Classical Versus Novel Treatment Regimens

  • Louis Maes
  • Raquel Andreia Inocencio da Luz
  • Paul Cos
  • Vanessa Yardley


The chapter will define drug insensitivity and drug resistance in the context of Leishmania infections, both cutaneous and visceral, and describe the impact on treatment this may have. The molecular mechanisms of drug resistance of antimonials, and of other standard antileishmanial drugs will be reviewed, and the evidence for novel treatment regimens, to compensate for drug resistance, will be explored.


Visceral Leishmaniasis Lipid Formulation Leishmania Species Flagellar Pocket Intracellular Thiol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Al-Jaser MA, el-Yazigi A, Croft SL (1995) Pharmacokinetics of antimony in patients treated with sodium stibogluconate for cutaneous leishmaniasis. Pharm Res 12:113–116CrossRefGoogle Scholar
  2. Allen S, Neal RA (1989) The in vitro susceptibility of macrophages infected with amastigotes of Leishmania spp. to pentavalent antimonial drugs and other compounds with special relevance to cutaneous leishmaniasis. In: Hart DT (ed) Leishmaniasis. Plenum Publishing Corporation, New York, pp 711–720Google Scholar
  3. Al-Mohammed HI, Chance ML, Bates PA (2005) Production and characterization of stable amphotericin-resistant amastigotes and promastigotes of Leishmania mexicana. Antimicrob Agents Chemother 49:3274–3280PubMedCrossRefGoogle Scholar
  4. Amato VS, et al (2008) Mucosal leishmaniasis. Current scenario and prospects for treatment. Acta Trop 105:1–9PubMedCrossRefGoogle Scholar
  5. Ashutosh, Sundar S, Goyal N (2007) Molecular mechanisms of antimony resistance in Leishmania. J Med Microbiol 56:143–153PubMedCrossRefGoogle Scholar
  6. Baird JK, Surjadjaja C (2011) Consideration of ethics in primaquine therapy against malaria transmission. Trends Parasitol 27:11–16PubMedCrossRefGoogle Scholar
  7. Balaña-Fouce R, et al (1998) The pharmacology of leishmaniasis. Gen Pharmacol 30:435–443PubMedCrossRefGoogle Scholar
  8. Berman J (2003) Current treatment approaches to leishmaniasis. Curr Opin Infect Dis 16:397–401PubMedCrossRefGoogle Scholar
  9. Berman J (2005) Miltefosine to treat leishmaniasis. Expert Opin Pharmacother 6:1381–1388PubMedCrossRefGoogle Scholar
  10. Berman JD, et al (1982) Susceptibility of clinically sensitive and resistant Leishmania to pentavalent antimony in vitro. Am J Trop Med Hyg 31:459–465PubMedGoogle Scholar
  11. Brochu C, et al (2003) Antimony uptake systems in the protozoan parasite Leishmania and accumulation differences in antimony-resistant parasites. Antimicrob Agents Chemother 47:3073–3079PubMedCrossRefGoogle Scholar
  12. Carter KC, et al (2006) Resistance of Leishmania donovani to sodium stibogluconate is related to the expression of host and parasite {gamma}-glutamylcysteine synthetase. Antimicrob Agents Chemother 50:88–95PubMedCrossRefGoogle Scholar
  13. Chakravarty J, Sundar S (2010) Drug resistance in leishmaniasis. J Glob Infect Dis 2:167–176PubMedCrossRefGoogle Scholar
  14. Chappuis F, et al (2007) Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nat Rev Microbiol 5:873–882PubMedCrossRefGoogle Scholar
  15. Coelho AC, Beverley SM, Cotrim PC (2003) Functional genetic identification of PRP1, an ABC transporter superfamily member conferring pentamidine resistance in Leishmania major. Mol Biochem Parasitol 130:83–90PubMedCrossRefGoogle Scholar
