title: Attenuation of echinocandin activity at elevated concentrations: a review of the paradoxical effect.
abstract: OBJECTIVE
  The echinocandins have been a welcome addition for the treatment of invasive fungal infections caused by Candida and Aspergillus species. Despite their excellent safety profile and clinical efficacy, concerns exist regarding an attenuation of activity at higher concentrations, known as the paradoxical effect. This article will review the literature describing this effect, the potential mechanisms responsible for it, and the clinical implications of this phenomenon.
  
  
  RESULTS
  In-vitro studies have reported a paradoxical effect at higher concentrations against both Candida and Aspergillus species. Recent data have demonstrated this effect in Candida to be species related and echinocandin specific. Although not completely understood, studies have pointed towards involvement of the protein kinase C cell wall integrity and calcineurin pathways as well as increases in cell wall chitin content as potential mechanisms behind the effect. Although some in-vivo studies with echinocandins have reported a paradoxical increase in markers of invasive disease, clinical data are scarce.
  
  
  CONCLUSIONS
  The clinical implications of the paradoxical attenuation of echinocandin activity observed in vitro and in vivo remain unknown. A complete understanding of this effect may further our knowledge of fungal responses to echinocandin cell wall damage and potentially improve treatment strategies.
authors.affiliation: The University of Texas at Austin College of Pharmacy, Austin, Texas, USA. wiederholdn@uthscsa.edu
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Wiederhold
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins / Q000494:pharmacology*; D006801:Humans; D009181:Mycoses / Q000188:drug therapy*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins