Drug Resistance in Leishmania: Clinical Perspectives

  • Shyam Sundar
  • Madhukar Rai
Part of the Infectious Disease book series (ID)

Leishmaniasis comprises a group of diverse clinico–pathological entities, caused by the obligate intracellular parasite of the genus Leishmania. It occurs in 88 countries in the tropical and temperate regions, 72 of them developing or least developed. Two million cases occur annually, 1–1.5 million of cutaneous leishmaniasis (CL) and its variations, and 500,000 of visceral leishmaniasis (VL). About 350 million people are at risk, with an overall prevalence of 12 million (1). There is gross underreporting of the cases from the endemic region, and there has been a progressive increase in the cases of leishmaniasis and it is being reported from newer areas. Although the distribution of Leishmania is limited by the distribution of sandfl y vectors, human leishmaniasis is on the increase worldwide. This has been attributed to massive rural–urban migration, widespread deforestation, and agro–industrial projects that are bringing nonimmune dwellers to rural endemic areas. Manmade projects such as dams and irrigation systems have also contributed to the spread of the disease (2).


Visceral Leishmaniasis Antimicrob Agent Cutaneous Leishmaniasis Liposomal Amphotericin Antileishmanial Activity 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Desjeux P. Human leishmaniases: epidemiology and public health aspects. World Health Stat Q 1992; 45:267–75.PubMedGoogle Scholar
  2. 2.
    Desjeux P. The increase in risk factors for leishmaniasis worldwide. Trans R Soc Trop Med Hyg 2001; 95:239–43.PubMedGoogle Scholar
  3. 3.
    Bora D. Epidemiology of visceral leishmaniasis in India. Natl Med J India 1999; 12:62–8.PubMedGoogle Scholar
  4. 4.
    Seaman J, Mercer AJ, Sondorp E. The epidemic of visceral leishmaniasis in western Upper Nile, southern Sudan: course and impact from 1984 to 1994. Int J Epidemiol 1996; 25:862–71.PubMedGoogle Scholar
  5. 5.
    Richens J. Genital manifestations of tropical diseases. Sex Transm Infect 2004; 80:12–7.PubMedGoogle Scholar
  6. 6.
    Alvar J, Canavate C, Gutierrez-Solar B, et al. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin Microbiol Rev 1997; 10:298–319.PubMedGoogle Scholar
  7. 7.
    Desjeux P, Alvar J. Leishmania/HIV co-infections: epidemiology in Europe. Ann Trop Med Parasitol 2003; 97 Suppl 1:3–15.PubMedGoogle Scholar
  8. 8.
    Killick-Kendrick R. Phlebotomine vectors of the leishmaniases: a review. Med Vet Entomol 1990; 4:1–24.PubMedGoogle Scholar
  9. 9.
    Magill AJ. Epidemiology of the leishmaniases. Dermatol Clin 1995; 13:505–23.PubMedGoogle Scholar
  10. 10.
    Leishmaniasis. Lancet 1968; 2:203–4.Google Scholar
  11. 11.
    Leng YJ, Zhang LM. Check list and geographical distribution of phle-botomine sandflies in China. Ann Trop Med Parasitol 1993; 87:83–94.PubMedGoogle Scholar
  12. 12.
    Morsy TA, el-Missiry AG, Kamel AM, Fayad ME, el-Sharkawy IM. Distribution of Phlebotomus species in the Nile Delta, Egypt. J Egypt Soc Parasitol 1990; 20:589–97.PubMedGoogle Scholar
  13. 13.
    Dedet J, Pratlong F. Taxonomy of Leishmania and geographical distribution of leishmaniasis. Ann Dermatol Venereol 2000; 127:421–4.PubMedGoogle Scholar
  14. 14.
    Dye C. The logic of visceral leishmaniasis control. Am J Trop Med Hyg 1996; 55:125–30.PubMedGoogle Scholar
  15. 15.
    Desjeux P, Piot B, O'Neill K, Meert JP. Co-infections of leishma-nia/HIV in south Europe. Med Trop (Mars) 2001; 61:187–93.Google Scholar
  16. 16.
    de la Loma A, Alvar J, Martinez Galiano E, Blazquez J, Alcala Munoz A, Najera R. Leishmaniasis or AIDS? Trans R Soc Trop Med Hyg 1985; 79:421–2.PubMedGoogle Scholar
  17. 17.
    Zijlstra EE, Musa AM, Khalil EA, el-Hassan IM, el-Hassan AM. Post-kala-azar dermal leishmaniasis. Lancet Infect Dis 2003; 3:87–98.PubMedGoogle Scholar
  18. 18.
