1921
Volume 101, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Abstract.

In India, visceral leishmaniasis (VL) caused by has been successfully treated with miltefosine with a cure rate of > 90%. To assess the efficacy and safety of oral miltefosine against Brazilian VL, which is caused by , a phase II, open-label, dose-escalation study of oral miltefosine was conducted in children (aged 2–12 years) and adolescent-adults (aged 13–60 years). Definitive cure was assessed at a 6-month follow-up visit. The cure rate was only 42% (6 of 14 patients) with a recommended treatment of 28 days and 68% (19 of 28 patients) with an extended treatment of 42 days. The in vitro miltefosine susceptibility profile of intracellular amastigote stages of the pretreatment isolates, from cured and relapsed patients, showed a positive correlation with the clinical outcome. The IC mean (SEM) of eventual cures was 5.1 (0.4) µM, whereas that of eventual failures was 12.8 (1.9) µM ( = 0.0002). An IC above 8.0 µM predicts failure with 82% sensitivity and 100% specificity. The finding of amastigotes resistant to miltefosine in isolates from patients who eventually failed treatment strongly suggests natural resistance to this drug, as miltefosine had never been used in Brazil before this trial was carried out.

[open-access] This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Loading

Article metrics loading...

The graphs shown below represent data from March 2017
/content/journals/10.4269/ajtmh.18-0949
2019-08-19
2019-10-18
Loading full text...

Full text loading...

/deliver/fulltext/14761645/101/4/tpmd180949.html?itemId=/content/journals/10.4269/ajtmh.18-0949&mimeType=html&fmt=ahah

References

  1. Werneck GL, Batista MS, Gomes JR, Costa DL, Costa CH, , 2003. Prognostic factors for death from visceral leishmaniasis in Teresina, Brazil. Infection 31: 174177. [Google Scholar]
  2. Ministério da Saúde ., 2011. Leishmaniose Visceral: Recomendações Clínicas para Redução da Letalidade. Brasília-DF, Brasil: Ministério da Saúde, 78 [Google Scholar]
  3. Jha TK, Sundar S, Thakur CP, Bachmann P, Karbwang J, Fischer C, Voss A, Berman J, , 1999. Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. N Engl J Med 341: 17951800. [Google Scholar]
  4. Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, Junge K, Bryceson A, Berman J, , 2002. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 347: 17391746. [Google Scholar]
  5. Sundar S, Singh A, Rai M, Prajapati VK, Singh AK, Ostyn B, Boelaert M, Dujardin JC, Chakravarty J, , 2012. Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after a decade of use. Clin Infect Dis 55: 543550. [Google Scholar]
  6. Rijal S, 2013. Increasing failure of miltefosine in the treatment of Kala-azar in Nepal and the potential role of parasite drug resistance, reinfection, or noncompliance. Clin Infect Dis 56: 15301538. [Google Scholar]
  7. Rahman M, 2011. Phase IV trial of miltefosine in adults and children for treatment of visceral leishmaniasis (kala-azar) in Bangladesh. Am J Trop Med Hyg 85: 6669. [Google Scholar]
  8. Segatto M, 2012. Genetic diversity of Leishmania infantum field populations from Brazil. Mem Inst Oswaldo Cruz 107: 3947. [Google Scholar]
  9. Carnielli JBT, 2018. A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis. EBioMedicine 36: 8391. [Google Scholar]
  10. Dorlo TPC, 2017. Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study. J Antimicrob Chemother 72: 31313140. [Google Scholar]
  11. Dorlo TP, 2014. Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure. J Infect Dis 210: 146153. [Google Scholar]
  12. Mbui J, 2019. Pharmacokinetics, safety and efficacy of an allometric miltefosine regimen for the treatment of visceral leishmaniasis in Eastern African children: an open-label, phase-II clinical trial. Clin Infect Dis 68: 15301538. [Google Scholar]
  13. Bhattacharya SK, 2007. Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis 196: 591598. [Google Scholar]
  14. Ostyn B, Hasker E, Dorlo TP, Rijal S, Sundar S, Dujardin JC, Boelaert M, , 2014. Failure of miltefosine treatment for visceral leishmaniasis in children and men in South-East Asia. PLoS One 9: e100220. [Google Scholar]
  15. Dorlo TP, Huitema AD, Beijnen JH, de Vries PJ, , 2012. Optimal dosing of miltefosine in children and adults with visceral leishmaniasis. Antimicrob Agents Chemother 56: 38643872. [Google Scholar]
  16. Prajapati VK, Sharma S, Rai M, Ostyn B, Salotra P, Vanaerschot M, Dujardin JC, Sundar S, , 2013. In vitro susceptibility of Leishmania donovani to miltefosine in Indian visceral leishmaniasis. Am J Trop Med Hyg 89: 750754. [Google Scholar]
  17. Bhandari V, Kulshrestha A, Deep DK, Stark O, Prajapati VK, Ramesh V, Sundar S, Schonian G, Dujardin JC, Salotra P, , 2012. Drug susceptibility in Leishmania isolates following miltefosine treatment in cases of visceral leishmaniasis and post kala-azar dermal leishmaniasis. PLoS Negl Trop Dis 6: e1657. [Google Scholar]
  18. Deep DK, Singh R, Bhandari V, Verma A, Sharma V, Wajid S, Sundar S, Ramesh V, Dujardin JC, Salotra P, , 2017. Increased miltefosine tolerance in clinical isolates of Leishmania donovani is associated with reduced drug accumulation, increased infectivity and resistance to oxidative stress. PLoS Negl Trop Dis 11: e0005641. [Google Scholar]
http://instance.metastore.ingenta.com/content/journals/10.4269/ajtmh.18-0949
Loading
/content/journals/10.4269/ajtmh.18-0949
Loading

Data & Media loading...

  • Received : 28 Nov 2018
  • Accepted : 03 Jun 2019
  • Published online : 19 Aug 2019

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error