World Health Organization, 2013. World Malaria Report 2013. Geneva, Switzerland: World Health Organization.
The malERA Consultative Group on Drugs, 2011. A research agenda for malaria eradication: drugs. PLoS Med 8: e1000402.
Wells TNC, Alonso PL, Gutteridge WE, 2009. New medicines to improve control and contribute to the eradication of malaria. Nat Rev Drug Discov 8: 879ā891.
Huijben S, Sim DG, Nelson WA, Read AF, 2011. The fitness of drug-resistant malaria parasites in a rodent model: multiplicity of infection. J Evol Biol 24: 2410ā2422.
Nankoberanyi S, Mbogo GW, LeClair NP, Conrad MD, Tumwebaze P, Tukwasibwe S, Kamya MR, Tappero J, Nsobya SL, Rosenthal PJ, 2014. Validation of the ligase detection reaction fluorescent microsphere assay for the detection of Plasmodium falciparum resistance mediating polymorphisms in Uganda. Malar J 13: 95.
Daniels R, Ndiaye D, Wall M, McKinney J, Sene PD, Sabeti PC, Volkman SK, Mboup S, Wirth DF, 2012. Rapid, field-deployable method for genotyping and discovery of single-nucleotide polymorphisms associated with drug resistance in Plasmodium falciparum. Antimicrob Agents Chemother 56: 2976ā2986.
Snounou G, Beck HP, 1998. The use of PCR genotyping in the assessment of recrudescence or reinfection after antimalarial drug treatment. Parasitol Today 14: 462ā467.
LeClair NP, Conrad MD, Baliraine FN, Nsanzabana C, Nsobya SL, Rosenthal PJ, 2013. Optimization of a ligase detection reaction-fluorescent microsphere assay for characterization of resistance-mediating polymorphisms in African samples of Plasmodium falciparum. J Clin Microbiol 51: 2564ā2570.
Daniels R, Volkman SK, Milner DA, Mahesh N, Neafsey DE, Park DJ, Rosen D, Angelino E, Sabeti PC, Wirth DF, Wiegand RC, 2008. A general SNP-based molecular barcode for Plasmodium falciparum identification and tracking. Malar J 7: 223.
Juliano JJ, Porter K, Mwapasa V, Sem R, Rogers WO, Ariey F, Wongsrichanalai C, Read A, Meshnick SR, 2010. Exposing malaria in-host diversity and estimating population diversity by capture-recapture using massively parallel pyrosequencing. Proc Natl Acad Sci USA 107: 20138ā20143.
Juliano JJ, Gadalla N, Sutherland CJ, Meshnick SR, 2010. The perils of PCR: can we accurately ācorrectā antimalarial trials? Trends Parasitol 26: 119ā124.
Juliano JJ, Ariey F, Sem R, Tangpukdee N, Krudsood S, Olson C, Looareesuwan S, Rogers WO, Wongsrichanalai C, Meshnick SR, 2009. Misclassification of drug failures in Plasmodium falciparum clinical trials in southeast Asia. J Infect Dis 200: 624ā628.
Beale GJ, Carter R, Walliker D, 1978. Genetics. Killick-Kendrick R, Peters W, eds. Rodent Malaria. London, United Kingdom: Academic Press, 213ā245.
Walliker D, Carter R, Sanderson A, 1975. Genetic studies on Plasmodium chabaudi: recombination between enzyme markers. Parasitology 70: 19ā24.
Jacobs RL, 1964. Role of p-aminobenzoic acid in Plasmodium berghei infection in the mouse. Exp Parasitol 15: 213.
Wargo AR, Huijben S, de Roode JC, Shepherd J, Read AF, 2007. Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model. Proc Natl Acad Sci USA 104: 19914ā19919.
Huijben S, Nelson WA, Wargo AR, Sim DG, Drew DR, Read AF, 2010. Chemotherapy, within-host ecology and the fitness of drug-resistant malaria parasites. Evolution 64: 2952ā2968.
Wargo AR, Randle N, Chan BHK, Thompson J, Read AF, Babiker HA, 2006. Plasmodium chabaudi: reverse transcription PCR for the detection and quantification of transmission stage malaria parasites. Exp Parasitol 112: 13ā20.
Huijben S, Bell AS, Sim DG, Tomasello D, Mideo N, Day T, Read AF, 2013. Aggressive chemotherapy and the selection of drug resistant pathogens. PLoS Pathog 9: e1003578.
