{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:32:05Z","timestamp":1791977525513,"version":"4.4.0"},"reference-count":37,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T00:00:00Z","timestamp":1726704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["TropicalMed"],"abstract":"<jats:p>Miltefosine, an orally administered drug, is an important component of the therapeutic arsenal against visceral and mucosal forms of leishmaniasis. However, data regarding the safety and tolerability of miltefosine treatment for cutaneous leishmaniasis (CL) are relatively limited. The aim of this study was to evaluate the tolerability, safety, and adverse events (AEs) of miltefosine treatment in patients with CL. In this cohort study, we reviewed the medical records of all miltefosine-treated patients between 1 January 2016 and 31 December 2022, at Israel Defense Forces military dermatology clinics and the dermatology and Tropical Medicine Clinics at Chaim Sheba Medical Center, Ramat-Gan, Israel. A total of 68 patients (54 males, 79%) with a median age of 30.3 \u00b1 15.6 years (range: 18\u201388) were included in this study. Leishmania species were identified as L. major (n = 37, 54.4%), L. tropica (n = 12, 17.6%), L. braziliensis (n = 18, 26.5%), and L. infantum (n = 1, 1.5%) using polymerase chain reaction (PCR). Miltefosine tablets were administered orally at a dose of 50 mg, three times daily, for 28 days. Overall, 44 patients (65%) completed the 28-day treatment, and the remaining patients required dose reduction or early discontinuation of treatment. AEs (of any degree) were common, reported in 91% of patients. Both previously reported and previously unreported AEs were documented. Gastrointestinal symptoms (66.1%) and malaise (23.5%) typically occurred during the first two weeks of treatment and tended to subside. Other AEs, including acute renal failure (20.6%), sudden and severe pleuritic chest pain (7.6%), acne exacerbation (11.8%), suppuration of CL lesions (17.8%), and AEs related to the male genitourinary system (39.6% of males), typically occurred towards the end of treatment. The latter included testicular pain, epididymitis, diminution or complete absence of ejaculate, inability to orgasm, and impotence. Severe AEs necessitated treatment discontinuation (29.4%) or hospitalization (10.3%). URTI-like symptoms, arthritis, cutaneous eruption, pruritus, and laboratory abnormalities were also observed. Overall, the cure rate (for all patients combined) evaluated 3 months after the completion of treatment was 60%. The tolerability of miltefosine treatment for CL is low. Close clinical and laboratory monitoring is required during treatment, as severe AEs are not uncommon. As new insights regarding its toxicities emerge, further studies are required to define the role of miltefosine in the treatment of CL.<\/jats:p>","DOI":"10.3390\/tropicalmed9090218","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T03:34:20Z","timestamp":1726716860000},"page":"218","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Tolerability and Safety of Miltefosine for the Treatment of Cutaneous Leishmaniasis"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3729-7699","authenticated-orcid":false,"given":"Nadav","family":"Astman","sequence":"first","affiliation":[{"name":"Department of Dermatology, Chaim Sheba Medical Center, Tel-Hashomer 5262000, Israel"},{"name":"Israel Defense Force (IDF) Medical Corps, Tel-Hashomer, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Arbel","sequence":"additional","affiliation":[{"name":"Israel Defense Force (IDF) Medical Corps, Tel-Hashomer, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oren","family":"Katz","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aviv","family":"Barzilai","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Chaim Sheba Medical Center, Tel-Hashomer 5262000, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7371-5814","authenticated-orcid":false,"given":"Michal","family":"Solomon","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Chaim Sheba Medical Center, Tel-Hashomer 5262000, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Center for Geographic Medicine, Chaim Sheba Medical Center, Tel-Hashomer 5262000, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/0166-6851(82)90042-1","article-title":"Metabolism of 1-0-[1\u2019-14C]octadecyl-sn-glycerol in Leishmania donovani promastigotes. Ether lipid synthesis and degradation of the ether bond","volume":"5","author":"Herrmann","year":"1982","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1093\/jac\/dks275","article-title":"Miltefosine: A review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis","volume":"67","author":"Dorlo","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e02507-18","DOI":"10.1128\/AAC.02507-18","article-title":"Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation","volume":"63","author":"Bhairosing","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/S0959-8049(05)80142-X","article-title":"Phase II study of daily oral miltefosine (hexadecylphosphocholine) in advanced colorectal cancer","volume":"29A","author":"Planting","year":"1993","journal-title":"Eur. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/S0959-8049(05)80369-7","article-title":"Phase II study of oral miltefosine in patients with squamous cell head and neck cancer","volume":"29A","author":"Verweij","year":"1993","journal-title":"Eur. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1007\/BF01211805","article-title":"A dose-finding study of miltefosine (hexadecylphosphocholine) in patients with metastatic solid tumours","volume":"118","author":"Verweij","year":"1992","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1128\/AAC.36.8.1630","article-title":"Hexadecylphosphocholine: Oral treatment of visceral leishmaniasis in mice","volume":"36","author":"Kuhlencord","year":"1992","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1016\/S0140-6736(98)04367-0","article-title":"Trial of oral miltefosine for visceral leishmaniasis","volume":"352","author":"Sundar","year":"1998","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1093\/cid\/civ004","article-title":"Miltefosine for visceral and cutaneous leishmaniasis: Drug characteristics and evidence-based treatment recommendations","volume":"60","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1056\/NEJMoa021556","article-title":"Oral miltefosine for Indian visceral leishmaniasis","volume":"347","author":"Sundar","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1086\/519690","article-title":"Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis","volume":"196","author":"Bhattacharya","year":"2007","journal-title":"J. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1056\/NEJM199912093412403","article-title":"Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis","volume":"341","author":"Jha","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E57","DOI":"10.1086\/322689","article-title":"Treatment of American cutaneous leishmaniasis with miltefosine, an oral agent","volume":"33","author":"Soto","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1086\/383321","article-title":"Miltefosine for new world cutaneous leishmaniasis","volume":"38","author":"Soto","year":"2004","journal-title":"Clin. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"210","DOI":"10.4269\/ajtmh.2008.78.210","article-title":"Efficacy of miltefosine for Bolivian cutaneous leishmaniasis","volume":"78","author":"Soto","year":"2008","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"351","DOI":"10.4269\/ajtmh.2010.10-0060","article-title":"Efficacy of miltefosine for the treatment of American cutaneous leishmaniasis","volume":"83","author":"Mestra","year":"2010","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Machado, P.R., Ampuero, J., Guimar\u00e3es, L.H., Villasboas, L., Rocha, A.T., Schriefer, A., Sousa, R.S., Talhari, A., Penna, G., and Carvalho, E.M. (2010). Miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Brazil: A randomized and controlled trial. PLoS Negl. Trop. Dis., 4.","DOI":"10.1371\/journal.pntd.0000912"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1111\/j.1365-4632.2011.04987.x","article-title":"Treatment of imported New World cutaneous leishmaniasis in Germany","volume":"50","author":"Harms","year":"2011","journal-title":"Int. J. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1093\/infdis\/jir816","article-title":"Noninferiority of miltefosine versus meglumine antimoniate for cutaneous leishmaniasis in children","volume":"205","author":"Rubiano","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.actatropica.2007.05.005","article-title":"Comparison of miltefosine and meglumine antimoniate for the treatment of zoonotic cutaneous leishmaniasis (ZCL) by a randomized clinical trial in Iran","volume":"103","author":"Mohebali","year":"2007","journal-title":"Acta Trop."},{"key":"ref_21","first-page":"132","article-title":"Miltefosine in cutaneous leishmaniasis","volume":"17","author":"Rahman","year":"2007","journal-title":"J. Coll. Physicians Surg. Pak."