    Zijlstra EE, el-Hassan AM, Ismael A. Endemic kala-azar in eastern Sudan: post-kala-azar dermal leishmaniasis. Am J Trop Med Hyg 1995; 52:299–305.PubMedGoogle Scholar
  19. 19.
    Thakur CP, Kumar K. Post kala-azar dermal leishmaniasis: a neglected aspect of kala-azar control programmes. Ann Trop Med Parasitol 1992; 86:355–9.PubMedGoogle Scholar
  20. 20.
    Addy M, Nandy A. Ten years of kala-azar in west Bengal, Part I. Did post-kala-azar dermal leishmaniasis initiate the outbreak in 24-Parganas? Bull World Health Organ 1992; 70:341–6.PubMedGoogle Scholar
  21. 21.
    Abdalla RE, Sherif H. Epidemic of cutaneous leishmaniasis in Northern Sudan. Ann Trop Med Parasitol 1978; 72:349–52.PubMedGoogle Scholar
  22. 22.
    Reyburn H, Rowland M, Mohsen M, Khan B, Davies C. The prolonged epidemic of anthroponotic cutaneous leishmaniasis in Kabul, Afghanistan: ‘bringing down the neighbourhood’. Trans R Soc Trop Med Hyg 2003; 97:170–6.PubMedGoogle Scholar
  23. 23.
    Aguilar CM, Fernandez E, de Fernandez R, Deane LM. Study of an outbreak of cutaneous leishmaniasis in Venezuela. The role of domestic animals. Mem Inst Oswaldo Cruz 1984; 79:181–95.Google Scholar
  24. 24.
    Follador I, Araujo C, Cardoso MA, et al. Outbreak of American cutaneous leishmaniasis in Canoa, Santo Amaro, Bahia, Brazil. Rev Soc Bras Med Trop 1999; 32:497–503.PubMedGoogle Scholar
  25. 25.
    SharifiI, Fekri AR, Aflatonian MR, Nadim A, Nikian Y, Kamesipour A. Cutaneous leishmaniasis in primary school children in the south-eastern Iranian city of Bam, 1994–95. Bull World Health Organ 1998; 76:289–93.PubMedGoogle Scholar
  26. 26.
    Gunduz K, Afsar S, Ayhan S, et al. Recidivans cutaneous leish-maniasis unresponsive to liposomal amphotericin B (AmBisome). J Eur Acad Dermatol Venereol 2000; 14:11–3.PubMedGoogle Scholar
  27. 27.
    Grimaldi G, Jr., Tesh RB, McMahon-Pratt D. A review of the geographic distribution and epidemiology of leishmaniasis in the New World. Am J Trop Med Hyg 1989; 41:687–725.PubMedGoogle Scholar
  28. 28.
    Barral A, Costa JM, Bittencourt AL, Barral-Netto M, Carvalho EM. Polar and subpolar diffuse cutaneous leishmaniasis in Brazil: clinical and immunopathologic aspects. Int J Dermatol 1995; 34:474–9.PubMedGoogle Scholar
  29. 29.
    Akuffo HO, Fehniger TE, Britton S. Differential recognition of Leishmania aethiopica antigens by lymphocytes from patients with local and diffuse cutaneous leishmaniasis. Evidence for antigen-induced immune suppression. J Immunol 1988; 141:2461–6.Google Scholar
  30. 30.
    Oliveira-Neto MP, Mattos M, Pirmez C, et al. Mucosal leishma-niasis (“espundia”) responsive to low dose of N-methyl glucamine (Glucantime) in Rio de Janeiro, Brazil. Rev Inst Med Trop Sao Paulo 2000; 42:321–5.PubMedGoogle Scholar
  31. 31.
    Larson EE, Marsden PD. The origin of espundia. Trans R Soc Trop Med Hyg 1987; 81:880.PubMedGoogle Scholar
  32. 32.
    Magill AJ, Grogl M, Gasser RA, Jr., Sun W, Oster CN. Visceral infection caused by Leishmania tropica in veterans of Operation Desert Storm. N Engl J Med 1993; 328:1383–7.PubMedGoogle Scholar
  33. 33.
    Sundar S, More DK, Singh MK, et al. Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the Indian epidemic. Clin Infect Dis 2000; 31:1104–7.PubMedGoogle Scholar
  34. 34.
    Sundar S, Singh VP, Sharma S, Makharia MK, Murray HW. Response to interferon-gamma plus pentavalent antimony in Indian visceral leishmaniasis. J Infect Dis 1997; 176:1117–9.PubMedGoogle Scholar
  35. 35.
    Bryceson A. A policy for leishmaniasis with respect to the prevention and control of drug resistance. Trop Med Int Health 2001; 6:928–34.PubMedGoogle Scholar
  36. 36.