  16. Coelho AC, et al (2007) Role of the ABC transporter PRP1 (ABCC7) in pentamidine resistance in Leishmania amastigotes. Antimicrob Agents Chemother 51:3030–3032PubMedCrossRefGoogle Scholar
  17. Coelho AC, et al (2008) Characterization of Leishmania (Leishmania) amazonensis promastigotes resistant to pentamidine. Exp Parasitol 120:98–102PubMedCrossRefGoogle Scholar
  18. Croft SL, Coombs GH (2003) Leishmaniasis – current chemotherapy and recent advances in the search for novel drugs. Trends Parasitol 19:502–508PubMedCrossRefGoogle Scholar
  19. Croft SL, Seifert K, Yardley V (2006a) Current scenario of drug development for leishmaniasis. Indian J Med Res 123:399–410PubMedGoogle Scholar
  20. Croft SL, Sundar S, Fairlamb AH (2006b) Drug resistance in leishmaniasis. Clin Microbiol Rev 19:111–126PubMedCrossRefGoogle Scholar
  21. Davidson RN, den Boer M, Ritmeijer K (2009) Paromomycin. Trans R Soc Trop Med Hyg 103:653–660PubMedCrossRefGoogle Scholar
  22. Denton H, McGregor JC, Coombs GH (2004) Reduction of anti-leishmanial pentavalent antimonial drugs by a parasite-specific thiol-dependent reductase, TDR1. Biochem J 381:405–412PubMedCrossRefGoogle Scholar
  23. Dorlo TP, et al (2008) Pharmacokinetics of miltefosine in old world cutaneous leishmaniasis patients. Antimicrob Agents Chemother 52:2855–2860PubMedCrossRefGoogle Scholar
  24. Dueñas-Romero AM, Loiseau PM, Saint-Pierre-Chazalet M (2007) Interaction of sitamaquine with membrane lipids of Leishmania donovani promastigotes. Biochim Biophys Acta 1768:246–252PubMedCrossRefGoogle Scholar
  25. Edwards T, et al (2011) Single-dose liposomal amphotericin B (AmBisome(R)) for the treatment of visceral leishmaniasis in East Africa: study protocol for a randomized controlled trial. Trials 12:66PubMedCrossRefGoogle Scholar
  26. El Fadili K, et al (2005) Role of the ABC transporter MRPA (PGPA) in antimony resistance in Leishmania infantum axenic and intracellular amastigotes. Antimicrob Agents Chemother 49:1988–1993PubMedCrossRefGoogle Scholar
  27. Ephros M, et al (1999) Stage-specific activity of pentavalent antimony against Leishmania donovani axenic amastigotes. Antimicrob Agents Chemother 43:278–282PubMedGoogle Scholar
  28. Escobar P, et al (2002) Sensitivities of Leishmania species to hexadecylphophocholine (miltefosine), ET-18-OCH3 (edelfosine) and amphotericin B. Acta Trop 81:151–157PubMedCrossRefGoogle Scholar
  29. Ferreira Cdos S, et al (2003) Thiol-induced reduction of antimony(V) into antimony(III): a comparative study with trypanothione, cysteinyl-glycine, cysteine and glutathione. Biometals 16:441–446PubMedCrossRefGoogle Scholar
  30. Frezard F, Demicheli C (2010) New delivery strategies for the old pentavalent antimonial drugs. Expert Opin Drug Deliv 7:1343–1358PubMedCrossRefGoogle Scholar
  31. Frézard F, et al (2001) Glutathione-induced conversion of pentavalent antimony to trivalent antimony in meglumine antimoniate. Antimicrob Agents Chemother 45:913–916PubMedCrossRefGoogle Scholar
  32. Goto H, Lindoso JA (2010) Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther 8:419–433PubMedCrossRefGoogle Scholar
  33. Gourbal B, et al (2004) Drug uptake and modulation of drug resistance in Leishmania by an aquaglyceroporin. J Biol Chem 279:31010–31017PubMedCrossRefGoogle Scholar
  34. Guerin PJ, et al (2002) Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis 2:494–501PubMedCrossRefGoogle Scholar
  35. Hailu A, et al (2005) Visceral leishmaniasis: new health tools are needed. PLoS Med 2:e211PubMedCrossRefGoogle Scholar
