The Eagle-like effect of echinocandins: what’s in a name?

Abstract

Despite several years of research, a lot of questions remain about the paradoxical attenuation of echinocandin activity against Candida and Aspergillus species at certain drug concentrations above the MIC values, the so-called paradoxical growth effect or Eagle-like effect. Although this phenomenon has been observed in several in vitro studies, confirming in vivo data are scarce. The clinical relevance remains unknown, although more and more data suggest that the clinical impact of this phenomenon might be heavily overrated. Detailed knowledge about the mechanisms responsible for this phenomenon and further research about the presence of the effect in the human body is necessary to decide whether the paradoxical growth effect of echinocandins can really interfere with an adequate treatment of invasive fungal diseases in clinical practice.

Keywords::

• anidulafungin
• Aspergillus spp.
• Candida spp.
• caspofungin
• Eagle effect
• Eagle-like effect
• echinocandins
• micafungin
• paradoxical growth

Financial & competing interests disclosure

K Vanstraelen has received travel support from Gilead, MSD and Pfizer and received lecture honoraria from Pfizer. K Lagrou has received research grants from Gilead, MSD and Pfizer, received travel support from Gilead, MSD and Pfizer and received lecture honoraria from Gilead, MSD and Pfizer. J Maertens has received research grants from Gilead, MSD, Pfizer and Astellas, received travel support from Gilead, MSD, Pfizer and Astellas and received lecture honoraria from Gilead, MSD, Pfizer and Astellas. I Spriet has received research grants from MSD and Pfizer, received travel support from Gilead, MSD and Pfizer and received lecture honoraria from Gilead, MSD and Pfizer. J Wauters has received research grants from MSD and Pfizer, and received travel support from MSD and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Paradoxical fungal growth as response to echinocandins was first discovered in 1988 with the investigational drug cilofungin. Clinical relevance of these in vitro observations was never explored for cilofungin because the drug was not approved for clinical use.

• • The paradoxical growth effect (PGE) has been shown in vitro with caspofungin, anidulafungin and micafungin, against several Aspergillus and Candida spp., but not against Candida glabrata. The phenomenon seems to be echinocandin-specific, species-specific and strain-specific, and the extent to which the PGE is manifested, can be influenced by the media and methods used for susceptibility tests.

• • The paradoxical effect of echinocandins is quadriphasic, and can be overcome by increasing the drug concentration.

• • In Candida spp., a weaker version of the PGE is also documented, the so-called ‘mini-paradoxical growth effect’, in which no complete re-growth of the Candida spp. is seen at a certain concentration range, but rather a survival of fungal cells despite exposure to echinocandins.

• • The underlying mechanisms are still being investigated, but the main associated molecular pathways are the calcineurin pathway, the protein kinase C pathway, the high-osmolarity glycerol response pathway and heat shock protein 90, all resulting in an increased chitin content in the fungal cell wall as response to increasing cell wall stress and a decreased amount of β-glucan in the cell wall. The exact role of the host immune system in causing a PGE in vivo is still unclear, but as the strong interplay between antifungals and the host immune system already has been proven, it could be of importance.

• • The PGE disappears in vitro in the presence of human plasma.

• • Concentrations reached in human plasma in clinical practice are in the range of those causing PGE in vitro.

• • The paradoxical growth is not reproduced repeatedly in murine models and until now, there is no proof of the PGE in humans.

Notes