The caspofungin paradoxical effect is a tolerant "Eagle effect" in the filamentous fungal pathogen Aspergillus fumigatus

Cell
responses against antifungals different from resistance have been rarely
studied in filamentous fungi, while terms such as tolerance and persistence are
well-described for bacteria and increasingly examined in yeast-like organisms. Aspergillus
fumigatus is
a filamentous
fungal pathogen that
causes a disease named aspergillosis and caspofungin (CAS), a fungistatic drug, used as second-line therapy.
Some A. fumigatus clinical isolates can survive and grow in CAS concentrations above the minimum effective
concentration (MEC), a phenomenon known as “caspofungin paradoxical effect” (CPE).
Here we evaluated the CPE in 67 A.
fumigatus clinical isolates by calculating the Recovery Rate (RR) value, where
isolates with RR ≥ 0.1 are considered CPE+ while isolates with RR
< 0.1 are classified as CPE-.
Conidia produced by three CPE+ clinical isolates, CEA17 (RR=0.42), Af293 (RR=0.59), CM7555 (RR=0.38) all showed the ability to
grow in high levels of CAS while all conidia produced by the CPE- isolate IFM61407 (RR=0.00)
showed no evidence of paradoxical growth. Given the importance of
calcium/calcineurin/transcription factor CrzA pathway in CPE regulation, we also demonstrated that all ΔcrzACEA17
(CPE+) conidia showed CPE while 100% of ΔcrzAAf293 (CPE-) were CPE-. As
all spores derived from an individual strain were phenotypically indistinct
with respect to CPE it is likely that CPE is a genetically encoded adaptive trait that should be considered an antifungal tolerant
phenotype. As the RR parameter shows
that the strength of the CPE is not
uniform between strains, we propose that the mechanisms that govern this
phenomenon are multi-factorial.