|Year : 2012 | Volume
| Issue : 2 | Page : 227-229
Relapse of kala-azar after use of multiple drugs: A case report and brief review of literature
K Pandey1, SB Pun2, BD Pandey2
1 Everest International Clinic and Research Center, Kathmandu, Nepal
2 Everest International Clinic and Research Center; Clinical Research Unit, Department of Medicine Sukraraj Tropical and Infectious Disease Hospital, Kathmandu, Nepal
|Date of Submission||08-Sep-2011|
|Date of Acceptance||19-Dec-2011|
|Date of Web Publication||28-May-2012|
Everest International Clinic and Research Center, Kathmandu
Source of Support: None, Conflict of Interest: None
We present a case of kala-azar infection that recurred in a patient after completion of the standard treatment course of miltefosine, amphotericin B-deoxycholate (short course), and amphotericin B lipid formulations. The patient was cured after continuous amphotericin B-deoxycholate administration for 4 weeks. This is a unique case of relapse following the use of three important drugs. Although amphotericin B-deoxycholate is a second line drug in Nepal, it has shown a satisfactory clinical response with continuous treatment for 4 weeks. Therefore, an extended course of amphotericin B-deoxycholate may be beneficial in patients with resistance to the standard short course and other anti-leishmania drugs.
Keywords: Amphotericin B, miltefosine, kala-azar
|How to cite this article:|
Pandey K, Pun S B, Pandey B D. Relapse of kala-azar after use of multiple drugs: A case report and brief review of literature. Indian J Med Microbiol 2012;30:227-9
|How to cite this URL:|
Pandey K, Pun S B, Pandey B D. Relapse of kala-azar after use of multiple drugs: A case report and brief review of literature. Indian J Med Microbiol [serial online] 2012 [cited 2020 Jan 22];30:227-9. Available from: http://www.ijmm.org/text.asp?2012/30/2/227/96703
| ~ Introduction|| |
Kala-azar (KA), also known as visceral leishmaniasis (VL), is an intracellular protozoan infection caused by Leishmania donovani that targets macrophages in the liver, spleen, and bone marrow. It is transmitted by the bite of an infected female sandfly, Phlebotomous argentipes. There are 500,000 new cases of KA every year worldwide, the majority of which occur in Bihar of India, followed by the border regions of Nepal and Bangladesh.  The actual incidence of KA in the Indian subcontinent is considered to be eight to ten times higher than the reported case numbers.  In Nepal, KA is mainly found in the Southern plains. Approximately 6.5 million people in Nepal are estimated to be at risk for this disease. A total of 31,988 cases of KA with 601 deaths were reported from 1980 to 2009, and the case fatality rate varied from 0.23 to 13.16.  Southeast Asian countries have committed to collaborate in an effort to eliminate KA from this region by 2015.  To achieve this goal, substantial progress is needed to increase the availability of existing rapid diagnosis and effective therapies.
Drugs currently available for the treatment of KA include miltefosine, amphotericin B- deoxycholate, liposomal amphotericin B, other lipid formulations, and paromomycin. Miltefosine is the first-line drug, and amphotericin B-deoxycholate is used as a second-line drug for treatment of KA under the National Drug Policy of Nepal. Until recently, there were no reported cases of KA relapse with the amphotericin B lipid formulations. In this report, we present the case of a patient who did not respond to treatment with miltefosine, amphotericin B-deoxycholate (short course), and amphotericin B lipid formulations, but recovered completely after 4 weeks of continuous treatment with amphotericin B-deoxycholate.