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1086\/648726","article-title":"Miltefosine treatment of Leishmania major infection: An observational study involving Dutch military personnel returning from northern Afghanistan","volume":"50","author":"Leenstra","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"ref_23","first-page":"adv00322","article-title":"Cutaneous Leishmaniasis Treated with Miltefosine: A Case Series of 10 Paediatric Patients","volume":"100","author":"Ollech","year":"2020","journal-title":"Acta Derm. Venereol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"ofw008","DOI":"10.1093\/ofid\/ofw008","article-title":"Miltefosine for mucosal and complicated cutaneous old world leishmaniasis: A case series and review of the literature","volume":"3","author":"Mosimann","year":"2016","journal-title":"Open Forum Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1056\/NEJMe020133","article-title":"Kala-azar\u2014progress against a neglected disease","volume":"347","author":"Murray","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1155\/2008\/802710","article-title":"Use of oral miltefosine for cutaneous leishmaniasis in Canadian soldiers returning from Afghanistan","volume":"19","author":"Keynan","year":"2008","journal-title":"Can. J. Infect. Dis. Med. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e2457","DOI":"10.1093\/cid\/ciaa1238","article-title":"Efficacy and tolerability of miltefosine in the treatment of cutaneous leishmaniasis","volume":"73","author":"Ware","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_28","unstructured":"WHO (2023, April 09). Statement on Miltefosine\u2014Potential Ocular Disorders in Patients Treated with Miltefosine for Post-Kala-Azar Dermal Leishmaniasis (PKDL). 10 February 2022. Available online: https:\/\/www.who.int\/news\/item\/10-02-2022-statement-on-miltefosine---potential-ocular-disorders-in-patients-treated-with-miltefosine-for-post-kala-azar-dermal-leishmaniasis-(pkdl)."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/S0732-8893(03)00093-2","article-title":"PCR diagnosis and characterization of Leishmania in local and imported clinical samples","volume":"47","author":"Nasereddin","year":"2003","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1007\/s00436-017-5454-6","article-title":"Detection and identification of Leishmania spp.: Application of two hsp70-based PCR-RFLP protocols to clinical samples from the New World","volume":"116","author":"Montalvo","year":"2017","journal-title":"Parasitol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Singh-Phulgenda, S., Dahal, P., Ngu, R., Maguire, B.J., Hawryszkiewycz, A., Rashan, S., Brack, M., Halleux, C.M., Alves, F., and Stepniewska, K. (2021). Serious adverse events following treatment of visceral leishmaniasis: A systematic review and meta-analysis. PLoS Negl. Trop. Dis., 15.","DOI":"10.1371\/journal.pntd.0009302"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1016\/j.trstmh.2006.02.010","article-title":"Development of miltefosine as an oral treatment for leishmaniasis","volume":"100","author":"Sindermann","year":"2006","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1128\/AAC.00014-08","article-title":"Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients","volume":"52","author":"Dorlo","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_34","first-page":"328","article-title":"Miltefosine Induced Reduced Male Fertility Capacity after Treatment of Post Kala-azar Dermal Leishmaniasis, Bangladesh","volume":"28","author":"Basher","year":"2019","journal-title":"Mymensingh Med. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"770","DOI":"10.4269\/ajtmh.14-0787","article-title":"Lymphatic dissemination in cutaneous leishmaniasis following local treatment","volume":"93","author":"Thomaidou","year":"2015","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1080\/15569527.2024.2380311","article-title":"Ophthalmic adverse effects of miltefosine in the treatment of leishmaniasis: A systematic review","volume":"43","author":"Pal","year":"2024","journal-title":"Cutan. Ocul. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1007\/s13346-021-00896-8","article-title":"Efficacy of topical Miltefosine formulations in an experimental model of cutaneous leishmaniasis","volume":"12","author":"Peralta","year":"2022","journal-title":"Drug Deliv. Transl. Res."}],"container-title":["Tropical Medicine and Infectious Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2414-6366\/9\/9\/218\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:59:16Z","timestamp":1760111956000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2414-6366\/9\/9\/218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,19]]},"references-count":37,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["tropicalmed9090218"],"URL":"https:\/\/doi.org\/10.3390\/tropicalmed9090218","relation":{},"ISSN":["2414-6366"],"issn-type":[{"value":"2414-6366","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,19]]}}}