Malaria treatment and drug resistance

Prompt and adequate treatment is a central component of malaria control and of reducing mortality. However, the malaria parasite, Plasmodium, may develop resistance within several years after the introduction of new drugs. Therefore, monitoring the efficacy of present and novel drugs is essential. Molecular markers of drug resistance support such monitoring.

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Data for treatment policies

National antimalarial drug policies are based on information as to the efficacy of available drugs. In western Uganda, the molecular markers of drug resistance suggest that a drug-based preventive approach for the prevention of malaria in pregnancy may have lost efficacy. In southern Rwanda, we recently detected Plasmodium falciparum K13 mutations, which in Southeast Asia are associated with reduced susceptibility to the artemisinins. In a current study, we aim at clarifying if and to which extent these and other mutations affect treatment outcomes in Rwanda. In a further study in India, similarly, the molecular markers of the predominating Plasmodium species are correlated with treatment outcomes.

Project Details

Principal Investigator: Prof. Dr. med. Frank P. Mockenhaupt

Co-workers: Costanza Tacoli, Prabhanjan Gai, Vera Braun, Konrad Siegert, Jakob Wedam

Cooperations: Institut für Public Health, Universitätsklinik Heidelberg
University of Rwanda, Butare, Rwanda
Virika Hospital, Fort Portal, Uganda
Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
Karnataka Institute for DNA Research, Dharwad-Hubli, Indien
Kasturba Medical College, Manipal University, Mangalore, Indien
Wenlock Hospital, Mangalore, Indien u.v.a.m.

Project duration: since 1998

Project status: ongoing

Funding: BMBF, GRK 2046, WHO, Charité, Sonnenfeld-Foundation

Papers

Tacoli C, Gai PP, Bayingana C, Sifft K, Geus D, Ndoli J, Sendegeya A, Gahutu JB, Mockenhaupt FP. Artemisinin Resistance-Associated K13 Polymorphisms of Plasmodium falciparum in Southern Rwanda, 2010-2015. Am J Trop Med Hyg. 2016 Nov 2;95(5):1090-1093.

WWARN Gametocyte Study Group. Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data. BMC Med. 2016 May 24;14:79.

Braun V, Rempis E, Schnack A, Decker S, Rubaihayo J, Tumwesigye NM, Theuring S, Harms G, Busingye P, Mockenhaupt FP. Lack of effect of intermittent preventive treatment for malaria in pregnancy and intense drug resistance in western Uganda. Malar J. 2015 Sep 26;14:372.

Coulibaly B, Pritsch M, Bountogo M, Meissner PE, Nebié E, Klose C, Kieser M, Berens-Riha N, Wieser A, Sirima SB, Breitkreutz J, Schirmer RH, Sié A, Mockenhaupt FP, Drakeley C, Bousema T, Müller O. Efficacy and safety of triple combination therapy with artesunate-amodiaquine-methylene blue for falciparum malaria in children: a randomized controlled trial in Burkina Faso. J Infect Dis. 2015 Mar 1;211(5):689-97.

Müller O, Mockenhaupt FP, Marks B, Meissner P, Coulibaly B, Kuhnert R, Buchner H, Schirmer RH, Walter-Sack I, Sié A, Mansmann U. Haemolysis risk in methylene blue treatment of G6PD-sufficient and G6PD-deficient West-African children with uncomplicated falciparum malaria: a synopsis of four RCTs. Pharmacoepidemiol Drug Saf. 2013 Apr;22(4):376-85.

Zeile I, Gahutu JB, Shyirambere C, Steininger C, Musemakweri A, Sebahungu F, Karema C, Harms G, Eggelte TA, Mockenhaupt FP. Molecular markers of Plasmodium falciparum drug resistance in southern highland Rwanda. Acta Trop. 2012 Jan;121(1):50-4.

Bountogo M, Zoungrana A, Coulibaly B, Klose C, Mansmann U, Mockenhaupt FP, Burhenne J, Mikus G, Walter-Sack I, Schirmer RH, Sié A, Meissner P, Müller O. Efficacy of methylene blue monotherapy in semi-immune adults with uncomplicated falciparum malaria: a controlled trial in Burkina Faso. Trop Med Int Health. 2010 Jun;15(6):713-7.

Danquah I, Coulibaly B, Meissner P, Petruschke I, Müller O, Mockenhaupt FP. Selection of pfmdr1 and pfcrt alleles in amodiaquine treatment failure in north-western Burkina Faso. Acta Trop. 2010 Apr;114(1):63-6.

