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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 hours 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 PCR, demonstrating genetic variability in18S rRNA sequences and possibly signaling the first identification of multiple Balamuthia strains with varying pathogenicities.

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          Author and article information

          Journal
          8703571
          6620
          Parasitol Res
          Parasitol. Res.
          Parasitology research
          0932-0113
          1432-1955
          13 November 2015
          02 September 2015
          December 2015
          01 December 2016
          : 114
          : 12
          : 4431-4439
          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
          [2 ]Methodist Children’s Hospital, San Antonio, TX, 78229 USA
          [3 ]Department of Pharmacy and Pharmacology, Slotervaart Hospital – The Netherlands Cancer Institute, 1066 EC, Amsterdam, The Netherlands
          [4 ]Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, Utrecht, the Netherlands
          [5 ]Department of Pathology, Methodist Hospital, San Antonio, TX, 78229 USA
          [6 ]Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA
          [7 ]School of Pharmacy, Department of Clinical Pharmacy, University of California, San Francisco, CA 94143, USA
          Author notes
          [* ]Please address correspondence to: Sharon L. Roy, str2@ 123456cdc.gov ; Ph. 404-718-4698; Fax 404-728-8040
          Article
          PMC4676568 PMC4676568 4676568 hhspa737047
          10.1007/s00436-015-4684-8
          4676568
          26329128
          0ab28bb3-5805-4aa2-9a38-06e17f6ac74c
          History
          Categories
          Article

          miltefosine, Balamuthia ,granulomatous,encephalitis
          miltefosine, Balamuthia , granulomatous, encephalitis

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