Paradoxical echinocandin activity: a limited in vitro phenomenon?

The echinocandins have been a welcome addition for the treatment of invasive fungal infections. Despite their excellent safety profile and clinical efficacy, concerns exist regarding an attenuation of activity at higher concentrations, known as the paradoxical effect. In vitro studies have reported this phenomenon against both Candida and Aspergillus species. Recent data have also demonstrated this effect to be species-related and echinocandin specific. Although not completely understood, studies have pointed towards involvement of the protein kinase C cell wall integrity pathway as well as increases in cell wall chitin content as potential mechanisms responsible for this phenomenon. Increases in galactomannan have been reported in vitro and in vivo following echinocandin exposure. Although some in vivo studies of invasive aspergillosis have also reported a paradoxical increase in other markers of invasive disease and fungal burden with echinocandin therapy, these observations are inconsistent. The paradoxical effect has also not been demonstrated clinically. Thus, the clinical implications of the paradoxical attenuation of echinocandin activity at elevated concentrations 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.