|Year : 2020 | Volume
| Issue : 1 | Page : 28-31
Treatment of post kala-azar dermal leishmaniasis with fungisome – A novel Indian liposomal amphotericin B
Akansha Anil Chadha1, Vidya Kharkar1, Uday Khopkar1, Bhushan Darkase1, Shivangi Patel2, Nilima A Kshirsagar2
1 Department of Dermatology, Venereology and Leprosy, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, Maharashtra, India
2 Department of National Chair Clinical Pharmacology, ICMR, Delhi, India
|Date of Submission||15-Oct-2019|
|Date of Decision||13-Mar-2020|
|Date of Acceptance||18-Apr-2020|
|Date of Web Publication||23-Jun-2020|
Dr. Nilima A Kshirsagar
Department of National Chair Clinical Pharmacology, ICMR, Delhi
Source of Support: None, Conflict of Interest: None
Post kala-azar dermal leishmaniasis (PKDL) is a late cutaneous manifestation of visceral leishmaniasis (VL), though it can occur without a history of visceral disease. The diagnosis and treatment of PKDL is important as cases of PKDL have been known to cause outbreaks of VL. We report a case of PKDL from an area with low endemicity of VL and has presented with PKDL without VL. Due to poor tolerance to conventional amphotericin B (CAmB), he was successfully treated with Fungisome™ – Indian liposomal amphotericin B (LAmB). We want to emphasize on the successful treatment of PKDL with Fungisome™ – an Indian LAmB. This is a first such case of PKDL being treated with LAmB (Fungisome™), developed jointly by the Department of Clinical Pharmacology, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, and the Department of Biochemistry, Delhi University with funding from the Department of Biotechnology. Translational research and commercialization was done by Lifecare Innovations, India.
Keywords: Fungisome, liposomal amphotericin B, post kala-azar dermal leishmaniasis
|How to cite this article:|
Chadha AA, Kharkar V, Khopkar U, Darkase B, Patel S, Kshirsagar NA. Treatment of post kala-azar dermal leishmaniasis with fungisome – A novel Indian liposomal amphotericin B. Indian J Drugs Dermatol 2020;6:28-31
|How to cite this URL:|
Chadha AA, Kharkar V, Khopkar U, Darkase B, Patel S, Kshirsagar NA. Treatment of post kala-azar dermal leishmaniasis with fungisome – A novel Indian liposomal amphotericin B. Indian J Drugs Dermatol [serial online] 2020 [cited 2020 Oct 24];6:28-31. Available from: https://www.ijdd.in/text.asp?2020/6/1/28/287436
| Introduction|| |
Post kala-azar dermal leishmaniasis (PKDL) is a late cutaneous manifestation of visceral leishmaniasis (VL). It can even occur without a history of visceral disease. Here, we report a case of PKDL with numerous infiltrated macules over the body along with nodulation over extremities. The patient did not tolerate conventional amphotericin B (CAmB) and was treated with Fungisome™ – liposomal amphotericin B (LAmB), followed by complete resolution of nodular lesions and partial subsidence of the macules. Fungisome™ has been used in the past for VL with good results. This is the first case report of PKDL treated with LAmB (Fungisome™). The dosages and renal side effects are discussed.
