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

• Published in: Parasitology research (1987) Vol. 114; no. 12; pp. 4431 - 4439
• Main Authors: Roy, Sharon L., Atkins, Jane T., Gennuso, Rosemaria, Kofos, Danny, Sriram, Rama R., Dorlo, Thomas P. C., Hayes, Teresa, Qvarnstrom, Yvonne, Kucerova, Zuzana, Guglielmo, B. Joseph, Visvesvara, Govinda S.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2015; Springer
• Subjects: Amebiasis - drug therapy; Amebiasis - parasitology; Amebicides - administration & dosage; Amebicides - pharmacokinetics; Amoebas; Balamuthia; Balamuthia mandrillaris - drug effects; Balamuthia mandrillaris - isolation & purification; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - parasitology; Brain - parasitology; Brain - pathology; Child; Dosage and administration; Drug therapy; Encephalitis; Encephalitis - drug therapy; Encephalitis - parasitology; Fatal Outcome; Granulomatous; Health aspects; Host-parasite relationships; Humans; Immunology; Male; Medical Microbiology; Microbiology; Miltefosine; Observations; Original Paper; Phosphorylcholine - administration & dosage; Phosphorylcholine - analogs & derivatives; Phosphorylcholine - pharmacokinetics; Encephalitis; Miltefosine; Granulomatous; Balamuthia
• ISSN: 0932-0113; 1432-1955; 1432-1955
• DOI: 10.1007/s00436-015-4684-8

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.