Aponte JJ, Schellenberg D, Egan A, Breckenridge A, Carneiro I, Critchley J, Danquah I, Dodoo A, Kobbe R, Lell B, May J, Premji Z, Sanz S, Sevene E, Soulaymani-Becheikh R, Winstanley P, Adjei S, Anemana S, Chandramohan D, Issifou S, Mockenhaupt F, Owusu-Agyei S, Greenwood B, Grobusch MP, Kremsner PG, Macete E, Mshinda H, Newman RD, Slutsker L, Tanner M, Alonso P, Menendez C. Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials. Lancet. 2009 Oct 31;374(9700):1533-42.

Coulibaly B, Zoungrana A, Mockenhaupt FP, Schirmer RH, Klose C, Mansmann U, Meissner PE, Müller O. Strong gametocytocidal effect of methylene blue-based combination therapy against falciparum malaria: a randomised controlled trial. PLoS One. 2009;4(5):e5318.

Danquah I, Dietz E, Zanger P, Reither K, Ziniel P, Bienzle U, Mockenhaupt FP. Reduced efficacy of intermittent preventive treatment of malaria in malnourished children. Antimicrob Agents Chemother. 2009 May;53(5):1753-9. Mockenhaupt FP, Bedu-Addo G, Eggelte TA, Hommerich L, Holmberg V, von Oertzen C, Bienzle U. Rapid increase in the prevalence of sulfadoxine-pyrimethamine resistance among Plasmodium falciparum isolated from pregnant women in Ghana. J Infect Dis. 2008 Nov 15;198(10):1545-9.

Mandi G, Mockenhaupt FP, Coulibaly B, Meissner P, Müller O. Efficacy of amodiaquine in the treatment of uncomplicated falciparum malaria in young children of rural north-western Burkina Faso. Malar J. 2008 Apr 17;7:58.

Zoungrana A, Coulibaly B, Sié A, Walter-Sack I, Mockenhaupt FP, Kouyaté B, Schirmer RH, Klose C, Mansmann U, Meissner P, Müller O. Safety and efficacy of methylene blue combined with artesunate or amodiaquine for uncomplicated falciparum malaria: a randomized controlled trial from Burkina Faso. PLoS One. 2008 Feb 20;3(2):e1630.

Meissner PE, Mandi G, Mockenhaupt FP, Witte S, Coulibaly B, Mansmann U, Frey C, Merkle H, Burhenne J, Walter-Sack I, Müller O. Marked differences in the prevalence of chloroquine resistance between urban and rural communities in Burkina Faso. Acta Trop. 2008 Jan;105(1):81-6.

Mockenhaupt FP, Reither K, Zanger P, Roepcke F, Danquah I, Saad E, Ziniel P, Dzisi SY, Frempong M, Agana-Nsiire P, Amoo-Sakyi F, Otchwemah R, Cramer JP, Anemana SD, Dietz E, Bienzle U. Intermittent preventive treatment in infants as a means of malaria control: a randomized, double-blind, placebo-controlled trial in northern Ghana. Antimicrob Agents Chemother. 2007 Sep;51(9):3273-81.

Ehrhardt S, Eggelte TA, Kaiser S, Adjei L, Burchard GD, Anemana SD, Bienzle U, Mockenhaupt FP. Large-scale surveillance of Plasmodium falciparum crt(K76T) in northern Ghana. Antimicrob Agents Chemother. 2007 Sep;51(9):3407-9.

Wichmann O, Eggelte TA, Gellert S, Osman ME, Mylius F, Ehrhardt S, Anemana SD, Bienzle U, Mockenhaupt FP. High residual chloroquine blood levels in African children with severe malaria seeking healthcare. Trans R Soc Trop Med Hyg. 2007 Jul;101(7):637-42.

Mockenhaupt FP, Bedu-Addo G, Junge C, Hommerich L, Eggelte TA, Bienzle U. Markers of sulfadoxine-pyrimethamine-resistant Plasmodium falciparum in placenta and circulation of pregnant women. Antimicrob Agents Chemother. 2007 Jan;51(1):332-4.

Schunk M, Kumma WP, Miranda IB, Osman ME, Roewer S, Alano A, Löscher T, Bienzle U, Mockenhaupt FP. High prevalence of drug-resistance mutations in Plasmodium falciparum and Plasmodium vivax in southern Ethiopia. Malar J. 2006 Jul 3;5:54.