Drew DR, Reece SE, 2007. Development of reverse-transcription PCR techniques to analyse the density and sex ratio of gametocytes in genetically diverse Plasmodium chabaudi infections. Mol Biochem Parasitol 156: 199ā209.
Cheesman SJ, de Roode JC, Read AF, Carter R, 2003. Real-time quantitative PCR for analysis of genetically mixed infections of malaria parasites: technique validation and applications. Mol Biochem Parasitol 131: 83ā91.
Wongsrichanalai C, Barcus MJ, Muth S, Sutamihardja A, Wernsdorfer WH, 2007. A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT). Am J Trop Med Hyg 77 (Suppl): 119ā127.
Bell AS, Huijben S, Paaijmans KP, Sim DG, Chan BHK, Nelson WA, Read AF, 2012. Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria. PLoS ONE 7: e37172.
R Core Team, 2012. R: A Language and Environment for Statistical Computing. Vienna, Austria: The R Foundation for Statistical Computing.
World Health Organization, 2010. Guidelines for the Treatment of Malaria, 2nd Ed. Geneva, Switzerland: World Health Organization. Available at: http://www.who.int/malaria/publications/atoz/9789241547925/en/.
Stepniewska K, White NJ, 2006. Some considerations in the design and interpretation of antimalarial drug trials in uncomplicated falciparum malaria. Malar J 5: 127.
Greenhouse B, Myrick A, Dokomajilar C, Woo JM, Carlson EJ, Rosenthal PJ, Dorsey G, 2006. Validation of microsatellite markers for use in genotyping polyclonal Plasmodium falciparum infections. Am J Trop Med Hyg 75: 836ā842.
Ngrenngarmlert W, Kwiek JJ, Kamwendo DD, Ritola K, Swanstrom R, Wongsrichanalai C, Miller RS, Ittarat W, Meshnick SR, 2005. Measuring allelic heterogeneity in Plasmodium falciparum by a heteroduplex tracking assay. Am J Trop Med Hyg 72: 694ā701.
Kwiek JJ, Alker AP, Wenink EC, Chaponda M, Kalilani LV, Meshnick SR, 2007. Estimating true antimalarial efficacy by heteroduplex tracking assay in patients with complex Plasmodium falciparum infections. Antimicrob Agents Chemother 51: 521ā527.
Juliano JJ, Bacon DJ, Mu J, Wang X, Meshnick SR, 2009. Novel dhps and pfcrt polymorphisms in Plasmodium falciparum detected by heteroduplex tracking assay. Am J Trop Med Hyg 80: 734ā736.
Manske M, Miotto O, Campino S, Auburn S, Almagro-Garcia J, Maslen G, O'Brien J, Djimde A, Doumbo O, Zongo I, Ouedraogo JB, Michon P, Mueller I, Siba P, Nzila A, Borrmann S, Kiara SM, Marsh K, Jiang H, Su XZ, Amaratunga C, Fairhurst R, Socheat D, Nosten F, Imwong M, White NJ, Sanders M, Anastasi E, Alcock D, Drury E, Oyola S, Quail MA, Turner DJ, Ruano-Rubio V, Jyothi D, Amenga-Etego L, Hubbart C, Jeffreys A, Rowlands K, Sutherland C, Roper C, Mangano V, Modiano D, Tan JC, Ferdig MT, Amambua-Ngwa A, Conway DJ, Takala-Harrison S, Plowe CV, Rayner JC, Rockett KA, Clark TG, Newbold CI, Berriman M, MacInnis B, Kwiatkowski DP, 2012. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. Nature 487: 375ā379.
Juliano JJ, Taylor SM, Meshnick SR, 2009. Polymerase chain reaction adjustment in antimalarial trials: molecular malarkey? J Infect Dis 200: 5ā7.
Stephens R, Culleton RL, Lamb TJ, 2012. The contribution of Plasmodium chabaudi to our understanding of malaria. Trends Parasitol 28: 73ā82.
Pollitt LC, Mideo N, Drew DR, Schneider P, Colegrave N, Reece SE, 2011. Competition and the evolution of reproductive restraint in malaria parasites. Am Nat 177: 358ā367.
Malfertheiner P, Megraud F, O'Morain C, Bazzoli F, El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers EJ, 2007. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 56: 772ā781.
Dellit TH, Owens RC, McGowan JE, Gerding DN, Weinstein RA, Burke JP, Huskins WC, Paterson DL, Fishman NO, Carpenter CF, Brennan PJ, Billeter M, Hooton TM, 2007. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 44: 159ā177.
