Celeste Alvarez1, David R Andes2, Jeong Yeon Kang1, Carmen Krug1, Glen S Kwon3. 1. Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA. 2. Section of Infectious Diseases, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53705-2281, USA. 3. Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA. glen.kwon@wisc.edu.
Abstract
PURPOSE: Amphotericin B (AmB) and 5-fluorocytosine (5-FC) exhibit additive to synergistic activity against systemic mycoses. Incompatibility of prescribed formulations precludes concomitant IV administration, a route with distinct advantages. Previously, we used PEG-DSPE micelles to produce a reformulation of Fungizone (AmB-SD), AmB solubilized by sodium deoxycholate, called mAmB-90. Herein, we describe a second reformulation that facilitates co-delivery of mAmB-90 and 5-FC, and evaluate the effect of PEG-DSPE micelles on the combination's activity against Candida albicans. METHODS: We assessed the effect of 5-FC addition on the stability, in vitro toxicity, and antifungal efficacy of mAmB-90. The aggregation state and particle size of mAmB-90 combined with 5-FC (FmAmB-90) was evaluated over 48 h. Hemolytic activity was measured in vitro. Antifungal activity was determined in vitro against C. albicans. The efficacy of monotherapy and combination treatment was evaluated in a neutropenic mouse model of disseminated candidiasis. RESULTS: The aggregation state, particle size, and hemolytic activity of mAmB-90 were unaffected by 5-FC. While antifungal activity was similar in vitro, mAmB-90 alone and combined with 5-FC was more potent than AmB-SD in vivo. CONCLUSIONS: Short-term stability and in vivo efficacy of our formulation suggest potential to simultaneously deliver AmB and 5-FC for potent antifungal efficacy.
PURPOSE:Amphotericin B (AmB) and 5-fluorocytosine (5-FC) exhibit additive to synergistic activity against systemic mycoses. Incompatibility of prescribed formulations precludes concomitant IV administration, a route with distinct advantages. Previously, we used PEG-DSPE micelles to produce a reformulation of Fungizone (AmB-SD), AmB solubilized by sodium deoxycholate, called mAmB-90. Herein, we describe a second reformulation that facilitates co-delivery of mAmB-90 and 5-FC, and evaluate the effect of PEG-DSPE micelles on the combination's activity against Candida albicans. METHODS: We assessed the effect of 5-FC addition on the stability, in vitro toxicity, and antifungal efficacy of mAmB-90. The aggregation state and particle size of mAmB-90 combined with 5-FC (FmAmB-90) was evaluated over 48 h. Hemolytic activity was measured in vitro. Antifungal activity was determined in vitro against C. albicans. The efficacy of monotherapy and combination treatment was evaluated in a neutropenicmouse model of disseminated candidiasis. RESULTS: The aggregation state, particle size, and hemolytic activity of mAmB-90 were unaffected by 5-FC. While antifungal activity was similar in vitro, mAmB-90 alone and combined with 5-FC was more potent than AmB-SD in vivo. CONCLUSIONS: Short-term stability and in vivo efficacy of our formulation suggest potential to simultaneously deliver AmB and 5-FC for potent antifungal efficacy.
Entities:
Keywords:
5-fluorocytosine; Aggregation state hypothesis; Amphotericin B; Candida albicans; PEG-DSPE
Authors: Annemarie E Brouwer; Hendrikus J M van Kan; Elizabeth Johnson; Adul Rajanuwong; Prapit Teparrukkul; Vannaporn Wuthiekanun; Wirongrong Chierakul; Nick Day; Thomas S Harrison Journal: Antimicrob Agents Chemother Date: 2006-12-28 Impact factor: 5.191
Authors: Pranab K Mukherjee; Daniel J Sheehan; Christopher A Hitchcock; Mahmoud A Ghannoum Journal: Clin Microbiol Rev Date: 2005-01 Impact factor: 26.132
Authors: A M Stamm; R B Diasio; W E Dismukes; S Shadomy; G A Cloud; C A Bowles; G H Karam; A Espinel-Ingroff Journal: Am J Med Date: 1987-08 Impact factor: 4.965