Osman ME, Mockenhaupt FP, Bienzle U, Elbashir MI, Giha HA. Field-based evidence for linkage of mutations associated with chloroquine (pfcrt/pfmdr1) and sulfadoxine-pyrimethamine (pfdhfr/pfdhps) resistance and for the fitness cost of multiple mutations in P. falciparum. Infect Genet Evol. 2007 Jan;7(1):52-9.

Mockenhaupt FP, Ehrhardt S, Eggelte TA, Agana-Nsiire P, Stollberg K, Mathieu A, Markert M, Otchwemah RN, Bienzle U. Chloroquine-treatment failure in northern Ghana: roles of pfcrt T76 and pfmdr1 Y86. Ann Trop Med Parasitol. 2005 Dec;99(8):723-32.

Mockenhaupt FP, Bousema JT, Eggelte TA, Ehrhardt S, Otchwemah RN, Sauerwein RW, Bienzle U. Concurrence of Plasmodium falciparum dhfr and crt mutations in northern Ghana. Malar J. 2005 Sep 15;4:42.

Mockenhaupt FP, Teun Bousema J, Eggelte TA, Schreiber J, Ehrhardt S, Wassilew N, Otchwemah RN, Sauerwein RW, Bienzle U. Plasmodium falciparum dhfr but not dhps mutations associated with sulphadoxine-pyrimethamine treatment failure and gametocyte carriage in northern Ghana. Trop Med Int Health. 2005 Sep;10(9):901-8.

Ehrhardt S, Mockenhaupt FP, Eggelte TA, Agana-Nsiire P, Stollberg K, Anemana SD, Otchwemah RN, Bienzle U. Chloroquine blood concentrations and molecular markers of chloroquine-resistant Plasmodium falciparum in febrile children in northern Ghana. Trans R Soc Trop Med Hyg. 2003 Nov-Dec;97(6):697-701.

Mockenhaupt FP, Ehrhardt S, Dzisi SY, Teun Bousema J, Wassilew N, Schreiber J, Anemana SD, Cramer JP, Otchwemah RN, Sauerwein RW, Eggelte TA, Bienzle U. A randomized, placebo-controlled, double-blind trial on sulfadoxine-pyrimethamine alone or combined with artesunate or amodiaquine in uncomplicated malaria. Trop Med Int Health. 2005 Jun;10(6):512-20.

Muehlen M, Schreiber J, Ehrhardt S, Otchwemah R, Jelinek T, Bienzle U, Mockenhaupt FP. Short communication: Prevalence of mutations associated with resistance to atovaquone and to the antifolate effect of proguanil in Plasmodium falciparum isolates from northern Ghana. Trop Med Int Health. 2004 Mar;9(3):361-3.

Ehrhardt S, Mockenhaupt FP, Agana-Nsiire P, Mathieu A, Anemana SD, Stark K, Otchwemah RN, Bienzle U. Efficacy of chloroquine in the treatment of uncomplicated, Plasmodium falciparum malaria in northern Ghana. Ann Trop Med Parasitol. 2002 Apr;96(3):239-47.

Mockenhaupt FP, Eggelte TA, Till H, Bienzle U. Plasmodium falciparum pfcrt and pfmdr1 polymorphisms are associated with the pfdhfr N108 pyrimethamine-resistance mutation in isolates from Ghana. Trop Med Int Health. 2001 Oct;6(10):749-55.

Mockenhaupt FP, Eggelte TA, Böhme T, Thompson WN, Bienzle U. Plasmodium falciparum dihydrofolate reductase alleles and pyrimethamine use in pregnant Ghanaian women. Am J Trop Med Hyg. 2001 Jul;65(1):21-6.

Mockenhaupt FP, May J, Bergqvist Y, Meyer CG, Falusi AG, Bienzle U. Evidence for a reduced effect of chloroquine against Plasmodium falciparum in alpha-thalassaemic children. Trop Med Int Health. 2001 Feb;6(2):102-7.

Mockenhaupt FP, May J, Bergqvist Y, Ademowo OG, Olumese PE, Falusi AG, Grossterlinden L, Meyer CG, Bienzle U. Concentrations of chloroquine and malaria parasites in blood in Nigerian children. Antimicrob Agents Chemother. 2000 Apr;44(4):835-9.

Mockenhaupt FP, May J, Eggelte TA, Thies FL, Ademowo OG, Bienzle U, Meyer CG. Short report: high prevalence and imbalanced age distribution of the Plasmodium falciparum dihydrofolate reductase gene Asn108 mutation in an area of low pyrimethamine usage in Nigeria. Am J Trop Med Hyg. 1999 Sep;61(3):375-7.