    Sundar S, Thakur BB, Tandon AK, et al. Clinicoepidemiological study of drug resistance in Indian kala-azar. BMJ 1994; 308:307.PubMedGoogle Scholar
  37. 37.
    Berman JD. Human leishmaniasis: clinical, diagnostic, and chemo-therapeutic developments in the last 10 years. Clin Infect Dis 1997; 24:684–703.PubMedGoogle Scholar
  38. 38.
    Herwaldt BL, Berman JD. Recommendations for treating leish-maniasis with sodium stibogluconate (Pentostam) and review of pertinent clinical studies. Am J Trop Med Hyg 1992; 46:296–306.PubMedGoogle Scholar
  39. 39.
    Laguna F, Videla S, Jimenez-Mejias ME, et al. Amphotericin B lipid complex versus meglumine antimoniate in the treatment of visceral leishmaniasis in patients infected with HIV: a randomized pilot study. J Antimicrob Chemother 2003; 52:464–8.PubMedGoogle Scholar
  40. 40.
    Russo R, Nigro LC, Minniti S, et al. Visceral leishmaniasis in HIV infected patients: treatment with high dose liposomal amphotericin B (AmBisome). J Infect 1996; 32:133–7.PubMedGoogle Scholar
  41. 41.
    Alvar J, Gutierrez-Solar B, Pachon I, et al. AIDS and Leishmania infantum. New approaches for a new epidemiological problem. Clin Dermatol 1996; 14:541–6.Google Scholar
  42. 42.
    Molina R, Gradoni L, Alvar J. HIV and the transmission of Leishmania. Ann Trop Med Parasitol 2003; 97 Suppl 1:29–45.PubMedGoogle Scholar
  43. 43.
    Jha TK. Evaluation of diamidine compound (pentamidine isethionate) in the treatment resistant cases of kala-azar occurring in North Bihar, India. Trans R Soc Trop Med Hyg 1983; 77:167–70.PubMedGoogle Scholar
  44. 44.
    Jha TK, Sharma VK. Pentamidine-induced diabetes mellitus. Trans R Soc Trop Med Hyg 1984; 78:252–3.PubMedGoogle Scholar
  45. 45.
    Jha SN, Singh NK, Jha TK. Changing response to diamidine compounds in cases of kala-azar unresponsive to antimonial. J Assoc Physicians India 1991; 39:314–6.PubMedGoogle Scholar
  46. 46.
    Thakur CP, Kumar M, Pandey AK. Comparison of regimes of treatment of antimony-resistant kala-azar patients: a randomized study. Am J Trop Med Hyg 1991; 45:435–41.PubMedGoogle Scholar
  47. 47.
    Mishra M, Singh MP, Choudhury D, Singh VP, Khan AB. Amphotericin B for second-line treatment of Indian kala-azar. Lancet 1991; 337:926.PubMedGoogle Scholar
  48. 48.
    Thakur CP, Singh RK, Hassan SM, Kumar R, Narain S, Kumar A. Amphotericin B deoxycholate treatment of visceral leishmaniasis with newer modes of administration and precautions: a study of 938 cases. Trans R Soc Trop Med Hyg 1999; 93:319–23.PubMedGoogle Scholar
  49. 49.
    Sundar S, Mehta H, Suresh AV, Singh SP, Rai M, Murray HW. Amphotericin B treatment for Indian visceral leishmaniasis: conventional versus lipid formulations. Clin Infect Dis 2004; 38:377–83.PubMedGoogle Scholar
  50. 50.
    Sundar S, Jha TK, Thakur CP, Mishra M, Singh VP, Buffels R. Single-dose liposomal amphotericin B in the treatment of visceral leishmaniasis in India: a multicenter study. Clin Infect Dis 2003; 37:800–4.PubMedGoogle Scholar
  51. 51.
    Sundar S, Agrawal G, Rai M, Makharia MK, Murray HW. Treatment of Indian visceral leishmaniasis with single or daily infusions of low dose liposomal amphotericin B: randomised trial. BMJ 2001; 323:419–22.PubMedGoogle Scholar
  52. 52.
    Sundar S, Agrawal NK, Sinha PR, Horwith GS, Murray HW. Short-course, low-dose amphotericin B lipid complex therapy for visceral leishmaniasis unresponsive to antimony. Ann Intern Med 1997; 127:133–7.PubMedGoogle Scholar
  53. 53.
    Berman JD. U.S Food and Drug Administration approval of AmBisome (liposomal amphotericin B) for treatment of visceral leishmaniasis. Clin Infect Dis 1999; 28:49–51.PubMedGoogle Scholar
  54. 54.
    Davidson RN, di Martino L, Gradoni L, et al. Short-course treatment of visceral leishmaniasis with liposomal amphotericin B (AmBisome). Clin Infect Dis 1996; 22:938–43.PubMedGoogle Scholar
  55. 55.
