Methods of treating infections caused by free-living amoeba are disclosed. The methods generally include systemic administration of an effective amount of miltefosine, such as an oral or intravenous formulation, and optionally local administration of an effective amount of miltefosine, such as a topical formulation of miltefosine. The methods may further include administration of one or more secondary agents. Exemplary secondary agents include steroids, polyhexamethylene biguanide (PHMB), chlorhexidine, propamidine isethionate, dibromopropamidine isethionate, neomycin, paromomycin, polymyxin B, clotrimazole, ketoconazole, miconazole, and itraconazole. The methods may be used to treat patients with infections caused by a free-living amoeba such as Naegleria fowleri, Balamuthia mandrillaris, Sappinia diploidea, and Acanthamoeba species. Exemplary infections include Acanthamoeba keratitis, granulomatous amoebic encephalitis, cutaneous acanthamoebiasis, primary amoebic meningoencephalitis, Sappinia amoebic encephalitis, or a disseminated disease associated with a free-living amoeba.