  36. Holzmuller P, Bras-Gonçalves R, Lemesre JL (2006) Phenotypical characteristics, biochemical pathways, molecular targets and putative role of nitric oxide-mediated programmed cell death in Leishmania. Parasitology 132(Suppl):S19–S32PubMedCrossRefGoogle Scholar
  37. Jha TK, et al (2005) A phase II dose-ranging study of sitamaquine for the treatment of visceral leishmaniasis in India. Am J Trop Med Hyg 73:1005–1011PubMedGoogle Scholar
  38. Jhingran A, et al (2009) Paromomycin: uptake and resistance in Leishmania donovani. Mol Biochem Parasitol 164:111–117PubMedCrossRefGoogle Scholar
  39. Laguna F (2003) Treatment of leishmaniasis in HIV-positive patients. Ann Trop Med Parasitol 97(Suppl 1):135–142PubMedCrossRefGoogle Scholar
  40. Maarouf M, et al (1997a) In vivo interference of paromomycin with mitochondrial activity of Leishmania. Exp Cell Res 232:339–348PubMedCrossRefGoogle Scholar
  41. Maarouf M, et al (1997b) Biochemical alterations in paromomycin-treated Leishmania donovani promastigotes. Parasitol Res 83:198–202PubMedCrossRefGoogle Scholar
  42. Maarouf M, et al (1998) Development and characterization of paromomycin-resistant Leishmania donovani promastigotes. Parasite 5:167–173PubMedGoogle Scholar
  43. Maharjan M, et al (2008) Role of aquaglyceroporin (AQP1) gene and drug uptake in antimony-resistant clinical isolates of Leishmania donovani. Am J Trop Med Hyg 79:69–75PubMedGoogle Scholar
  44. Malafaia G (2009) Protein-energy malnutrition as a risk factor for visceral leishmaniasis: a review. Parasite Immunol 31:587–596PubMedCrossRefGoogle Scholar
  45. Maltezou HC (2010) Drug resistance in visceral leishmaniasis. J Biomed Biotechnol 2010:617521PubMedCrossRefGoogle Scholar
  46. Mandal G, et al (2007) Increased levels of thiols protect antimony unresponsive Leishmania donovani field isolates against reactive oxygen species generated by trivalent antimony. Parasitology 134:1679–1687PubMedCrossRefGoogle Scholar
  47. Mandal S, et al (2010) Assessing aquaglyceroporin gene status and expression profile in antimony-susceptible and -resistant clinical isolates of Leishmania donovani from India. J Antimicrob Chemother 65:496–507PubMedCrossRefGoogle Scholar
  48. Martin D (2010) Identification and development of new chemical entities to treat visceral leishmaniasis: a bump road. ICOPA XII, Melbourne, Australia: 26Google Scholar
  49. Matlashewski G, et al (2011) Visceral leishmaniasis: elimination with existing interventions. Lancet Infect Dis 11:322–325PubMedCrossRefGoogle Scholar
  50. Meheus F, et al (2010) Cost-effectiveness analysis of combination therapies for visceral leishmaniasis in the Indian subcontinent. PLoS Negl Trop Dis 4:e818PubMedCrossRefGoogle Scholar
  51. Mishra J, Carpenter S, Singh S (2010) Low serum zinc levels in an endemic area of visceral leishmaniasis in Bihar, India. Indian J Med Res 131:793–798PubMedGoogle Scholar
  52. Mitropoulos P, Konidas P, Durkin-Konidas M (2010) New world cutaneous leishmaniasis: updated review of current and future diagnosis and treatment. J Am Acad Dermatol 63:309–322PubMedCrossRefGoogle Scholar
  53. Mittal MK, et al (2007) Characterization of natural antimony resistance in Leishmania donovani isolates. Am J Trop Med Hyg 76:681–688PubMedGoogle Scholar
  54. Moore EM, Lockwood DN (2010) Treatment of visceral leishmaniasis. J Glob Infect Dis 2(2):151–158PubMedCrossRefGoogle Scholar
  55. Moore E, et al (2001) Comparison of generic and proprietary sodium stibogluconate for the treatment of visceral leishmaniasis in Kenya. Bull World Health Organ 79:388–393PubMedGoogle Scholar