    Seaman J, Boer C, Wilkinson R, et al. Liposomal amphotericin B (AmBisome) in the treatment of complicated kala-azar under field conditions. Clin Infect Dis 1995; 21:188–93.PubMedGoogle Scholar
  56. 56.
    Sundar S, Jha TK, Thakur CP, et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 2002; 347:1739–46.PubMedGoogle Scholar
  57. 57.
    Sundar S. Drug resistance in Indian visceral leishmaniasis. Trop Med Int Health 2001; 6:849–54.PubMedGoogle Scholar
  58. 58.
    Peters W. The treatment of kala-azar — new approaches to an old problem. Indian J Med Res 1981; 73 Suppl:1–18.PubMedGoogle Scholar
  59. 59.
    Anonymous. Proceedings of the Meeting of an Expert Group on Kala-azar held at Indian Council of Medical Research Headquarters on 9 September, 1977, New Delhi. Indian Council of Medical Research, New Delhi 1977.Google Scholar
  60. 60.
    Aikat BK, Sahaya S, Pathania AG, et al. Clinical profile of cases of kala-azar in Bihar. Indian J Med Res 1979; 70:563–70.PubMedGoogle Scholar
  61. 61.
    Thakur CP, Kumar M, Singh SK, et al. Comparison of regimens of treatment with sodium stibogluconate in kala-azar. Br Med J (Clin Res Ed) 1984; 288:895–7.Google Scholar
  62. 62.
    The leishmaniases. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 1984; 701:1–140.Google Scholar
  63. 63.
    Thakur CP, Kumar M, Kumar P, Mishra BN, Pandey AK. Rationalisation of regimens of treatment of kala-azar with sodium stibogluconate in India: a randomised study. Br Med J (Clin Res Ed) 1988; 296:1557–61.Google Scholar
  64. 64.
    Thakur CP, Kumar M, Pandey AK. Evaluation of efficacy of longer durations of therapy of fresh cases of kala-azar with sodium sti-bogluconate. Indian J Med Res 1991; 93:103–10.PubMedGoogle Scholar
  65. 65.
    Jha T, Singh N, Jha S. Therapeutic use of sodium stibogluconate in kala-alar from some hyperendemic districts of N. Bihar, India (Abstract). J Assoc Physicians India 1992; 40:868.Google Scholar
  66. 66.
    Rijal S, Chappuis F, Singh R, et al. Treatment of kala-azar in southeastern Nepal: decreasing efficacy of sodium stibogluconate and need for a policy to limit further decline. Trans R Soc Trop Med Hyg 2003; 97(3):350–4.PubMedGoogle Scholar
  67. 67.
    Laguna F, Videla S, Jimenez-Mejias ME, et al. Amphotericin B lipid complex versus meglumine antimoniate in the treatment of visceral leishmaniasis in patients infected with HIV: a randomized pilot study. J Antimicrob Chemother 2003; 52(3):464–8.PubMedGoogle Scholar
  68. 68.
    Berman JD, Chulay JD, Hendricks LD, Oster CN. Susceptibility of clinically sensitive and resistant Leishmania to pentavalent antimony in vitro. Am J Trop Med Hyg 1982; 31:459–65.PubMedGoogle Scholar
  69. 69.
    Bryceson AD, Chulay JD, Ho M, et al. Visceral leishmaniasis unresponsive to antimonial drugs. I. Clinical and immunological studies. Trans R Soc Trop Med Hyg 1985; 79:700–4.Google Scholar
  70. 70.
    Lira R, Sundar S, Makharia A, et al. Evidence that the high incidence of treatment failures in Indian kala-azar is due to the emergence of antimony-resistant strains of Leishmania donovani. J Infect Dis 1999; 180:564–7.PubMedGoogle Scholar
  71. 71.
    Carrio J, Portus M. In vitro susceptibility to pentavalent antimony in Leishmania infantum strains is not modified during in vitro or in vivo passages but is modified after host treatment with meglumine antimoniate. BMC Pharmacol 2002; 2:11.PubMedGoogle Scholar
  72. 72.
    Bhattacharyya A, Mukherjee M, Duttagupta S. Studies on stiba-nate unresponsive isolates of Leishmania donovani. J Biosci 2002; 27:503–8.PubMedGoogle Scholar
  73. 73.
    Faraut-Gambarelli F, Piarroux R, Deniau M, et al. In vitro and in vivo resistance of Leishmania infantum to meglumine antimo-niate: a study of 37 strains collected from patients with visceral leishmaniasis. Antimicrob Agents Chemother 1997; 41:827–30.PubMedGoogle Scholar
  74. 74.
