Treatment of Granulomatous Amoebic Encephalitis with Voriconazole and Miltefosine in an Immunocompetent Soldier

Webster, Duncan; Umar, Imram; Kolyvas, George; Bilbao, Juan; Guiot, Marie‐Christine; Duplisea, Kevin; Qvarnström, Yvonne; Visvesvara, Govinda S.

doi:10.4269/ajtmh.2012.12-0100

Cited by 54 publications

(34 citation statements)

References 24 publications

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“…However, substantial miltefosine concentrations were demonstrated in the brain parenchyma and CSF of patients treated for Balamuthia and Naegleria infections (Schuster et al, 2006). Furthermore, Webster et al (2012) reported successful treatment of immune-comptent patient with granulomatous amoebic encephalitis caused by Acanthamoeba spp. with oral miltefosine.…”

Section: Introductionmentioning

confidence: 97%

Could miltefosine be used as a therapy for toxoplasmosis?

Eissa

Barakat

Amer

et al. 2015

Experimental Parasitology

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Section: Introductionmentioning

confidence: 97%

Could miltefosine be used as a therapy for toxoplasmosis?

Eissa

Barakat

Amer

et al. 2015

Experimental Parasitology

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“…However, these regimens exhibit poor efficacy because under adverse conditions Acanthamoeba trophozoites can convert to a protective cyst form, which is resistant to antimicrobial agents. Moreover, no effective treatment has been established for GAE, although a few cases have been successfully treated using chemotherapy with sulfadiazine (combined with ketoconazole or fluconazole), voriconazole, and miltefosine (7,8). Thus, development of novel therapeutic agents against Acanthamoeba should be focused on the critical targets involved in cellular metabolism, viability, or pathogenicity.…”

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confidence: 99%

Artemether Exhibits Amoebicidal Activity against Acanthamoeba castellanii through Inhibition of the Serine Biosynthesis Pathway

Deng

Wei

Man

et al. 2015

Antimicrob Agents Chemother

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dAcanthamoeba sp. parasites are the causative agents of Acanthamoeba keratitis, fatal granulomatous amoebic encephalitis, and cutaneous infections. However, there are currently no effective drugs for these organisms. Here, we evaluated the activity of the antimalarial agent artemether against Acanthamoeba castellanii trophozoites and identified potential targets of this agent through a proteomic approach. Artemether exhibited in vitro amoebicidal activity in a time-and dose-dependent manner and induced ultrastructural modification and cell apoptosis. The iTRAQ quantitative proteomic analysis identified 707 proteins that were differentially expressed after artemether treatment. We focused on phosphoglycerate dehydrogenase and phosphoserine aminotransferase in the serine biosynthesis pathway because of their importance to the growth and proliferation of protozoan and cancer cells. The expression of these proteins in Acanthamoeba was validated using quantitative real-time PCR and Western blotting after artemether treatment. The changes in the expression levels of phosphoserine aminotransferase were consistent with those of phosphoglycerate dehydrogenase. Therefore, the downregulation of phosphoserine aminotransferase may be due to the downregulation of phosphoglycerate dehydrogenase. Furthermore, exogenous serine might antagonize the activity of artemether against Acanthamoeba trophozoites. These results indicate that the serine biosynthesis pathway is important to amoeba survival and that targeting these enzymes would improve the treatment of Acanthamoeba infections. Artemether may be used as a phosphoglycerate dehydrogenase inhibitor to control or block Acanthamoeba infections.

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“…While this antimicrobial treatment can kill the trophozoites, the resistance of Acanthamoeba cysts to antimicrobials can lead to the recurrence of keratitis. For GAE, combination therapies were found more successful than single-drug therapies, and therefore, current therapeutic agents include a combination of ketoconazole, fluconazole, itraconazole, pentamidine isethionate, sulfadiazine, amphotericin B, azithromycin, rifampin, voriconazole, and miltefosine (12)(13)(14)(15). Because of the lack of optimal antimicrobial therapy, GAE is often fatal, and fewer than 10 GAE patients have been successfully treated with multidrug regimens (16).…”

mentioning

confidence: 99%

In Vitro Efficacy of Corifungin against Acanthamoeba castellanii Trophozoites and Cysts

Debnath

Tunac²,

Silva-Olivares

et al. 2014

Antimicrob Agents Chemother

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cPainful blinding keratitis and fatal granulomatous amebic encephalitis are caused by the free-living amebae Acanthamoeba spp. Several prescription eye medications are used to treat Acanthamoeba keratitis, but the infection can be difficult to control because of recurrence of infection. For the treatment of encephalitis, no single drug was found useful, and in spite of the use of a combination of multiple drugs, the mortality rate remains high. Therefore, efficient, novel drugs are urgently needed for the treatment of amebic keratitis and granulomatous amebic encephalitis. In this study, we identified corifungin, a water-soluble polyene macrolide, as amebicidal. In vitro, it was effective against both the trophozoites and the cysts. Transmission electron microscopy of Acanthamoeba castellanii incubated with corifungin showed the presence of swollen mitochondria, electrondense granules, degeneration of cytoplasm architecture, and loss of nuclear chromatin structure. These changes were followed by lysis of amebae. Corifungin also induced the encystment process of A. castellanii. There were alterations in the cyst cell wall followed by lysis of the cysts. Corifungin is a promising therapeutic option for keratitis and granulomatous amebic encephalitis. Free-living Acanthamoeba spp. cause keratitis, a serious eye infection that can occur in healthy individuals wearing contact lenses, as well as chronic granulomatous amebic encephalitis (GAE) leading to death in immunocompromised persons. Acanthamoeba has a worldwide distribution and is the most common ameba found in the environment. Coincident with the number of Acanthamoeba keratitis cases in the United States has been an increase in developing countries. Wearing of contact lenses is now recognized as the leading risk factor for keratitis (1-3). In the United States, the estimated number of keratitis cases is 1.36 per million contact lens wearers (4, 5). GAE is a relatively rare disease. Approximately 150 cases have been reported worldwide (5). GAE results from inhalation of amebae through the nasal cavities and lungs, or introduction through skin lesions followed by access to the central nervous system by hematogenous spread or through the olfactory neuroepithelium (6). Clinical manifestations include headache, fever, nausea, vomiting, behavioral changes, stiff neck, lethargy, increased intracranial pressure, and, in the later stage, loss of consciousness, seizures, coma, and death (7-9).The drugs recommended for the treatment of Acanthamoeba keratitis include polyhexamethylene biguanide (0.02%) or chlorhexidine (0.02%) along with a diamidine (either 0.1% propamidine or 0.1% hexamidine) (10). Corticosteroids are applied topically to control corneal inflammation, pain, and scleritis, particularly following keratoplasty (11). While this antimicrobial treatment can kill the trophozoites, the resistance of Acanthamoeba cysts to antimicrobials can lead to the recurrence of keratitis. For GAE, combination therapies were found more successful than single-drug therapies, a...

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Treatment of Granulomatous Amoebic Encephalitis with Voriconazole and Miltefosine in an Immunocompetent Soldier

Cited by 54 publications

References 24 publications

Could miltefosine be used as a therapy for toxoplasmosis?

Could miltefosine be used as a therapy for toxoplasmosis?

Artemether Exhibits Amoebicidal Activity against Acanthamoeba castellanii through Inhibition of the Serine Biosynthesis Pathway

In Vitro Efficacy of Corifungin against Acanthamoeba castellanii Trophozoites and Cysts

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