Günthard HF, Aberg JA, Eron JJ, Hoy JF, Telenti A, Benson CA, Burger DM, Cahn P, Gallant JE, Glesby MJ, Reiss P, Saag MS, Thomas DL, Jacobsen DM, Volberding PA, International Antiviral Society-USA Panel, 2014. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA 312: 410ā425.
Gonzalez-Serna A, Min JE, Woods C, Chan D, Lima VD, Montaner JSG, Harrigan PR, Swenson LC, 2014. Performance of HIV-1 drug resistance testing at low-level viremia and its ability to predict future virologic outcomes and viral evolution in treatment-naive individuals. Clin Infect Dis 58: 1165ā1173.
Nguyen K-SH, Neal JW, Wakelee H, 2014. Review of the current targeted therapies for non-small-cell lung cancer. World J Clin Oncol 5: 576ā587.
Saumet A, Mathelier A, Lecellier C-H, 2014. The potential of microRNAs in personalized medicine against cancers. Biomed Res Int 2014: 642916.
Madan RA, Gulley JL, 2015. (R)Evolutionary therapy: the potential of immunotherapy to fulfill the promise of personalized cancer treatment. J Natl Cancer Inst 107: 347.
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Abstract Views | 23 | 23 | 11 |
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Resistant malaria parasites are frequently found in mixed infections with drug-sensitive parasites. Particularly early in the evolutionary process, the frequency of these resistant mutants can be extremely low and below the level of molecular detection. We tested whether the rarity of resistance in infections impacted the health outcomes of treatment failure and the potential for onward transmission of resistance. Mixed infections of different ratios of resistant and susceptible Plasmodium chabaudi parasites were inoculated in laboratory mice and dynamics tracked during the course of infection using highly sensitive genotype-specific quantitative polymerase chain reaction (qPCR). Frequencies of resistant parasites ranged from 10% to 0.003% at the onset of treatment. We found that the rarer the resistant parasites were, the lower the likelihood of their onward transmission, but the worse the treatment failure was in terms of parasite numbers and disease severity. Strikingly, drug resistant parasites had the biggest impact on health outcomes when they were too rare to be detected by any molecular methods currently available for field samples. Indeed, in the field, these treatment failures would not even have been attributed to resistance.
Financial support: This work was funded by the Institute of General Medical Science (R01 GM089932). Silvie Huijben was supported by a Branco Weiss Fellowship and Marie Curie Actions IIF Project 623703.
Authors' addresses: Silvie Huijben, ISglobal, Barcelona Centre for International Health Research (CRESIB), Hospital ClĆnic, Universitat de Barcelona, Barcelona, Spain, E-mail: silviehuijben@gmail.com. Brian H. K. Chan, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom, E-mail: brian.chan@liverpool.ac.uk. Andrew F. Read, Center for Disease Dynamics, The Pennsylvania State University, University Park, PA, E-mail: a.read@psu.edu.
World Health Organization, 2013. World Malaria Report 2013. Geneva, Switzerland: World Health Organization.
The malERA Consultative Group on Drugs, 2011. A research agenda for malaria eradication: drugs. PLoS Med 8: e1000402.
Wells TNC, Alonso PL, Gutteridge WE, 2009. New medicines to improve control and contribute to the eradication of malaria. Nat Rev Drug Discov 8: 879ā891.
Huijben S, Sim DG, Nelson WA, Read AF, 2011. The fitness of drug-resistant malaria parasites in a rodent model: multiplicity of infection. J Evol Biol 24: 2410ā2422.
Nankoberanyi S, Mbogo GW, LeClair NP, Conrad MD, Tumwebaze P, Tukwasibwe S, Kamya MR, Tappero J, Nsobya SL, Rosenthal PJ, 2014. Validation of the ligase detection reaction fluorescent microsphere assay for the detection of Plasmodium falciparum resistance mediating polymorphisms in Uganda. Malar J 13: 95.
Daniels R, Ndiaye D, Wall M, McKinney J, Sene PD, Sabeti PC, Volkman SK, Mboup S, Wirth DF, 2012. Rapid, field-deployable method for genotyping and discovery of single-nucleotide polymorphisms associated with drug resistance in Plasmodium falciparum. Antimicrob Agents Chemother 56: 2976ā2986.
Snounou G, Beck HP, 1998. The use of PCR genotyping in the assessment of recrudescence or reinfection after antimalarial drug treatment. Parasitol Today 14: 462ā467.