    Momeni AZ, Reiszadae MR, Aminjavaheri M. Treatment of cutaneous leishmaniasis with a combination of allopurinol and low-dose meglumine antimoniate. Int J Dermatol 2002; 41:441–3.PubMedGoogle Scholar
  75. 75.
    Grogl M, Thomason TN, Franke ED. Drug resistance in leishma-niasis: its implication in systemic chemotherapy of cutaneous and mucocutaneous disease. Am J Trop Med Hyg 1992; 47:117–26.PubMedGoogle Scholar
  76. 76.
    Sereno D, Lemesre JL. Axenically cultured amastigote forms as an in vitro model for investigation of antileishmanial agents. Antimicrob Agents Chemother 1997; 41:972–6.PubMedGoogle Scholar
  77. 77.
    Jackson JE, Tally JD, Tang DB. An in vitro micromethod for drug sensitivity testing of Leishmania. Am J Trop Med Hyg 1989; 41:318–30.PubMedGoogle Scholar
  78. 78.
    Bodley AL, McGarry MW, Shapiro TA. Drug cytotoxicity assay for African trypanosomes and Leishmania species. J Infect Dis 1995; 172:1157–9.PubMedGoogle Scholar
  79. 79.
    Jackson JE, Tally JD, Ellis W Y, et al. Quantitative in vitro drug potency and drug susceptibility evaluation of Leishmania ssp. from patients unresponsive to pentavalent antimony therapy. Am J Trop Med Hyg 1990; 43:464–80.Google Scholar
  80. 80.
    Bates PA, Robertson CD, Tetley L, Coombs GH. Axenic cultivation and characterization of Leishmania mexicana amastigote-like forms. Parasitology 1992; 105 (Pt 2):193–202.PubMedGoogle Scholar
  81. 81.
    Berman JD. Chemotherapy for leishmaniasis: biochemical mechanisms, clinical efficacy, and future strategies. Rev Infect Dis 1988; 10:560–86.PubMedGoogle Scholar
  82. 82.
    Chang KP, Nacy CA, Pearson RD. Intracellular parasitism of macrophages in leishmaniasis: in vitro systems and their applications. Methods Enzymol 1986; 132:603–26.PubMedGoogle Scholar
  83. 83.
    Neal RA, Croft SL. An in-vitro system for determining the activity of compounds against the intracellular amastigote form of Leishmania donovani. J Antimicrob Chemother 1984; 14:463–75.PubMedGoogle Scholar
  84. 84.
    Gaspar R, Opperdoes FR, Preat V, Roland M. Drug targeting with polyalkylcyanoacrylate nanoparticles: in vitro activity of primaquine-loaded nanoparticles against intracellular Leishmania donovani. Ann Trop Med Parasitol 1992; 86:41–9.PubMedGoogle Scholar
  85. 85.
    Abok K, Cadenas E, Brunk U. An experimental model system for leishmaniasis. Effects of porphyrin-compounds and menadione on Leishmania parasites engulfed by cultured macrophages. APMIS 1988; 96:543–51.PubMedGoogle Scholar
  86. 86.
    Mattock NM, Peters W. The experimental chemotherapy of leish-maniasis. I: Techniques for the study of drug action in tissue culture. Ann Trop Med Parasitol 1975; 69:349–57.PubMedGoogle Scholar
  87. 87.
    Di Giorgio C, Ridoux O, Delmas F, Azas N, Gasquet M, Timon-David P. Flow cytometric detection of Leishmania parasites in human monocyte-derived macrophages: application to antileishma-nial-drug testing. Antimicrob Agents Chemother 2000; 44:3074–8.Google Scholar
  88. 88.
    Ephros M, Bitnun A, Shaked P, Waldman E, Zilberstein D. Stage-specific activity of pentavalent antimony against Leishmania dono-vani axenic amastigotes. Antimicrob Agents Chemother 1999; 43:278–82.PubMedGoogle Scholar
  89. 89.
    Singh N, Singh RT, Sundar S. Novel mechanism of drug resistance in kala-azar field isolates. J Infect Dis 2003; 188:600–7.PubMedGoogle Scholar
  90. 90.
    Frezard F, Demicheli C, Ferreira CS, Costa MA. Glutathione-induced conversion of pentavalent antimony to trivalent antimony in meglumine antimoniate. Antimicrob Agents Chemother 2001; 45:913–6.PubMedGoogle Scholar
  91. 91.
    Shaked-Mishan P, Ulrich N, Ephros M, Zilberstein D. Novel intra-cellular SbV reducing activity correlates with antimony susceptibility in Leishmania donovani. J Biol Chem 2001; 276:3971–6.PubMedGoogle Scholar
  92. 92.
