Amphotericin B transfer to CSF following intravenous administration of liposomal amphotericin B

Abstract

After the intravenous administration of LAmB, AmB CSF levels were low, confirming published animal data. CSF levels remained at a steady-state level for longer than 48 h. As indicated by published post mortem data, higher levels in brain tissue, which would be necessary for the successful treatment of CNS infections, might be possible.

In vitro activity of voriconazole and amphotericin B against Candida albicans, Candida krusei, and Cryptococcus neoformans in human cerebrospinal fluid

“…Conducting PK studies on AmB in CSF is complicated by the very low concentrations of AmB. The available literature suggests a median penetration ratio of 0.13% for liposomal AmB into CSF of pediatric patients; however, the penetration ratio seems to increase with an increasing time interval between drug administration and CSF sampling, indicating delayed tissue distribution [10]. Despite limited penetration of AmB into CSF in PK studies, it is frequently used to treat CNS mycoses and shows good clinical outcomes [11].…”

“…Considering the poor penetration of AmB into CSF, this concentration will probably not be reached with the current dosing schemes where the blood-brain barriers are intact (reported concentration range in CSF of 10-120 ng/ml). Even keeping in mind the assumption that AmB concentrations will be higher in patients with neurological infections due to the increased permeability of the blood-brain barrier, a rise in the AmB concentrations in CSF by 33-to 400-fold is unlikely [10].…”

Efficacy and toxicity evaluation of new amphotericin B micelle systems for brain fungal infections

“…Candida meningoencephalitis has a high morbidity and mortality in immunocompromised individuals such as AIDs patients or in situations of prolonged immunosuppression, for example hematologic malignancies and transplants (Sánchez-Portocarrero et al, 2000). In premature infants and paediatric patients, Candida meningoencephalitis is a particularly serious nosocomial fungal infection (Groll et al, 2000;Kang et al, 2009;Strenger et al, 2014). Amphotericin B (AmB), a hydrophobic antibiotic with a broad antifungal spectrum, is commonly used in the treatment of severe systemic fungal infections (Cifani et al, 2012;Strenger et al, 2014).…”

“…In premature infants and paediatric patients, Candida meningoencephalitis is a particularly serious nosocomial fungal infection (Groll et al, 2000;Kang et al, 2009;Strenger et al, 2014). Amphotericin B (AmB), a hydrophobic antibiotic with a broad antifungal spectrum, is commonly used in the treatment of severe systemic fungal infections (Cifani et al, 2012;Strenger et al, 2014). However, the blood brain barrier (BBB) remains a pharmacological obstacle to commercial formulations of amphotericin B (Groll et al, 2000;Serena et al, 2007;Shao et al, 2010;Ruhnke et al, 2007).…”

Mind the Gaps: Ontogeny of Human Brain P-gp and Its Impact on Drug Toxicity

“…Human Protein expression of brain P-gp by immunohistochemistry of post-mortem human brain cortex samples (13) Gestational age c 21 days of rat age reported to correspond to around 1-2 years of human age; 9 months of Rhesus monkey age reported to correspond to around 4 years of human age (33,34) (58-60), the methods used were not sensitive enough to quantify the low concentrations expected due to high plasma protein binding of AmB. A more recent study in subjects approximately 8 years old used a highly sensitive AmB assay and established that CSF concentrations corresponded to 0.13% of serum levels (61); this translates into a CSF-to-free serum-level ratio of approximately 0.26 (assuming 99.5% plasma protein binding (62)), confirming restricted BBB penetration. AmB CSF concentrations reported in pre-term neonates are surprisingly high, i.e., up to 40-90% of the concentration measured in paired serum samples (63).…”