| Case Report|| |
A 56-year-old male patient from Jaunpur district of Uttar Pradesh, India, body weight of 50 kg presented with multiple asymptomatic, normoesthetic, hypopigmented infiltrated macules of varying sizes all over the body since 6 months and multiple firm-to-hard painless nodules ranging from 1 cm to 5 cm on the extremities and mucosa since 3 months [Figure 1]. Biopsy from the macule showed a sparse superficial perivascular infiltrate of lymphocytes and histiocytes, and the nodule showed diffuse dense infiltrate involving the upper and mid dermis with tiny slightly basophilic intracytoplasmic dots of size 1–2 μ, suggesting Leishmaniadonovani (LD) bodies along with plasma cells [Figure 2]. Leishmania antibody immunoglobulin G was positive. On the basis of these findings, the patient was diagnosed with PKDL and started on conventional AmB 0.5 mg/kg given for 30 days along with tablet fluconazole 150 mg and rifampicin 600 mg daily. The patient was not tolerating conventional AmB, suffering from fever, chills and rising creatinine. Post treatment, the nodular lesions reduced in size and the hypopigmented macules became slightly faint. However, after 6 months, the biopsy continued to show granulomas with LD bodies and plasma cells, hence the patient was started on Fungisome™ (off-label use for PKDL with patient's consent). Marketed LAmB (Fungisome™) was provided by Lifecare Innovations, India. The infusion was sonicated as per the manufacturer's instructions. The patient was initially given 3 mg/kg, the dose was increased to 5 mg/kg which was followed by rising creatinine and granular casts in urine after 48 h. After reducing the dose to 3 mg/kg, the creatinine value was fluctuating, and hence, the dose was further reduced to 1mg/kg alternate days which the patient tolerated [Table 1]. The total dose given was 25 mg/kg.
|Figure 1: Numerous infiltrated hypopigmented macules of variable sizes over the trunk and extremities with erythematous, firm-to-hard papules, and nodules over the extremities|
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|Figure 2: Biopsy from the nodule showing diffuse granuloma occupying the dermis consisting of lymphocytes, histiocytes and plasma cells (black arrows), and tiny slightly basophilic intracytoplasmic dots of size 1–2 microns suggesting Leishmania donovani bodies (red circle) (Hematoxylin and eosin stain, ×10 and × 40)|
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|Table 1: Dosing of liposomal amphotericin B vis-à-vis renal function tests|
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The particle size of sonicated LAmB was found to be average 168.87 ± 21.12 nm (90–375 nm) [Figure 3].
|Figure 3: Transmission electron microscope images of liposomal amphotericin Fungisome™ after sonication|
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The nodules disappeared after 6 months. However, the hypopigmented patches responded even slowly. Rifampicin was continued for 18 months at 450 mg and fluconazole was tapered off in 24 months. There is no evidence of relapse after 3 years of follow-up [Figure 4].
|Figure 4: Posttreatment images of the patient on follow-up. The macules became fainter, infiltration was gone, and nodules flattened|
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| Discussion|| |
In India, leishmaniasis is endemic in states of Bihar, West Bengal, Jharkhand and Uttar Pradesh with sporadic cases from Assam, Himachal Pradesh, Kerala, Madhya Pradesh, Sikkim and Uttarakhand.
VL is characterized by prolonged fever, hepatosplenomegaly, anemia and weight loss. Post kala-azar dermal leishmaniasis (PKDL), on the other hand, is a late complication in patients who have recovered from VL characterized by hypopigmented macules, papules and nodules. The primary causative agent for both VL and PKDL is LD and Phlebotomus argentipes is the vector.
The exact frequency of PKDL in India is not known because studies with active follow-up are not available. Passive case finding has yielded a rate of 0.3% of PKDL cases following cure of VL. Upto 10% of patients with VL in the Indian subcontinent go onto develop PKDL following treatment for VL. However, in 10%–23% of cases, there is no history of previous VL, like in this case. Serological tests are useful for the diagnosis of PKDL in such patients who have not previously suffered from VL.,
The infection being anthropozoonotic without established animal reservoirs, these cases of PKDL are believed to be responsible for the interepidemic spread and the cyclical outbreaks of VL. A study carried out in India found that 7%–33% of macular PKDL lesions show amastigotes compared with 67%–100% of nodular lesions. The current focus of the Southeast Asia Kala-Azar elimination program has shifted to active case detection and treatment of potential sources of infection of which PKDL is the most important.