    Ouellette M, Legare D, Haimeur A, Grondin K, Roy G, Brochu C, Papadopoulou B. ABC transporters in Leishmania and their role in drug resistance. Drug Resist Updat 1998; 1:43–48.PubMedGoogle Scholar
  93. 93.
    Perez-Victoria JM, Di Pietro A, Barron D, Ravelo AG, Castanys S, Gamarro F. Multidrug resistance phenotype mediated by the P-glycoprotein-like transporter in Leishmania: a search for reversal agents. Curr Drug Targets 2002; 3:311–33.PubMedGoogle Scholar
  94. 94.
    Legare D, Richard D, Mukhopadhyay R, et al. The Leishmania ATP-binding cassette protein PGPA is an intracellular metal-thiol transporter ATPase. J Biol Chem 2001; 276:26301–7.PubMedGoogle Scholar
  95. 95.
    Dey S, Ouellette M, Lightbody J, Papadopoulou B, Rosen BP. An ATP-dependent As(III)-glutathione transport system in membrane vesicles of Leishmania tarentolae. Proc Natl Acad Sci U S A 1996; 93:2192–7.PubMedGoogle Scholar
  96. 96.
    Perez-Victoria JM, Perez-Victoria FJ, Parodi-Talice A, et al. Alkyl-lysophospholipid resistance in multidrug-resistant Leishmania tropica and chemosensitization by a novel P-glycoprotein-like transporter modulator. Antimicrob Agents Chemother 2001; 45:2468–74.PubMedGoogle Scholar
  97. 97.
    Perez-Victoria FJ, Castanys S, Gamarro F. Leishmania donovani resistance to miltefosine involves a defective inward translocation of the drug. Antimicrob Agents Chemother 2003; 47:2397–403.PubMedGoogle Scholar
  98. 98.
    Perez-Victoria FJ, Gamarro F, Ouellette M, Castanys S. Functional cloning of the miltefosine transporter. A novel P-type phospholi-pid translocase from Leishmania involved in drug resistance. J Biol Chem 2003; 278:49965–71.Google Scholar
  99. 99.
    Haimeur A, Brochu C, Genest P, Papadopoulou B, Ouellette M. Amplification of the ABC transporter gene PGPA and increased trypanothione levels in potassium antimonyl tartrate (SbIII) resistant Leishmania tarentolae. Mol Biochem Parasitol 2000; 108:131–5.PubMedGoogle Scholar
  100. 100.
    Legare D, Papadopoulou B, Roy G, et al. Efflux systems and increased trypanothione levels in arsenite-resistant Leishmania. Exp Parasitol 1997; 87:275–82.PubMedGoogle Scholar
  101. 101.
    Haimeur A, Guimond C, Pilote S, et al. Elevated levels of polyamines and trypanothione resulting from overexpression of the ornithine decarboxylase gene in arsenite-resistant Leishmania. Mol Microbiol 1999; 34:726–35.PubMedGoogle Scholar
  102. 102.
    Grondin K, Haimeur A, Mukhopadhyay R, Rosen BP, Ouellette M. Co-amplification of the gamma-glutamylcysteine synthetase gene gsh1 and of the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO J 1997; 16:3057–65.PubMedGoogle Scholar
  103. 103.
    Carter KC, Sundar S, Spickett C, Pereira OC, Mullen AB. The in vivo susceptibility of Leishmania donovani to sodium stibogluco-nate is drug specific and can be reversed by inhibiting glutathione biosynthesis. Antimicrob Agents Chemother 2003; 47:1529–35.PubMedGoogle Scholar
  104. 104.
    Zilberstein D, Ephros M. Clinical and laboratory aspects of leishmania chemotherapy in the ear of drug resistance. In: Seed J, ed. World Class Parasites, Vol. 4. London: Kluwer, 2002, pp 115–136.Google Scholar
  105. 105.
    Veeken H, Ritmeijer K, Seaman J, Davidson R. A randomized comparison of branded sodium stibogluconate and generic sodium stibogluconate for the treatment of visceral leishmaniasis under field conditions in Sudan. Trop Med Int Health 2000; 5:312–7.PubMedGoogle Scholar
  106. 106.
    Moore E, O'Flaherty D, Heuvelmans H, et al. Comparison of generic and proprietary sodium stibogluconate for the treatment of visceral leishmaniasis in Kenya. Bull World Health Organ 2001; 79:388–93.PubMedGoogle Scholar
  107. 107.
    Ritmeijer K, Veeken H, Melaku Y, et al. Ethiopian visceral leishmaniasis: generic and proprietary sodium stibogluconate are equivalent; HIV co-infected patients have a poor outcome. Trans R Soc Trop Med Hyg 2001; 95:668–72.PubMedGoogle Scholar
  108. 108.