LeClair NP, Conrad MD, Baliraine FN, Nsanzabana C, Nsobya SL, Rosenthal PJ, 2013. Optimization of a ligase detection reaction-fluorescent microsphere assay for characterization of resistance-mediating polymorphisms in African samples of Plasmodium falciparum. J Clin Microbiol 51: 2564ā2570.
Daniels R, Volkman SK, Milner DA, Mahesh N, Neafsey DE, Park DJ, Rosen D, Angelino E, Sabeti PC, Wirth DF, Wiegand RC, 2008. A general SNP-based molecular barcode for Plasmodium falciparum identification and tracking. Malar J 7: 223.
Juliano JJ, Porter K, Mwapasa V, Sem R, Rogers WO, Ariey F, Wongsrichanalai C, Read A, Meshnick SR, 2010. Exposing malaria in-host diversity and estimating population diversity by capture-recapture using massively parallel pyrosequencing. Proc Natl Acad Sci USA 107: 20138ā20143.
Juliano JJ, Gadalla N, Sutherland CJ, Meshnick SR, 2010. The perils of PCR: can we accurately ācorrectā antimalarial trials? Trends Parasitol 26: 119ā124.
Juliano JJ, Ariey F, Sem R, Tangpukdee N, Krudsood S, Olson C, Looareesuwan S, Rogers WO, Wongsrichanalai C, Meshnick SR, 2009. Misclassification of drug failures in Plasmodium falciparum clinical trials in southeast Asia. J Infect Dis 200: 624ā628.
Beale GJ, Carter R, Walliker D, 1978. Genetics. Killick-Kendrick R, Peters W, eds. Rodent Malaria. London, United Kingdom: Academic Press, 213ā245.
Walliker D, Carter R, Sanderson A, 1975. Genetic studies on Plasmodium chabaudi: recombination between enzyme markers. Parasitology 70: 19ā24.
Jacobs RL, 1964. Role of p-aminobenzoic acid in Plasmodium berghei infection in the mouse. Exp Parasitol 15: 213.
Wargo AR, Huijben S, de Roode JC, Shepherd J, Read AF, 2007. Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model. Proc Natl Acad Sci USA 104: 19914ā19919.
Huijben S, Nelson WA, Wargo AR, Sim DG, Drew DR, Read AF, 2010. Chemotherapy, within-host ecology and the fitness of drug-resistant malaria parasites. Evolution 64: 2952ā2968.
Wargo AR, Randle N, Chan BHK, Thompson J, Read AF, Babiker HA, 2006. Plasmodium chabaudi: reverse transcription PCR for the detection and quantification of transmission stage malaria parasites. Exp Parasitol 112: 13ā20.
Huijben S, Bell AS, Sim DG, Tomasello D, Mideo N, Day T, Read AF, 2013. Aggressive chemotherapy and the selection of drug resistant pathogens. PLoS Pathog 9: e1003578.
Drew DR, Reece SE, 2007. Development of reverse-transcription PCR techniques to analyse the density and sex ratio of gametocytes in genetically diverse Plasmodium chabaudi infections. Mol Biochem Parasitol 156: 199ā209.
Cheesman SJ, de Roode JC, Read AF, Carter R, 2003. Real-time quantitative PCR for analysis of genetically mixed infections of malaria parasites: technique validation and applications. Mol Biochem Parasitol 131: 83ā91.
Wongsrichanalai C, Barcus MJ, Muth S, Sutamihardja A, Wernsdorfer WH, 2007. A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT). Am J Trop Med Hyg 77 (Suppl): 119ā127.
Bell AS, Huijben S, Paaijmans KP, Sim DG, Chan BHK, Nelson WA, Read AF, 2012. Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria. PLoS ONE 7: e37172.
R Core Team, 2012. R: A Language and Environment for Statistical Computing. Vienna, Austria: The R Foundation for Statistical Computing.
World Health Organization, 2010. Guidelines for the Treatment of Malaria, 2nd Ed. Geneva, Switzerland: World Health Organization. Available at: http://www.who.int/malaria/publications/atoz/9789241547925/en/.
Stepniewska K, White NJ, 2006. Some considerations in the design and interpretation of antimalarial drug trials in uncomplicated falciparum malaria. Malar J 5: 127.
Greenhouse B, Myrick A, Dokomajilar C, Woo JM, Carlson EJ, Rosenthal PJ, Dorsey G, 2006. Validation of microsatellite markers for use in genotyping polyclonal Plasmodium falciparum infections. Am J Trop Med Hyg 75: 836ā842.