| ~ Case Report|| |
The patient was a 40-year-old male from the rural area Maganatha Dhorannan VDC ward-2 of the Mahottari district of Nepal. He developed intermittent fever, headache, abdominal pain, and chills and rigors. Initially, he visited different government hospitals and private clinics in the Mahottari district and despite receiving antibiotics, his fever did not subside. In January 2010, the patient visited hospital for proper diagnosis and treatment. On examination, he was conscious and hydrated, weighing 70 kg, with a body temperature of 37°C. He was found to have splenomegaly extending 5 cm below the left costal margin. The patient was suspected of having KA based on clinical symptoms. He was admitted to the hospital and rk39 test (InSure; InBios International, Seattle, WA, USA) showed a positive result. Diagnosis of KA was confirmed by the presence of Leishman donovan bodies (LD bodies) in bone marrow aspirates [Figure 1]. Kidney and liver function tests were normal and other laboratory parameters were within normal limits, except haemoglobin, which was decreased to 9 g/dl. Records indicated that he was previously treated for KA with miltefosine and amphotericin B-deoxycholate. On account of his treatment history, he was given amphotericin B lipid formulations at a dose of 5 mg/kg for a period of 4 days. Following treatment, the patient's fever subsided and his spleen size decreased to 2 cm below the left costal margin. He was discharged from hospital in good health indicated by improved appetite and no fever.
|Figure 1: Image of amastigotes form of Leishmania donovani in Giemsa's solution-stained bone marrow slide. Bone marrow aspirates were smeared on glass slides, fi xed with methanol and stained with Giemsa solution. It was observed under a light microscope (Magnifi cation, ×1,000) to detect any amastigote form (Oval in shape with nucleus in the centre) of Leishmania donovani|
Click here to view
After three months, the patient returned to hospital with clinical symptoms consistent with KA. On clinical examination, splenomegaly had increased to 7 cm below the left costal margin, and laboratory parameters showed a haemoglobin level of 9.2 g/dl, and a leukocyte count of 4800/mm 3 with 70% neutrophils and 25% lymphocytes. Total serum protein, albumin, and globulins were normal. Bone marrow aspirates were positive for LD bodies. On account of his previous treatment with miltefosine and amphotericin B lipid formulations, the patient was started on a course of amphotericin B-deoxycholate. He was treated with 0.5 mg/kg of amphotericin B-deoxycholate on the first day, and the dose was increased to 1 mg/kg for the next 27 days. Two units of whole blood transfusion were given during the course of treatment. Renal and hepatic functions were monitored weekly and the test results remained normal during the treatment period. The patient was encouraged to drink adequate fluids during the course of treatment. The patient improved clinically and his spleen size decreased to 2 cm (below the left costal margin). Bone marrow aspirates were negative for LD body at the end of the treatment period. The patient was discharged from the hospital in good condition, and remained in good health for a follow up period of over one year.
| ~ Discussion|| |
Sodium stibogluconate (SSG) was recommended as a first-line therapy for KA from the 1970s until 2003; however, it has shown increasing failure rates, particularly in the Indian subcontinent. A report from Bihar has shown failure rates over 60%  and reports indicate that the failure rate in Nepal varies from 10% to 30%.  Failure of SSG led to the rediscovery of amphotericin B-deoxycholate as a useful treatment in Nepal and India.  Currently, miltefosine is used as a first-line therapy and amphotericin B-Deoxycholate as a second-line therapy. Liposomal amphotericin B and injectable paromomycin are not yet available for treatment of KA in Nepal,  leaving only a few drug choices for the treatment of KA.
The patient presented in this study showed recurrent KA symptoms. He was treated with miltefosine and amphotericin B-deoxycholate, then after relapse was switched to treatment with the new drug amphotericin B lipid formulations, which has fewer side effects than amphotericin B-deoxycholate. There has previously been one reported case of KA relapse with miltefosine in Nepal which was reported by our research group.  Based on our knowledge, there were no reported cases of relapse with amphotericin B lipid formulations in Nepal. A clinical trial on the use of amphotericin B for the treatment of KA was performed to compare the use of conventional versus lipid formulations in Indian patients.  The result showed that liposomal amphotericin B was more effective than the amphotericin B lipid complex and amphotericin B-deoxycholate. Liposomal amphotericin B is very effective but remains expensive, and is not available for treatment of KA in Nepal. For this reason, we treated the patient with amphotericin B lipid formulations after relapse with miltefosine and amphotericin B-deoxycholate short course. After 3 months, the patient again showed the same clinical symptoms and was diagnosed with KA based on his clinical and laboratory parameters. This time, the patient was treated with amphotericin B-deoxycholate continuously for 4 weeks. The cause of relapse in this patient remains unclear, as it was not possible to perform molecular work on this parasite. However, based on our review of the literature, we speculate that relapse could have been due to the Leishmania strain, incomplete treatment, and/or visceral parasite burden. In Nepal, the mode of transmission of KA is anthroponotic; humans with KA or post-KA dermal leishmaniasis serve as the major reservoir. Incomplete or irregular treatment leads to drug resistance, and potential relapse of infection. 
