Dakar, Senegal) from November 2013 to January 2014. Methods: Eighteen P. falciparum isolates were sussessfully assessed for ex vivo susceptibility to chloroquine (CQ), quinine (QN), monodesethylamodiaquine (MDAQ), the active metabolite of amodiaquine, mefloquine (MQ), lumefantrine (LMF), artesunate (AS), dihydroartemisinin (DHA), the active metabolite of artemisinin derivatives, pyronaridine (PND), piperaquine (PPQ), and, Proveblue (PVB), a methylene blue preparation, using the HRP2-based ELISA test. Results: The prevalence of isolates with reduced susceptibility was 55.6% for MQ, 50% for CQ, 5.6% for QN and MDAQ, and 0% for DHA, AS and LMF. The mean IC50 for PND, PPQ and PVB were 5.8 nM, 32.2 nM and 5.3 nM, respectively. Conclusions: The prevalence of isolates with a reduced susceptibility to MQ remains high and stable in Dakar. Since 2004, the prevalence of CQ resistance decreased, but rebounded in 2013 in Dakar. PND, PPQ and PVB showed high in vitro activity in P. falciparum parasites from Dakar. © 2015 Fall et al.; licensee BioMed Central.

Ariey F.,Institute Pasteur Paris | Ariey F.,French National Center for Scientific Research | Witkowski B.,Institute Pasteur in Cambodia | Amaratunga C.,National Institute of Allergy and Infectious Diseases | And 39 more authors.
Nature | Year: 2014

Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7-1343700 kelch propeller domain ('K13-propeller') with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread. © 2014 Macmillan Publishers Limited.

Torrentino-Madamet M.,Institute Of Recherche Biomedicale Des Armees | Torrentino-Madamet M.,Aix - Marseille University | Torrentino-Madamet M.,Center National Of Reference Du Paludisme | Fall B.,Laboratoire Detude Of La Chimiosensibilite Du Paludisme | And 18 more authors.
Malaria Journal | Year: 2015

Background: The emergence of Plasmodium falciparum resistance to artemisinin and its derivatives, manifested as delayed parasite clearance following the treatment, has developed in Southeast Asia. The spread of resistance to artemisinin from Asia to Africa may be catastrophic for malaria control and elimination worldwide. Recently, mutations in the propeller domain of the Kelch 13 (k13) gene (PF3D71343700) were associated with in vitro resistance to artemisinin and with delayed clearance after artemisinin treatment in southern Asia. The aim of the study was to characterize the genetic variability of k13 and to evaluate the molecular resistance to artemisinin for the first time in Senegal. Methods: Plasmodium falciparum isolates were collected from 138 malaria patients in Dakar and its districts during the rainy season of October 2012 to January 2013 at the Hôpital Principal de Dakar. The k13 gene was amplified using nested PCR and sequenced. Results: A very limited variability within the k13 gene in Senegalese P. falciparum isolates was identified. No polymorphism was detected in the six k13-propeller blades. Only two mutations, T149S (6.3%) and K189T (42.2%), and one (N) or two (NN) asparagine insertion at the codon 142 (4.7 and 6.3%, respectively) were detected in the Plasmodium/Apicomplexa-specific domain. None of the polymorphisms associated with artemisinin resistance in Southeast Asia was detected in the 138 P. falciparum from Dakar. Discussion: The present data do not suggest widespread artemisinin resistance in Dakar in 2012-2013. Notably, the C580Y, R539T or Y493H substitutions that were associated with in vitro resistance or delayed parasite clearance in Southeast Asia were not observed in Dakar, nor were any of the polymorphisms observed in parasites from Southeast Asia, nor the M476I mutation that was selected in vitro with artemisinin pressure in a African parasite line. © 2014 Torrentino-Madamet et al.; licensee BioMed Central Ltd.

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