    Mishra M, Biswas UK, Jha DN, Khan AB. Amphotericin versus pentamidine in antimony-unresponsive kala-azar. Lancet 1992; 340:1256–7.PubMedGoogle Scholar
  109. 109.
    Sundar S. Treatment of visceral leishmaniasis. Med Microbiol Immunol (Berl) 2001; 190:89–92.Google Scholar
  110. 110.
    Nacher M, Carme B, Sainte Marie D, et al. Influence of clinical presentation on the efficacy of a short course of pentamidine in the treatment of cutaneous leishmaniasis in French Guiana. Ann Trop Med Parasitol 2001; 95:331–6.PubMedGoogle Scholar
  111. 111.
    Soto J, Buffet P, Grogl M, Berman J. Successful treatment of Colombian cutaneous leishmaniasis with four injections of pen-tamidine. Am J Trop Med Hyg 1994; 50:107–11.PubMedGoogle Scholar
  112. 112.
    Correia D, Macedo VO, Carvalho EM, et al. Comparative study of meglumine antimoniate, pentamidine isethionate and amino-sidine sulfate in the treatment of primary skin lesions caused by Leishmania (Viannia) braziliensis. Rev Soc Bras Med Trop 1996; 29:447–53.PubMedGoogle Scholar
  113. 113.
    de Paula CD, Sampaio JH, Cardoso DR, Sampaio RN. A comparative study between the efficacy of pentamidine isothionate given in three doses for one week and N-methil-glucamine in a dose of 20 mg SbV/day for 20 days to treat cutaneous leishmania-sis. Rev Soc Bras Med Trop 2003; 36:365–71.PubMedGoogle Scholar
  114. 114.
    Amato V, Amato J, Nicodemo A, Uip D, Amato-Neto V, Duarte M. Treatment of mucocutaneous leishmaniasis with pentamidine isothionate. Ann Dermatol Venereol 1998; 125:492–5.PubMedGoogle Scholar
  115. 115.
    Di Giorgio C, Faraut-Gambarelli F, Imbert A, Minodier P, Gasquet M, Dumon H. Flow cytometric assessment of ampho-tericin B susceptibility in Leishmania infantum isolates from patients with visceral leishmaniasis. J Antimicrob Chemother 1999; 44:71–6.Google Scholar
  116. 116.
    Durand R, Paul M, Pratlong F, et al. Leishmania infantum: lack of parasite resistance to amphotericin B in a clinically resistant visceral leishmaniasis. Antimicrob Agents Chemother 1998; 42:2141–3.PubMedGoogle Scholar
  117. 117.
    Sundar S, Jha TK, Thakur CP, Mishra M, Singh VR, Buffels R. Low-dose liposomal amphotericin B in refractory Indian visceral leishmaniasis: a multicenter study. Am J Trop Med Hyg 2002; 66:143–6.PubMedGoogle Scholar
  118. 118.
    Thakur CP. A single high dose treatment of kala-azar with Ambisome (amphotericin B lipid complex): a pilot study. Int J Antimicrob Agents 2001; 17:67–70.PubMedGoogle Scholar
  119. 119.
    Chunge CN, Owate J, Pamba HO, Donno L. Treatment of visceral leishmaniasis in Kenya by aminosidine alone or combined with sodium stibogluconate. Trans R Soc Trop Med Hyg 1990; 84:221–5.PubMedGoogle Scholar
  120. 120.
    Jha TK, Olliaro P, Thakur CP, et al. Randomised controlled trial of aminosidine (paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India. BMJ 1998; 316:1200–5.PubMedGoogle Scholar
  121. 121.
    Thakur CP, Kanyok TP, Pandey AK, et al. A prospective randomized, comparative, open-label trial of the safety and efficacy of paromomycin (aminosidine) plus sodium stibogluconate versus sodium stibogluconate alone for the treatment of visceral leish-maniasis. Trans R Soc Trop Med Hyg 2000; 94:429–31.PubMedGoogle Scholar
  122. 122.
    el-On J, Halevy S, Grunwald MH, Weinrauch L. Topical treatment of Old World cutaneous leishmaniasis caused by Leishmania major: a double-blind control study. J Am Acad Dermatol 1992; 27:227–31.PubMedGoogle Scholar
  123. 123.
    Krause G, Kroeger A. Topical treatment of American cutaneous leishmaniasis with paramomycin and methylbenzethonium chloride: a clinical study under field conditions in Ecuador. Trans R Soc Trop Med Hyg 1994; 88:92–4.PubMedGoogle Scholar
  124. 124.
    Bhattacharya SK, Jha TK, Sundar S, et al. Efficacy and tolerabil-ity of miltefosine for childhood visceral leishmaniasis in India. Clin Infect Dis 2004; 38:217–21.PubMedGoogle Scholar
  125. 125.