Ngrenngarmlert W, Kwiek JJ, Kamwendo DD, Ritola K, Swanstrom R, Wongsrichanalai C, Miller RS, Ittarat W, Meshnick SR, 2005. Measuring allelic heterogeneity in Plasmodium falciparum by a heteroduplex tracking assay. Am J Trop Med Hyg 72: 694ā701.
Kwiek JJ, Alker AP, Wenink EC, Chaponda M, Kalilani LV, Meshnick SR, 2007. Estimating true antimalarial efficacy by heteroduplex tracking assay in patients with complex Plasmodium falciparum infections. Antimicrob Agents Chemother 51: 521ā527.
Juliano JJ, Bacon DJ, Mu J, Wang X, Meshnick SR, 2009. Novel dhps and pfcrt polymorphisms in Plasmodium falciparum detected by heteroduplex tracking assay. Am J Trop Med Hyg 80: 734ā736.
Manske M, Miotto O, Campino S, Auburn S, Almagro-Garcia J, Maslen G, O'Brien J, Djimde A, Doumbo O, Zongo I, Ouedraogo JB, Michon P, Mueller I, Siba P, Nzila A, Borrmann S, Kiara SM, Marsh K, Jiang H, Su XZ, Amaratunga C, Fairhurst R, Socheat D, Nosten F, Imwong M, White NJ, Sanders M, Anastasi E, Alcock D, Drury E, Oyola S, Quail MA, Turner DJ, Ruano-Rubio V, Jyothi D, Amenga-Etego L, Hubbart C, Jeffreys A, Rowlands K, Sutherland C, Roper C, Mangano V, Modiano D, Tan JC, Ferdig MT, Amambua-Ngwa A, Conway DJ, Takala-Harrison S, Plowe CV, Rayner JC, Rockett KA, Clark TG, Newbold CI, Berriman M, MacInnis B, Kwiatkowski DP, 2012. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. Nature 487: 375ā379.
Juliano JJ, Taylor SM, Meshnick SR, 2009. Polymerase chain reaction adjustment in antimalarial trials: molecular malarkey? J Infect Dis 200: 5ā7.
Stephens R, Culleton RL, Lamb TJ, 2012. The contribution of Plasmodium chabaudi to our understanding of malaria. Trends Parasitol 28: 73ā82.
Pollitt LC, Mideo N, Drew DR, Schneider P, Colegrave N, Reece SE, 2011. Competition and the evolution of reproductive restraint in malaria parasites. Am Nat 177: 358ā367.
Malfertheiner P, Megraud F, O'Morain C, Bazzoli F, El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers EJ, 2007. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 56: 772ā781.
Dellit TH, Owens RC, McGowan JE, Gerding DN, Weinstein RA, Burke JP, Huskins WC, Paterson DL, Fishman NO, Carpenter CF, Brennan PJ, Billeter M, Hooton TM, 2007. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 44: 159ā177.
Günthard HF, Aberg JA, Eron JJ, Hoy JF, Telenti A, Benson CA, Burger DM, Cahn P, Gallant JE, Glesby MJ, Reiss P, Saag MS, Thomas DL, Jacobsen DM, Volberding PA, International Antiviral Society-USA Panel, 2014. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA 312: 410ā425.
Gonzalez-Serna A, Min JE, Woods C, Chan D, Lima VD, Montaner JSG, Harrigan PR, Swenson LC, 2014. Performance of HIV-1 drug resistance testing at low-level viremia and its ability to predict future virologic outcomes and viral evolution in treatment-naive individuals. Clin Infect Dis 58: 1165ā1173.
Nguyen K-SH, Neal JW, Wakelee H, 2014. Review of the current targeted therapies for non-small-cell lung cancer. World J Clin Oncol 5: 576ā587.
Saumet A, Mathelier A, Lecellier C-H, 2014. The potential of microRNAs in personalized medicine against cancers. Biomed Res Int 2014: 642916.
Madan RA, Gulley JL, 2015. (R)Evolutionary therapy: the potential of immunotherapy to fulfill the promise of personalized cancer treatment. J Natl Cancer Inst 107: 347.
Past two years | Past Year | Past 30 Days | |
---|---|---|---|
Abstract Views | 23 | 23 | 11 |
Full Text Views | 269 | 96 | 0 |
PDF Downloads | 38 | 15 | 0 |