Drug Resistance in Visceral Leishmaniasis

Visceral leishmaniasis remains a public health problem worldwide. This illness was included by the World Health Organization in the list of neglected tropical diseases targeted for elimination by 2015. The widespread emergence of resistance to pentavalent antimonials in India where half cases occur globally and the unavailability of a vaccine in clinical use constitute major obstacles in achieving this goal. The last decade new antileishmanials became available, including the oral agent miltefosine. However, in poor endemic countries their wide use was curtailed because of the high costs, and also due to concerns of toxicity and emergence of resistance. Various mechanisms of antileishmanial resistance were identified recently in field isolates. Their elucidation will boost the design of new drugs and the molecular surveillance of resistance. Combination regimens should be evaluated in large trials. Overall, the development of antileishmanials has been generally slow; new drugs are needed. In order to control visceral leishmaniasis worldwide, treatment advances should become affordable in the poorest countries, where they are needed most.

[1]  M. Ouellette,et al.  Resistance of Leishmania donovani to Sodium Stibogluconate Is Related to the Expression of Host and Parasite γ-Glutamylcysteine Synthetase , 2006, Antimicrobial Agents and Chemotherapy.

[2]  V. Yardley,et al.  Epidemiological dynamics of antimonial resistance in Leishmania donovani: genotyping reveals a polyclonal population structure among naturally-resistant clinical isolates from Nepal. , 2007, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[3]  R. Jochim,et al.  Leishmania commandeers the host inflammatory response through neutrophils. , 2009, Trends in parasitology.

[4]  Maria Paola Costi,et al.  Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux , 2006, Antimicrobial Agents and Chemotherapy.

[5]  D. Sacks,et al.  Interleukin-10 and the pathogenesis of human visceral leishmaniasis. , 2007, Trends in immunology.

[6]  S. Sundar,et al.  Clinicoepidemiological study of drug resistance in Indian kala - azar , 1994, BMJ.

[7]  S. K. Choudhuri,et al.  Inhibition of ABC Transporters Abolishes Antimony Resistance in Leishmania Infection , 2007, Antimicrobial Agents and Chemotherapy.

[8]  G. Van der Auwera,et al.  Epidemiology and Clinical Features of Patients with Visceral Leishmaniasis Treated by an MSF Clinic in Bakool Region, Somalia, 2004–2006 , 2007, PLoS neglected tropical diseases.

[9]  S. Sundar,et al.  Immunochemotherapy for a systemic intracellular infection: accelerated response using interferon-gamma in visceral leishmaniasis. , 1995, The Journal of infectious diseases.

[10]  N. Malla,et al.  Leishmania donovani: effect of verapamil on in vitro susceptibility of promastigote and amastigote stages of Indian clinical isolates to sodium stibogluconate. , 2006, Experimental parasitology.

[11]  R. Madhubala,et al.  Paromomycin: uptake and resistance in Leishmania donovani. , 2009, Molecular and biochemical parasitology.

[12]  U. Biswas,et al.  Amphotericin versus sodium stibogluconate in first-line treatment of Indian kala-azar , 1994, The Lancet.

[13]  S. Sundar Drug resistance in Indian visceral leishmaniasis , 2001, Tropical medicine & international health : TM & IH.

[14]  L. Campino,et al.  Leishmania infantum: mixed T-helper-1/T-helper-2 immune response in experimentally infected BALB/c mice. , 2007, Experimental parasitology.

[15]  M. Ouellette,et al.  Gene Amplification in Leishmania tarentolae Selected for Resistance to Sodium Stibogluconate , 1998, Antimicrobial Agents and Chemotherapy.

[16]  R. López-Vélez,et al.  The Relationship between Leishmaniasis and AIDS: the Second 10 Years , 2008, Clinical Microbiology Reviews.

[17]  T. Theander,et al.  Leishmania donovani: an in vitro study of antimony-resistant amphotericin B-sensitive isolates. , 2006, Experimental parasitology.

[18]  L. Gradoni,et al.  Drug regimens for visceral leishmaniasis in Mediterranean countries , 2008, Tropical medicine & international health : TM & IH.

[19]  A. Meliço-Silvestre,et al.  Miltefosine for visceral leishmaniasis relapse treatment and secondary prophylaxis in HIV-infected patients , 2008, Scandinavian journal of infectious diseases.

[20]  R. Davidson,et al.  A comparison of miltefosine and sodium stibogluconate for treatment of visceral leishmaniasis in an Ethiopian population with high prevalence of HIV infection. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[21]  Dhiraj Kumar,et al.  Visceral leishmaniasis, or kala azar (KA): high incidence of refractoriness to antimony is contributed by anthroponotic transmission via post-KA dermal leishmaniasis. , 2006, The Journal of infectious diseases.

