title: Assessing the antifungal activity and toxicity profile of amphotericin B lipid complex (ABLC; Abelcet) in combination with caspofungin in experimental systemic aspergillosis.
abstract: The purpose of this study was to assess the antifungal activity and renal and hepatic toxicity of amphotericin B lipid complex (ABLC; Abelcet) following co-administration of Caspofungin to rats infected with Aspergillus fumigatus. Aspergillus fumigatus inoculum (1.3-2.3 x 10(7) colony forming units [CFU]) was injected via the jugular vein; 48 h later male albino Sprague-Dawley rats (350-400 g) were administered either a single intravenous (i.v.) dose of Fungizone(R) (1 mg AmpB/kg), ABLC (1 or 5 mg AmpB/kg), or an equivalent volume of normal saline (NS) (vehicle control) once daily for 4 days. Rats were further randomized into groups to receive 3 mg/kg Caspofungin or physiologic saline i.v. once daily for 4 days. To assess antifungal activity, brain, lung, heart, liver, spleen, and kidney sections were homogenized with NS (2 mL; 1 g of each tissue/mL) and a 0.1-mL aliquot was spread plated onto a Sabouraud dextrose agar plate. The plates were incubated for 48 h at 37 degrees C, at which time the numbers of CFU were determined and corrected for tissue weight. To assess renal and hepatic toxicity, serum creatinine and aspartate aminotransferase levels were determined. Fungizone and ABLC at a dosing regimen of 1 mg/kg i.v. once daily for four consecutive days and Caspofungin at a dosing regimen of 3 mg/kg i.v. once daily for four consecutive days had similar effectiveness in decreasing the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to non-treated controls. A combination of ABLC (1 mg/kg i.v. x 4 days) and Caspofungin (3 mg/kg i.v. x 4 days) significantly decreased the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to Caspofungin alone and non-treated controls. ABLC at a dosing regiment of 5 mg/kg i.v. once daily for four consecutive days was more effective in decreasing the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to Fungizone or ABLC alone at 1 mg/kg and Caspofungin alone at 3 mg/kg. However, a combination of ABLC (5 mg/kg i.v. x 4 days) and Caspofungin (3 mg/kg i.v. x 4 days) was not more effective than ABLC at 5 mg/kg or the combination of ABLC at 1 mg/kg and Caspofungin 3 mg/kg in reducing the total number of Aspergillus fumigatus CFUs compared to controls. Except for non-treated infected control rats, none of the treatment groups tested displayed a greater than 50% increase in serum creatinine concentrations from baseline. In addition, only ABLC at a dosing regimen of 1 mg/kg i.v. once daily for four consecutive days displayed a greater than 50% increase in AST concentration from baseline. Taken together, these findings suggest that ABLC at 5 mg/kg once daily x 4 days appears to be the best therapeutic choice in this animal model.
authors.affiliation: Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Olena
authors.initials: O
authors.lastname: Sivak
authors.forename: Karen
authors.initials: K
authors.lastname: Bartlett
authors.forename: Verica
authors.initials: V
authors.lastname: Risovic
authors.forename: Eugene
authors.initials: E
authors.lastname: Choo
authors.forename: Fawziah
authors.initials: F
authors.lastname: Marra
authors.forename: D Scotty
authors.initials: DS
authors.lastname: Batty
authors.forename: Kishor M
authors.initials: KM
authors.lastname: Wasan
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000633:toxicity; D001228:Aspergillosis / Q000097:blood / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000254:growth & development; D000077336:Caspofungin; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D054714:Echinocandins; D006801:Humans; D055666:Lipopeptides; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000633:toxicity; D010713:Phosphatidylcholines / Q000008:administration & dosage* / Q000633:toxicity; D010715:Phosphatidylglycerols / Q000008:administration & dosage* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D054714:Echinocandins; D055666:Lipopeptides; D010456:Peptides, Cyclic; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; C068538:liposomal amphotericin B; D000666:Amphotericin B; D000077336:Caspofungin