title: Antifungal Efficacy of an Intravenous Formulation Containing Monomeric Amphotericin B, 5-Fluorocytosine, and Saline for Sodium Supplementation.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Short-term stability and in vivo efficacy of our formulation suggest potential to simultaneously deliver AmB and 5-FC for potent antifungal efficacy.
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA.
authors.forename: Celeste
authors.initials: C
authors.lastname: Alvarez
authors.affiliation: Section of Infectious Diseases, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53705-2281, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA.
authors.forename: Jeong Yeon
authors.initials: JY
authors.lastname: Kang
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Krug
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA. glen.kwon@wisc.edu.
authors.forename: Glen S
authors.initials: GS
authors.lastname: Kwon
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003840:Deoxycholic Acid / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D005437:Flucytosine / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D008823:Micelles; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D012964:Sodium / Q000494:pharmacology*; D012965:Sodium Chloride / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D004337:Drug Carriers; D008823:Micelles; D010714:Phosphatidylethanolamines; C107570:polyethylene glycol-distearoylphosphatidylethanolamine; D003840:Deoxycholic Acid; D011092:Polyethylene Glycols; D012965:Sodium Chloride; D000666:Amphotericin B; D012964:Sodium; D005437:Flucytosine
keywords: 5-fluorocytosine; Aggregation state hypothesis; Amphotericin B; Candida albicans; PEG-DSPE