[22]  S. Sundar,et al.  Refractoriness to the treatment of sodium stibogluconate in Indian kala-azar field isolates persist in in vitro and in vivo experimental models , 2005, Parasitology Research.

[23]  M. Ouellette,et al.  Role of ABC transporter MRPA, gamma-glutamylcysteine synthetase and ornithine decarboxylase in natural antimony-resistant isolates of Leishmania donovani. , 2006, The Journal of antimicrobial chemotherapy.

[24]  M. Chowdhury,et al.  Ketoconazole in the treatment of visceral leishmaniasis (kala-azar) , 1996, Tropical doctor.

[25]  C. P. Thakur,et al.  Comparison of three treatment regimens with liposomal amphotericin B (AmBisome) for visceral leishmaniasis in India: a randomized dose-finding study. , 1996, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[26]  R. Reinhardt,et al.  Identification of a Leishmania infantum gene mediating resistance to miltefosine and SbIII. , 2008, International journal for parasitology.

[27]  S. Sundar,et al.  Antileishmanial activity of nano-amphotericin B deoxycholate. , 2008, Journal of Antimicrobial Chemotherapy.

[28]  S. Sundar,et al.  Low-dose liposomal amphotericin B in refractory Indian visceral leishmaniasis: a multicenter study. , 2002, The American journal of tropical medicine and hygiene.

[29]  V. Yardley,et al.  Gene Expression Analysis of the Mechanism of Natural Sb(V) Resistance in Leishmania donovani Isolates from Nepal , 2005, Antimicrobial Agents and Chemotherapy.

[30]  Shyam Sundar,et al.  Identification of genetic markers in sodium antimony gluconate (SAG) sensitive and resistant Indian clinical isolates of Leishmania donovani through amplified fragment length polymorphism (AFLP). , 2009, Acta tropica.

[31]  L. Chow,et al.  Flavonoid Dimers as Bivalent Modulators for Pentamidine and Sodium Stiboglucanate Resistance in Leishmania , 2006, Antimicrobial Agents and Chemotherapy.

[32]  B. Sen Gupta History of kala-azar in India. 1947. , 2006, The Indian journal of medical research.

[33]  F. Tacchini-Cottier,et al.  Neutrophils Contribute to Development of a Protective Immune Response during Onset of Infection with Leishmania donovani , 2007, Infection and Immunity.

[34]  R. Coffman,et al.  Interleukin-10 (IL-10) in Experimental Visceral Leishmaniasis and IL-10 Receptor Blockade as Immunotherapy , 2002, Infection and Immunity.

[35]  S. Croft,et al.  Characterisation of Leishmania donovani promastigotes resistant to hexadecylphosphocholine (miltefosine). , 2003, International journal of antimicrobial agents.

[36]  L. Pardo,et al.  Dihydro-beta-agarofuran sesquiterpenes: a new class of reversal agents of the multidrug resistance phenotype mediated by P-glycoprotein in the protozoan parasite Leishmania. , 2005, Current pharmaceutical design.

[37]  P. Loiseau,et al.  Alteration of Fatty Acid and Sterol Metabolism in Miltefosine-Resistant Leishmania donovani Promastigotes and Consequences for Drug-Membrane Interactions , 2005, Antimicrobial Agents and Chemotherapy.

[38]  S. Croft,et al.  In Vitro and In Vivo Interactions between Miltefosine and Other Antileishmanial Drugs , 2006, Antimicrobial Agents and Chemotherapy.

[39]  J. Torrado,et al.  Amphotericin B formulations and drug targeting. , 2008, Journal of pharmaceutical sciences.

[40]  S. Sundar,et al.  Amphotericin B treatment for Indian visceral leishmaniasis: response to 15 daily versus alternate-day infusions. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[41]  R. Piarroux,et al.  Pediatric visceral leishmaniasis in southern France. , 1998, The Pediatric infectious disease journal.

[42]  Shyam Sundar,et al.  Injectable paromomycin for Visceral leishmaniasis in India. , 2007, The New England journal of medicine.

[43]  P. Olliaro,et al.  Randomised controlled trial of aminosidine (paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India. , 1998, BMJ.

[44]  Suman Gupta,et al.  Efficacy of picroliv in combination with miltefosine, an orally effective antileishmanial drug against experimental visceral leishmaniasis. , 2005, Acta tropica.

[45]  O. Kaneko,et al.  Relapse of visceral leishmaniasis after miltefosine treatment in a Nepalese patient. , 2009, The American journal of tropical medicine and hygiene.

[46]  Syamal Roy,et al.  Sub-optimal dose of Sodium Antimony Gluconate (SAG)-diperoxovanadate combination clears organ parasites from BALB/c mice infected with antimony resistant Leishmania donovani by expanding antileishmanial T-cell repertoire and increasing IFN-gamma to IL-10 ratio. , 2009, Experimental parasitology.

