Relative Frequency of Paradoxical Growth and Trailing Effect with Caspofungin, Micafungin, Anidulafungin, and the Novel Echinocandin Rezafungin against Candida Species

Abstract

Rezafungin is a next-generation echinocandin that has favorable pharmacokinetic properties. We compared the occurrence of paradoxical growth (PG) and trailing effect (TE) characteristics to echinocadins with rezafungin, caspofungin, micafungin and anidulafungin using 365 clinical Candida isolates belonging to 13 species. MICs were determined by BMD method according to CLSI (M27 Ed4). Disconnected growth (PG plus TE) was most frequent with caspofungin (49.6%), followed by anidulafungin (33.7%), micafungin (25.7%), while it was least frequent with rezafungin (16.9%). PG was relatively common in the case of caspofungin (30.1%) but was rare in the case of rezafungin (3.0%). C. tropicalis, C. albicans, C. orthopsilosis and C. inconspicua exhibited PG most frequently with caspofungin, micafungin or anidulafungin. PG never occurred in the case of C. krusei isolates. Against C. tropicalis and C. albicans, echinocandins frequently showed PG after 24 h followed by TE after 48 h. All four echinocandins exhibited TE for the majority of C. auris and C. dubliniensis isolates. Disconnected growth was common among Candida species and was echinocandin- and species-dependent. In contrast to earlier echinocandins, PG was infrequently found with rezafungin.

Comparison of In Vitro Killing Activity of Rezafungin, Anidulafungin, Caspofungin, and Micafungin against Four Candida auris Clades in RPMI-1640 in the Absence and Presence of Human Serum

“…Another explanation for the weak fungistatic effect of echinocandins is that decreased amount of β-glucan induces a variety of stress adaptation pathways resulting in increased cell wall chitin [ 10 , 24 , 25 , 26 ]. Increased chitin content helps to stabilize the fungal cell wall, therefore mitigating the impact of echinocandins.…”

“…Increased chitin content helps to stabilize the fungal cell wall, therefore mitigating the impact of echinocandins. Although this adaptive response does not lead to mutations in the FKS genes, the early adaptation to echinocandin exposure enhances survival of the drug effect and may allow the development of stable resistance mechanisms over time for surviving cells, possibly leading to clinical resistance in the long run [ 24 , 25 , 26 ]. The mini-paradoxical effect in RPMI-1640, which disappeared in the case of some isolates in the presence of serum, may represent such adaptation.…”

In Vitro Interaction and Killing-Kinetics of Amphotericin B Combined with Anidulafungin or Caspofungin against Candida auris

“…Additionally, it has been suggested that the aggregation may not be enough for C. auris isolates to overcome echinocandin exposure [ 10 ], while other mechanisms have also been proposed to explain the limited fungistatic activity of echinocandins, such as the increased cell wall chitin as a response to the decrease in the amount of β-glucan induced by the echinocandin exposure [ 27 , 28 ]. In this line, other reports found increased chitin amounts in C. auris , compared to other species more susceptible to echinocandin drugs [ 29 ].…”

Proteomic Analysis of Caspofungin-Induced Responses in Planktonic Cells and Biofilms of Candida albicans

“…Elevated chitin biosynthesis is linked with reduced susceptibility to echinocandins both in vitro and in vivo ( Perlin, 2015 ). Indeed, increased chitin content of cell wall has been observed during the paradoxical growth of Candida species, representing a rescue mechanism against high levels of echinocandins ( Stevens et al, 2004 ; Melo et al, 2007 ; Rueda et al, 2014 ; Toth et al, 2020 ). Additionally, ergosterol is a major constituent of the fungal plasma membrane ( Dupont et al, 2012 ).…”