JAC Advance Access originally published online on March 30, 2007
Journal of Antimicrobial Chemotherapy 2007 59(5):941-951; doi:10.1093/jac/dkm077
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Effects of dosing regimen on accumulation, retention and prophylactic efficacy of liposomal amphotericin B
1 Department of Biological Sciences, California State Polytechnic University, Pomona, CA 91768, USA 2 Pathology Associates Division, Charles River Laboratories, Inc., Davis, CA 95616, USA 3 RichPro Associates, 2095 Lavender Hill Ct., Lincoln, CA 95648, USA
Received 19 December 2006; returned 9 January 2007; revised 10 February 2007; accepted 12 February 2007
* Corresponding author. Tel: +1-909-869-4047; Fax: +1-909-869-4078; E-mail: jpadler{at}csupomona.edu
Objectives: We hypothesized that effective prophylactic treatment of fungal infections would require adequate drug penetration and retention at potential infection sites. Using a mouse model, we examined liposomal amphotericin B (L-AmB) biodistribution, cell localization and retention in kidneys, lungs, liver and spleen to evaluate effective dosing regimens for prophylaxis of Candida glabrata and Candida albicans infections.
Methods: Following treatment of mice with cumulative doses of L-AmB (60–225 mg/kg), a bioassay was done to determine tissue drug concentrations 12 h to 6 weeks post-treatment. Immunohistochemical staining with anti-amphotericin B antibodies was used for cellular drug localization. Mice were treated prophylactically with 15–90 mg/kg L-AmB and challenged intravenously 1–7 days later with C. glabrata or they were given a total of 60 mg/kg as daily or intermittent dosing followed by intravenous challenge with C. albicans 3 or 6 weeks later.
Results: On the basis of µg/g tissue, the relative amount of drug was in the order spleen > liver > kidneys > lungs. Amphotericin B levels were maintained above the MIC for many fungi for 1 week in lungs and for as long as 6 weeks in kidneys and spleen. Drug localized in kidney tubular epithelial cells and in macrophages of liver and spleen. In prophylactic models, fungal burden was reduced by several 1000-fold or was undetectable within target tissues (kidneys, spleen).
Conclusions: These observations underscore the importance of including drug tissue levels to obtain a better understanding of L-AmB efficacy. The sustained concentrations of bioactive AmB in many tissues provide a further rationale for investigating L-AmB prophylactic regimens.
Keywords: lipid formulations , bioavailability , candidiasis , antifungal agents