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Assessment of blood–brain barrier penetration of miltefosine used to treat a fatal case of granulomatous amebic encephalitis possibly caused by an unusual Balamuthia mandrillaris strain

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Abstract

Balamuthia mandrillaris, a free-living ameba, causes rare but frequently fatal granulomatous amebic encephalitis (GAE). Few patients have survived after receiving experimental drug combinations, with or without brain lesion excisions. Some GAE survivors have been treated with a multi-drug regimen including miltefosine, an investigational anti-leishmanial agent with in vitro amebacidal activity. Miltefosine dosing for GAE has been based on leishmaniasis dosing because no data exist in humans concerning its pharmacologic distribution in the central nervous system. We describe results of limited cerebrospinal fluid (CSF) and serum drug level testing performed during clinical management of a child with fatal GAE who was treated with a multiple drug regimen including miltefosine. Brain biopsy specimens, CSF, and sera were tested for B. mandrillaris using multiple techniques, including culture, real-time polymerase chain reaction, immunohistochemical techniques, and serology. CSF and serum miltefosine levels were determined using a liquid chromatography method coupled to tandem mass spectrometry. The CSF miltefosine concentration on hospital admission day 12 was 0.4 μg/mL. The serum miltefosine concentration on day 37, about 80 h post-miltefosine treatment, was 15.3 μg/mL. These are the first results confirming some blood–brain barrier penetration by miltefosine in a human, although with low-level CSF accumulation. Further evaluation of brain parenchyma penetration is required to determine optimal miltefosine dosing for Balamuthia GAE, balanced with the drug’s toxicity profile. Additionally, the Balamuthia isolate was evaluated by real-time polymerase chain reaction (PCR), demonstrating genetic variability in 18S ribosomal RNA (18S rRNA) sequences and possibly signaling the first identification of multiple Balamuthia strains with varying pathogenicities.

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The authors declare that they have no conflicts of interest.

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The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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Authors and Affiliations

  1. Division of Foodborne, Waterborne and Environmental Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, 30329, USA

    Sharon L. Roy, Rama R. Sriram, Zuzana Kucerova & Govinda S. Visvesvara

  2. Methodist Children’s Hospital, San Antonio, TX, 78229, USA

    Jane T. Atkins, Rosemaria Gennuso & Danny Kofos

  3. Department of Pharmacy and Pharmacology, Slotervaart Hospital—The Netherlands Cancer Institute, 1066 EC, Amsterdam, The Netherlands

    Thomas P. C. Dorlo

  4. Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, Utrecht, The Netherlands

    Thomas P. C. Dorlo

  5. Department of Pathology, Methodist Hospital, San Antonio, TX, 78229, USA

    Teresa Hayes

  6. Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, 30329, USA

    Yvonne Qvarnstrom

  7. Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, San Francisco, CA, 94143, USA

    B. Joseph Guglielmo

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  1. Sharon L. Roy
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  3. Rosemaria Gennuso
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  7. Teresa Hayes
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  8. Yvonne Qvarnstrom
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  9. Zuzana Kucerova
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  10. B. Joseph Guglielmo
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  11. Govinda S. Visvesvara
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Correspondence to Sharon L. Roy.

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Roy, S.L., Atkins, J.T., Gennuso, R. et al. Assessment of blood–brain barrier penetration of miltefosine used to treat a fatal case of granulomatous amebic encephalitis possibly caused by an unusual Balamuthia mandrillaris strain. Parasitol Res 114, 4431–4439 (2015). https://doi.org/10.1007/s00436-015-4684-8

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  • DOI: https://doi.org/10.1007/s00436-015-4684-8

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