  56. Morrone A, et al (2011) Epidemiological and geographical aspects of leishmaniasis in Tigray, northern Ethiopia: a retrospective analysis of medical records, 2005–2008. Trans R Soc Trop Med Hyg 105(5):273–280PubMedCrossRefGoogle Scholar
  57. Mukherjee A, et al (2006) Roles for mitochondria in pentamidine susceptibility and resistance in Leishmania donovani. Mol Biochem Parasitol 145:1–10PubMedCrossRefGoogle Scholar
  58. Murray HW (2001) Clinical and experimental advances in treatment of visceral leishmaniasis. Antimicrob Agents Chemother 45:2185–2197PubMedCrossRefGoogle Scholar
  59. Murray HW, et al (2005) Advances in leishmaniasis. Lancet 366:1561–1577PubMedCrossRefGoogle Scholar
  60. Navin TR, et al (1992) Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis 165:528–534PubMedCrossRefGoogle Scholar
  61. Ouellette M, Drummelsmith J, Papadopoulou B (2004) Leishmaniasis: drugs in the clinic, resistance and new developments. Drug Resist Updat 7:257–266PubMedCrossRefGoogle Scholar
  62. Palumbo E (2008) Oral miltefosine treatment in children with visceral leishmaniasis: a brief review. Braz J Infect Dis 12:2–4PubMedGoogle Scholar
  63. Pérez-Victoria JM, et al (2001) Alkyl-lysophospholipid resistance in multidrug-resistant Leishmania tropica and chemosensitization by a novel P-glycoprotein-like transporter modulator. Antimicrob Agents Chemother 45:2468–2474PubMedCrossRefGoogle Scholar
  64. Pérez-Victoria FJ, et al (2006) Mechanisms of experimental resistance of Leishmania to miltefosine: implications for clinical use. Drug Resist Updat 9:26–39PubMedCrossRefGoogle Scholar
  65. Ritmeijer K, et al (2001) Ethiopian visceral leishmaniasis: generic and proprietary sodium stibogluconate are equivalent; HIV co-infected patients have a poor outcome. Trans R Soc Trop Med Hyg 95:668–672PubMedCrossRefGoogle Scholar
  66. Roberts WL, Berman JD, Rainey PM (1995) In vitro antileishmanial properties of tri- and pentavalent antimonial preparations. Antimicrob Agents Chemother 39:1234–1239PubMedCrossRefGoogle Scholar
  67. Roberts CW, Walker W, Alexander J (2001) Sex-associated hormones and immunity to protozoan parasites. Clin Microbiol Rev 14:476–488PubMedCrossRefGoogle Scholar
  68. Rosenthal E, et al (2009) Liposomal amphotericin B as treatment for visceral leishmaniasis in Europe, 2009. Med Mal Infect 39:741–744PubMedCrossRefGoogle Scholar
  69. Roychoudhury J, Ali N (2008) Sodium stibogluconate: therapeutic use in the management of leishmaniasis. Indian J Biochem Biophys 45:16–22Google Scholar
  70. Russo R, et al (2003) Visceral leishmaniasis in those infected with HIV: clinical aspects and other opportunistic infections. Ann Trop Med Parasitol 97(Suppl 1):99–105PubMedCrossRefGoogle Scholar
  71. Saint-Pierre-Chazalet M, et al (2009) Membrane sterol depletion impairs miltefosine action in wild-type and miltefosine-resistant Leishmania donovani promastigotes. J Antimicrob Chemother 64:993–1001PubMedCrossRefGoogle Scholar
  72. Seifert K, et al (2003) Characterisation of Leishmania donovani promastigotes resistant to hexadecylphosphocholine (miltefosine). Int J Antimicrob Agents 22:380–387PubMedCrossRefGoogle Scholar
  73. Seifert K, et al (2007) Inactivation of the miltefosine transporter, LdMT, causes miltefosine resistance that is conferred to the amastigote stage of Leishmania donovani and persists in vivo. Int J Antimicrob Agents 30:229–235PubMedCrossRefGoogle Scholar