Despite the high efficacy of newer drugs, namely miltefosine, paromomycin and liposomal amphotericin B, there is always the danger of resistance developing over time, particularly if the dose used is too low or adherence is suboptimal. The Ministers of Health of Bangladesh, India, and Nepal signed a memorandum of understanding in Geneva in 2005 for joint efforts to eliminate KA from the Indian subcontinent by the year 2015.  The goal is to reduce the annual incidence of KA in endemic regions to less than one person in 10,000, at the district level or sub-district level by 2015.  An increasing trend of KA relapse challenges the aim of the KA elimination program. This report is important because it describes the first reported case of KA with relapse to miltefosine and amphotericin B lipid formulations, under the recommended scheme of treatment. Although amphotericin B-deoxycholate is a second line drug, it produced a good clinical and parasitological response when administered continuously for four weeks, and the patient remained healthy for a follow-up period of over one year. To minimize the risk of drug failure and ensure the long life of drugs, amphotericin B-deoxycholate with longer treatment can be used, but careful monitoring is required during the treatment.
| ~ Acknowledgment|| |
We would like to thank the Director and all staff of STIDH for participating in the treatment, and Mr. Kiran Pandey at Everest International Clinic and Research Center, Kathmandu, Nepal for his support.
| ~ References|| |
|1.||World Health Organization. Leishmaniasis Disease Burden. Available from: http://www.who.int/leishmaniasis [Last accessed on 2011 Aug 24]. |
|2.||Sundar S, Mondal D, Rijal S, Bhattacharya S, Ghalib H, Kroeger A, et al. Implementation research to support the initiative on the elimination of kala-azar from Bangladesh, India and Nepal-the challenges for diagnosis and treatment. Trop Med Int Health 2008;13:2-5. |
|3.||Report of the Internal Assessment of Malaria Control and Kala-azar Elimination Activities. Government of Nepal, Ministry of Health and Population, Department of Health Services, Epidemiology and Disease Control Division, Teku, Kathmandu, Nepal. 2010 |
|4.||WHO/TDR. Press release: Elimination of kala-azar from endemic countries in the south-east Asia region. Health ministers' sign memorandum of understanding. Geneva/New Delhi, May 18, 2005. Available from: http://www.who.int/tdrold/diseases/leish/press_release.htm. [Last accessed on 2008 June 10]. |
|5.||Sundar S, More DK, Singh MK, Singh VP, Sharma S, Makharia A, 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. |
|6.||Rijal S, Chappuis F, Singh R, Bovier PA, Acharya P, Karki BM, et al. Treatment of visceral leishmaniasis in south-eastern Nepal: Decreasing efficacy of sodium stibogluconate and need for a policy to limit further decline. Trans R Soc Trop Med Hyg 2003;97:350-4. |
|7.||Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P, et al. Visceral leishmaniasis: Current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis 2002;2:494-501. |
|8.||Pandey BD, Pandey K, Kaneko O, Yanagi T, Hirayama K. Relapse of visceral leishmaniasis after miltefosine treatment in a Nepalese patient. Am J Trop Med Hyg 2009;80:580-2. |
|9.||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. |
|10.||Sundar S, More DK, Singh MK, Singh VP, Sharma S, Makharia A, 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. |