The National Vector Borne Disease Control Programme has outlined the treatment of PKDL as miltefosine orally (for 20-50 kg body weight, a dose of 100 mg/day and for >50 kg body weight, a dose of 150 mg/day) for 12 weeks OR AmB deoxycholate (CAmB) 1mg/kg/d by infusion, up to 60–80 doses over 4 months. Liposomal AmB Ambisome has been tested in different doses, and a good treatment response was observed for 15 mg/kg Ambisome regimen, with 89.7% of patients showing complete resolution of papular lesions and major to complete repigmentation of macular lesions. It has been recommended by the WHO for first-line use in the Indian subcontinent, although not yet included in Indian guidelines.
In the Medicines sans Frontieres program in Fulbaria, a total dose of 30 mg/kg of Ambisome (LAmB) administered in divided doses over a period of 3 weeks achieved a good response in 86.5% of patients. A similar Ambisome regimen had similar efficacy outcomes in India. On the basis of this, we administered a total dose of 1250 (25mg/kg) of Fungisome over 40 days starting with 3 mg/kg/dose. Due to poor renal tolerance in this patient, the dose was reduced to 1 mg/kg on alternate days.
Fungisome™ is a mix-lamellarity LAmB consisting of liposomes of phosphatidylcholine-cholesterol with Amphotericin B (45:1 ratio). It is sonicated for 45 min to get small unilamellar liposomes before infusion. It has been tested for VL with cure rates ranging from 90%–100%.,
Azotemia, renal tubular acidosis, impaired renal concentrating ability and electrolyte abnormalities such as hypokalemia and sodium and magnesium wasting are the manifestations of AmB-induced nephrotoxicity. All these abnormalities occur to varying degrees in almost all patients receiving the Amphotericin B infusions (CAmB). Renal function gradually returns to baseline, although, in some instances, permanent damage is sustained, especially when the cumulative dose exceeds 5 g. Salt depletion enhances the development of nephrotoxicity. Analysis of the urinary sediment may (rarely) reveal hematuria, pyuria, tubular cell casts and (very rarely) proteinuria. On the other hand, Liposomal AmB is reported to show considerably less nephrotoxicity as compared to conventional AmB. A study by Sundar etal., 2015, reported that when single-dose Fungisome™ was used for the treatment of Indian VL, only one patient out of fifty patients was observed suffering from nephrotoxicity which was manifested by an increase in serum creatinine level from 0.88 to 4.03 mg/dl on day 4 after infusion which returned to normal by day 11. In our case, Fungisome™, when increased to 3 and 5 mg/kg/dose, was not tolerated due to the development of renal toxicity with granular cysts in the urine and rising creatinine from 1.0 mg % to 1.8 mg % which improved on reducing the dose to 1 mg/kg/dose given on alternate days.
The parasite load being lower in PKDL compared to VL, a longer duration of anti-leishmanial therapy is usually given as there is no conclusive laboratory or clinical marker other than the disappearance of clinical lesions. In our patient, the persistence of the organism in the skin biopsy samples from the nodules at 6 months and poor tolerance of AmB by the patient compelled us to use Fungisome™. Rifampicin, mainly used in the pre miltefosine era, is known to exhibit some weak antileishmanial activity. Fluconazole is known to be of use in cutaneous leishmaniasis; however, it has not been reported to have been used in PKDL. Due to the lack of a definite treatment outcome, our patient was maintained on these two drugs for about 18 months to 2 years without any tolerance issues. There has been no evidence of relapse after 3 years of follow-up.
| Conclusion|| |
In the Indian subcontinent, untreated cases of VL and PKDL are considered to be the sole reservoir for the transmission of the causative parasite. The occurrence of PKDL without prior history of VL, especially in areas of low endemicity, is a matter of concern and needs to be resolved as we approach the elimination target. For that, early diagnosis and effective treatment of PKDL is very important. Indian LAmB is a promising drug formulation for the treatment of PKDL.
The authors wish to acknowledge Ms. Shibani Supe for her contribution to this article. The authors would like to acknowledge Dr. JN Verma, founder and MD of Lifecare Innovations, for providing Fungisome™ free of cost for this study.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]