  74. Seifert K, Escobar P, Croft SL (2010) In vitro activity of anti-leishmanial drugs against Leishmania donovani is host cell dependent. J Antimicrob Chemother 65:508–511PubMedCrossRefGoogle Scholar
  75. Shaked-Mishan P, et al (2001) Novel intracellular SbV reducing activity correlates with antimony susceptibility in Leishmania donovani. J Biol Chem 276:3971–3976PubMedCrossRefGoogle Scholar
  76. Shakya N, Bajpai P et al (2011) Therapeutic switching in Leishmania chemotherapy: a distinct approach towards unsatisfied treatment needs. J Parasit Dis 35(2):104–112, EPub May 2011PubMedCrossRefGoogle Scholar
  77. Singh N (2006) Drug resistance mechanisms in clinical isolates of Leishmania donovani. Indian J Med Res 123:411–422PubMedGoogle Scholar
  78. Singh S, Sivakumar R (2004) Challenges and new discoveries in the treatment of leishmaniasis. J Infect Chemother 10:307–315PubMedCrossRefGoogle Scholar
  79. Singh RK, Pandey HP, Sundar S (2006) Visceral leishmaniasis (kala-azar): challenges ahead. Indian J Med Res 123:331–344PubMedGoogle Scholar
  80. Sundar S, Chatterjee M (2006) Visceral leishmaniasis – current therapeutic modalities. Indian J Med Res 123:345–352PubMedGoogle Scholar
  81. Sundar S, et al (2003) Oral miltefosine treatment in children with mild to moderate Indian visceral leishmaniasis. Pediatr Infect Dis J 22:434–438PubMedGoogle Scholar
  82. Sundar S, et al (2011a) Pharmacokinetics of oral sitamaquine taken with or without food and safety and efficacy for treatment of visceral leishmaniais: a randomized study in Bihar, India. Am J Trop Med Hyg 84:892–900PubMedCrossRefGoogle Scholar
  83. Sundar S, et al (2011b) Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet 377:477–486PubMedCrossRefGoogle Scholar
  84. Tekwani BL, Walker LA (2006) 8-Aminoquinolines: future role as antiprotozoal drugs. Curr Opin Infect Dis 19:623–631PubMedCrossRefGoogle Scholar
  85. van Griensven J, Boelaert M (2011) Combination therapy for visceral leishmaniasis. Lancet 377:443–444PubMedCrossRefGoogle Scholar
  86. Vanlerberghe V, et al (2007) Drug policy for visceral leishmaniasis: a cost-effectiveness analysis. Trop Med Int Health 12:274–283PubMedCrossRefGoogle Scholar
  87. Wakelin D (1989) Nature and nurture: overcoming constraints on immunity. Parasitology 99(Suppl):S21–S35PubMedCrossRefGoogle Scholar
  88. Wernsdorfer WH (1992) The biological and epidemiological basis of drug resistance in malaria parasites. Southeast Asian J Trop Med Public Health 23(Suppl 4):123–129PubMedGoogle Scholar
  89. Wyllie S, Vickers TJ, Fairlamb AH (2008) Roles of trypanothione s-transferase and tryparedoxin peroxidase in resistance to antimonials. Antimicrob Agents Chemother 524:1359–1365CrossRefGoogle Scholar
  90. Yardley V, Gamarro F, Croft SL (2010) Antileishmanial and antitrypanosomal activities of the 8-aminoquinoline tafenoquine. Antimicrob Agents Chemother 54:5356–5358PubMedCrossRefGoogle Scholar
  91. Zhou Y, et al (2004) Leishmania major LmACR2 is a pentavalent antimony reductase that confers sensitivity to the drug pentostam. J Biol Chem 279:37445–37451PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • Louis Maes
    • 1
  • Raquel Andreia Inocencio da Luz
    • 1
  • Paul Cos
    • 1
  • Vanessa Yardley
    • 2
  1. 1.Faculty of Pharmaceutical, Biomedical and Veterinary SciencesUniversity of AntwerpAntwerpBelgium
  2. 2.Faculty of Infectious and Tropical DiseasesLondonUK

Personalised recommendations