Effects of dosing regimen on accumulation, retention and prophylactic efficacy of liposomal amphotericin B.
OBJECTIVE
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 microg/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.
Smith
Peter J
PJ
Department of Biological Sciences, California State Polytechnic University, Pomona, CA 91768, USA.
Olson
Jon A
JA
Constable
David
D
Schwartz
Julie
J
Proffitt
Richard T
RT
Adler-Moore
Jill P
JP
D000666:Amphotericin B / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D019072:Antibiotic Prophylaxis; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects*; D041221:Candida glabrata / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy* / Q000517:prevention & control*; D005260:Female; D007668:Kidney / Q000187:drug effects; D008081:Liposomes; D051379:Mice; D008811:Mice, Inbred DBA; D013154:Spleen / Q000187:drug effects
D000935:Antifungal Agents; D008081:Liposomes; C068538:liposomal amphotericin B; D000666:Amphotericin B