    Soto J, Toledo J, Gutierrez P, et al. Treatment of American cutaneous leishmaniasis with miltefosine, an oral agent. Clin Infect Dis 2001; 33:E57–61.PubMedGoogle Scholar
  126. 126.
    Sherwood JA, Gachihi GS, Muigai RK, et al. Phase 2 efficacy trial of an oral 8-aminoquinoline (WR6026) for treatment of visceral leishmaniasis. Clin Infect Dis 1994; 19:1034–9.PubMedGoogle Scholar
  127. 127.
    Dietze R, Carvalho SF, Valli LC, et al. Phase 2 trial of WR6026, an orally administered 8-aminoquinoline, in the treatment of visceral leishmaniasis caused by Leishmania chagasi. Am J Trop Med Hyg 2001; 65:685–9.PubMedGoogle Scholar
  128. 128.
    Martinez S, Marr JJ. Allopurinol in the treatment of American cutaneous leishmaniasis. N Engl J Med 1992; 326:741–4.PubMedGoogle Scholar
  129. 129.
    Momeni AZ, Aminjavaheri M. Successful treatment of non-healing cases of cutaneous leishmaniasis, using a combination of meglu-mine antimoniate plus allopurinol. Eur J Dermatol 2003; 13:40–3.PubMedGoogle Scholar
  130. 130.
    Chunge CN, Gachihi G, Muigai R, et al. Visceral leishmaniasis unresponsive to antimonial drugs. III. Successful treatment using a combination of sodium stibogluconate plus allopurinol. Trans R Soc Trop Med Hyg 1985; 79:715–8.PubMedGoogle Scholar
  131. 131.
    Croft SL, Yardley V. Chemotherapy of leishmaniasis. Curr Pharm Des 2002; 8:319–42.PubMedGoogle Scholar
  132. 132.
    Alrajhi AA, Ibrahim EA, De Vo l EB, Khairat M, Faris RM, Maguire JH. Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major. N Engl J Med 2002; 346:891–5.PubMedGoogle Scholar
  133. 133.
    Arevalo I, Ward B, Miller R, et al. Successful treatment of drug-resistant cutaneous leishmaniasis in humans by use of imiqui-mod, an immunomodulator. Clin Infect Dis 2001; 33:1847–51.PubMedGoogle Scholar
  134. 134.
    Reyburn H, Ashford R, Mohsen M, Hewitt S, Rowland M. A randomized controlled trial of insecticide-treated bednets and chaddars or top sheets, and residual spraying of interior rooms for the prevention of cutaneous leishmaniasis in Kabul, Afghanistan. Trans R Soc Trop Med Hyg 2000; 94:361–6.PubMedGoogle Scholar
  135. 135.
    Elnaiem DA, Elnahas AM, Aboud MA. Protective efficacy of lambdacyhalothrin-impregnated bednets against Phlebotomus orientalis, the vector of visceral leishmaniasis in Sudan. Med Vet Entomol 1999; 13:310–4.PubMedGoogle Scholar
  136. 136.
    Reithinger R, Coleman PG, Alexander B, Vieira EP, Assis G, Davies CR. Are insecticide-impregnated dog collars a feasible alternative to dog culling as a strategy for controlling canine visceral leishmaniasis in Brazil? Int J Parasitol 2004; 34:55–62.PubMedGoogle Scholar
  137. 137.
    Maroli M, Mizzon V, Siragusa C, D'Oorazi A, Gradoni L. Evidence for an impact on the incidence of canine leishmania-sis by the mass use of deltamethrin-impregnated dog collars in southern Italy. Med Vet Entomol 2001; 15:358–63.PubMedGoogle Scholar
  138. 138.
    Halbig P, Hodjati MH, Mazloumi-Gavgani AS, Mohite H, Davies CR. Further evidence that deltamethrin-impregnated collars protect domestic dogs from sandfly bites. Med Vet Entomol 2000; 14:223–6.PubMedGoogle Scholar
  139. 139.
    SharifiI, FeKri AR, Aflatonian MR, et al. Randomised vaccine trial of single dose of killed Leishmania major plus BCG against anthroponotic cutaneous leishmaniasis in Bam, Iran. Lancet 1998; 351:1540–3.PubMedGoogle Scholar
  140. 140.
    Khalil EA, El Hassan AM, Zijlstra EE, et al. Autoclaved Leishmania major vaccine for prevention of visceral leishmania-sis: a randomised, double-blind, BCG-controlled trial in Sudan. Lancet 2000; 356:1565–9.PubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Shyam Sundar
    • 1
  • Madhukar Rai
    • 1
  1. 1.Department of Medicine, Institute of Medical SciencesBanaras Hindu UniversityVaranasiIndia

Personalised recommendations