[47]  C. P. Thakur,et al.  Comparison of treatment regimens of kala-azar based on culture & sensitivity of amastigotes to sodium antimony gluconate. , 2008, The Indian journal of medical research.

[48]  A. Banerjee,et al.  Immune responses in kala-azar. , 2006, The Indian journal of medical research.

[49]  A. Satoskar,et al.  Endogenous IL‐4 is necessary for effective drug therapy against visceral leishmaniasis , 2000, European journal of immunology.

[50]  P. Leprohon,et al.  Parasite susceptibility to amphotericin B in failures of treatment for visceral leishmaniasis in patients coinfected with HIV type 1 and Leishmania infantum. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[51]  S. Sundar,et al.  Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. , 2007, The Journal of infectious diseases.

[52]  Ravinder,et al.  Characterization of natural antimony resistance in Leishmania donovani isolates. , 2007, The American journal of tropical medicine and hygiene.

[53]  C. Bern,et al.  The epidemiology of visceral leishmaniasis in Bangladesh: prospects for improved control. , 2006, The Indian journal of medical research.

[54]  C. P. Thakur,et al.  Rationalisation of regimens of treatment of kala-azar with sodium stibogluconate in India: a randomised study , 1988, British medical journal.

[55]  J. M. Pérez-Victoria,et al.  Characterization of an ABCG-Like Transporter from the Protozoan Parasite Leishmania with a Role in Drug Resistance and Transbilayer Lipid Movement , 2008, Antimicrobial Agents and Chemotherapy.

[56]  S. Sundar,et al.  Functionality of drug efflux pumps in antimonial resistant Leishmania donovani field isolates. , 2009, Indian journal of biochemistry & biophysics.

[57]  H. Maltezou,et al.  Visceral leishmaniasis during childhood in southern Greece. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[58]  W. M. Elamin,et al.  Antimony-resistant Leishmania donovaniin eastern Sudan: incidence and in vitro correlation. , 2003, Eastern Mediterranean health journal = La revue de sante de la Mediterranee orientale = al-Majallah al-sihhiyah li-sharq al-mutawassit.

[59]  S. Vyas,et al.  Antileishmanial efficacy of amphotericin B bearing emulsomes against experimental visceral leishmaniasis , 2007, Journal of drug targeting.

[60]  C. P. Thakur,et al.  Comparison of regimens of treatment with sodium stibogluconate in kala-azar. , 1984, British medical journal.

[61]  S. Sundar,et al.  Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the Indian epidemic. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[62]  R. Davidson,et al.  Treatment of kala-azar in southern Sudan using a 17-day regimen of sodium stibogluconate combined with paromomycin: a retrospective comparison with 30-day sodium stibogluconate monotherapy. , 2007, The American journal of tropical medicine and hygiene.

[63]  H. Maltezou Visceral leishmaniasis: advances in treatment. , 2008, Recent patents on anti-infective drug discovery.

[64]  Neeloo Singh Drug resistance mechanisms in clinical isolates of Leishmania donovani. , 2006, The Indian journal of medical research.

[65]  S. Croft,et al.  Inactivation of the miltefosine transporter, LdMT, causes miltefosine resistance that is conferred to the amastigote stage of Leishmania donovani and persists in vivo. , 2007, International journal of antimicrobial agents.

[66]  A. Fairlamb,et al.  Roles of Trypanothione S-Transferase and Tryparedoxin Peroxidase in Resistance to Antimonials , 2008, Antimicrobial Agents and Chemotherapy.

[67]  M. Dea-Ayuela,et al.  In vitro effect of new formulations of amphotericin B on amastigote and promastigote forms of Leishmania infantum. , 2007, International journal of antimicrobial agents.

[68]  M. Rai,et al.  New treatment approach in Indian visceral leishmaniasis: single-dose liposomal amphotericin B followed by short-course oral miltefosine. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[69]  S. K. Dana,et al.  Hybrid Cell Vaccination Resolves Leishmania donovani Infection by Eliciting a Strong CD8+ Cytotoxic T-Lymphocyte Response with Concomitant Suppression of Interleukin-10 (IL-10) but Not IL-4 or IL-13 , 2007, Infection and Immunity.

[70]  B. Saha,et al.  Miltefosine Promotes IFN-γ-Dominated Anti-Leishmanial Immune Response1 , 2009, The Journal of Immunology.

[71]  Sarman Singh,et al.  Ketoconazole in treatment of visceral leishmaniasis , 1990, The Lancet.

[72]  P. Kumar,et al.  Possibility of membrane modification as a mechanism of antimony resistance in Leishmania donovani. , 2007, Parasitology international.

[73]  S. Croft,et al.  Mechanisms of experimental resistance of Leishmania to miltefosine: Implications for clinical use. , 2006, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.