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
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.
KeywordsBalamuthia Granulomatous Encephalitis Miltefosine
Conflict of interest
The authors declare that they have no conflicts of interest.
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.
- Centers for Disease Control and Prevention (2010) Balamuthia mandrillaris transmitted through organ transplantation—Mississippi, 2009. MMWR Morb Mortal Wkly Rep 59:1165–1170Google Scholar
- Centers for Disease Control and Prevention (2013) Investigational drug available directly from CDC for the treatment of infections with free-living amebae. MMWR Morb Mortal Wkly Rep 62:666Google Scholar
- Dorlo TPC, Hillebrand MJX, Rosing H, Eggelte TA, de Vries PJ, Beijnen JH (2008a) Development and validation of a quantitative assay for the measurement of miltefosine in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 865:55–62. doi: 10.1016/j.jchromb.2008.02.005 CrossRefPubMedGoogle Scholar
- Food and Drug Administration (2015) Impavido/Miltefosine—label and approval history. In: Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist. Accessed 01 July 2015.
- Petersen CA, Greenlee MHW (2011) Neurologic manifestations of Leishmania spp. infection. J Neuroparasitology 2: doi: 10.4303/jnp/N110401
- Schuster FL, Dunnebacke TH, Booton GC, Yagi S, Kohlmeier CK, Glaser C, Vugia D, Bakardjiev A, Azimi P, Maddux-Gonzalez M, Visvesvara GS (2003) Environmental isolation of Balamuthia mandrillaris associated with a case of amebic encephalitis. J Clin Microbiol 41:3175–3180PubMedCentralCrossRefPubMedGoogle Scholar
- U.S. Food and Drug Administration (2014) Impavido (Miltefosine). Drugs@FDA—FDA approved drug products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed 27 March 2015
- Visvesvara GS, Roy S, Maguire JH (2011) Pathogenic and opportunistic free-living amebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia pedata. In: Guerrant RL, Walker DH, Weller PF (eds) Tropical infectious diseases—principles, pathogens, & practice, 3rd edn. Elsevier, Churchill Livingstone, Philadelphia, pp 707–713CrossRefGoogle Scholar
- World Health Organization (2011) Miltefosine (Inclusion)—adults and children. 18th expert committee on the selection and use of essential medicines. World Health Organization. http://www.who.int/selection_medicines/committees/expert/18/applications/miltefosine/en/. Accessed 27 March 2015