Topical treatment of persistent cutaneous leishmaniasis with ethanolic lipid amphotericin B

A 1.5-year-old infant was referred because of spreading skin lesions diagnosed earlier as cutaneous leishmaniasis that did not respond to repeated courses with paromomycin-containing ointment. After consideration of the alternative therapeutic options, the infant was treated with topical colloidal solution of amphotericin B for 3 weeks. This mode of therapy resulted in resolution of the skin lesions. No local or systemic side effects were observed. There were no signs of recurrence 3 months after cessation of the treatment. Cutaneous leishmaniasis is an endemic disease in certain regions of Israel. In this region it is usually a benign disease limited to the skin. Treatment with topical paromomycin-containing preparations have proved effective in some cases, 1 but not in others, 2, 3 and often causes substantial skin irritation. Available systemic treatments may be associated with toxicity (e.g. pentavalent antimonials) or with variable efficacy (e.g. ketoconazole). Amphotericin B (AmB), a polyene antibiotic with high activity against L eishmania, has been used as a systemic agent in Leishmania infection. However, less toxic drugs are preferred for systemic treatment, whereas AmB is usually reserved for patients who failed to respond to other treatments. We have recently reported preliminary results showing that a colloidal dispersion of AmB and cholesteryl sulfate had a significant therapeutic effect in the treatment of cutaneous leishmaniasis lesions in adults. 4 We present a child with persistent cutaneous leishmaniasis that was successfully treated with topical AmB. Case report. A 1.5-year-old infant was referred for diagnosis and treatment of spreading papular skin lesions on the dorsal aspect of the right forearm. The patient was an otherwise healthy child living in a kibbutz in the Arava desert. The initial skin lesions had appeared 8 months earlier and were attributed to insect bites. Gradually the two initial lesions enlarged and became ulcerated in a period of a few weeks (Fig. 1A). The clinical diagnosis of cutaneous leishmaniasis was confirmed by demonstration of Leishmania amastigotes on a skin snip smear in another hospital. The child was treated topically with paromomycin ointment (Leshcutan; Teva Pharmaceuticals Industry, Ltd., Patah Tiqva, Israel). Reportedly this therapy resulted in partial healing of the original lesions, but a new ulcer developed nearby. Four additional courses of paromomycin ointment did not result in complete clearance of the lesions.Fig. 1: Home photo of the initial lesions (A) and the emergence of a new skin nodule above the elbow (black arrow) and reactivation of inflammation in an old papule (white arrow) (B).Two months after cessation of the treatment, the patient had a solitary pink, firm, nontender smooth and shiny papule on the extensor surface of his right arm. Proximal to this lesion were two atrophic slightly hypopigmented scars 5 to 6 mm in diameter. The rest of the physical examination was unremarkable. All the lesions including the pink papule were clinically diagnosed as residual scars, and the infant’s parents were advised against any further treatment. Two months later a tender firm erythematous cutaneous nodule appeared above the right elbow, while the pink papule had become scaly and slightly enlarged (Fig. 1B). Histopathologic examination of biopsies from the nodule and the residual skin papule revealed deep dermal granulomatous infiltrates that also involved peripheral nerves. Cytoplasmic inclusion bodies were not observed. Ziehl-Neelsen stain did not reveal acid-fast bacilli. In view of the emergence of new granulomatous lesions in a linear array, the earlier laboratory evidence of leishmaniasis and the current histologic findings, the diagnosis of reactivation of cutaneous leishmaniasis with sporotrichoid spread was made. At this stage the remaining therapeutic options included cryotherapy, intralesional injections of sodium stibogluconate (Pentostam) or systemic treatment with either allopurinol, sodium stibogluconate or ketoconazole. Because of the deep dermal involvement, intralesional Pentostam injections were advised, but in view of the associated pain the parents declined this therapy. Systemic therapy for the limited skin involvement seemed unjustified. In view of our recent experience with topical ethanolic lipid AmB in cutaneous leishmaniasis in adults, 4, 5 this alternative was offered and accepted by the parents. The infant was treated with topical ethanolic lipid AmB applied twice daily, 1 drop to each lesion, for 3 weeks Two weeks after the start of the therapy, gradual decrease in the size of the lesions was observed which continued until complete resolution of the skin lesions 2 months later. The skin at the sites of the original lesions remained slightly depressed. The calculated total dose of AmB was 1 mg. No local or systemic side effects were observed. On follow-up examination 3 months after cessation of the treatment, there were no signs of recurrence. Discussion. Southern Israel is endemic for cutaneous leishmaniasis, mainly caused by Leishmania major and transmitted to humans from rodents by the sandfly Phlebotomus papatasi. 6 In less arid areas Leishmania tropica may prevail and be transmitted by Phlebotomus sargenti. From 2 to 6 weeks after inoculation, a small erythematous papule appears and gradually evolves into a nontender crust-covered shallow ulcer. If untreated such lesions usually remain stable for 6 to 12 months before gradual spontaneous involution that results in atrophic scarring. 6 In the early acute phase of cutaneous leishmaniasis, when skin lesions appear as ordinary insect bites, formation of granulomas is uncommon. The granulomatous process starts in the upper dermis in the late acute phase and is clinically evident by development of ulcers with firm nontender margins. During this stage, which lasts several weeks, intracellular Leishmania parasites can be found in ∼50% of the cases. 7 In long-standing lesions and in Leishmania recidivans, granulomas are found in both superficial and deep dermis with variable epidermal changes ranging from almost normal to lichenoid dermatitis or pseudoepitheliomatous hyperplasia. It is rare to find Leishmania parasites at this stage. 7 Occasionally deep tissues, such as muscle and peripheral nerves, can be involved. 8, 9 Extension of cutaneous leishmaniasis via lymphatics may result in an unusual sporotrichoid pattern of the disease. 10 Various physical therapeutic modalities, such as cryotherapy, thermotherapy and electrotherapy, have been reported with variable efficacy. 11 Except for cryotherapy physical modalities require special setting and equipment, which was unavailable in our clinic. Until 1994 intralesional pentavalent antimony injections were the only topical drug therapy for cutaneous leishmaniasis. In the last decade, after the reports of El-On et al. 12 on the efficacy of topical therapy with paromomycin ointment, application of Leshcutan ointment (15% paromomycin and 12% methyl benzethonium chloride) has become the treatment of choice for cutaneous leishmaniasis in Israel, particularly in children. This treatment results in cure of about three-fourths of the patients after a single 2-week course of therapy. 12 Because of the pain associated with cryotherapy and intralesional injections of Pentostam, these modalities are reserved for unresponsive lesions in children. AmB, a potent antifungal and antiparasitic agent with a broad spectrum of activity against organisms containing ergosterol in their membranes, has been shown recently to exert a curative effect in cutaneous leishmaniasis in adults. 4, 5 Twice daily application of a colloidal dispersion of AmB and cholesteryl sulfate, in the presence of 5% ethanol, resulted in healing of the skin lesions within ∼4 weeks after the start of the therapy. 5. Neither in adults 4, 5 nor in the case presented were local or systemic side effects observed. The outcome in our patient and in previously reported cases indicate that topical AmB could be superior to other available topical therapies for cutaneous leishmaniasis. Further studies are needed to assess the efficacy and safety of topical AmB for cutaneous leishmaniasis in children.