In vitro activity of ibrexafungerp against clinically relevant echinocandin-resistant Candida strains

Abstract

Invasive candidiasis is a major hospital-acquired infection. Usually, echinocandins are considered first-line treatment. However, resistant phenotypes have emerged. Ibrexafungerp (IBX) is a new antifungal substance with potent anti-Candida activity. We challenged IBX with a library of 192 pheno-/genotypically echinocandin-resistant Candida isolates, focusing on the substance susceptibility, its activity on certain FKS hotspot (HS) mutated strains, and applying WTULs (wild-type upper limits). Therefore, a 9-year-old strain and patient data collection provided by the German National Reference Center for Invasive Fungal Infections were analyzed. Species identification was confirmed through ITS-sequencing. Molecular susceptibility testing was performed by sequencing HS of the FKS gene. Anidulafungin (AND) and IBX EUCAST-broth-microdilution was conducted. The four most common echinocandin-resistance mediating mutations were found in Candida glabrata [112/192 isolates; F659-(43×) and S663-(48×)] and Candida albicans [63/192 isolates; F641-(15×) and S645-(39×)]. Mutations at the HS-start sequence were associated with higher IBX MIC-values (F659 and F641 (MIC 50/90 mg/L: >4/>4 and 2/4 mg/L) in comparison to AND (F659 and F641 (MIC 50/90: 1/4 and 0.25/1 mg/L). MIC-values in HS-center mutations were almost equal [MIC50/90 in S663: 2/4 (AND and IBX); in S645: 0.5/1 (AND) and 0.25/1 (IBX) mg/L]. In total, 61 vs 78 of 192 echinocandin-resistant isolates may be classified as IBX wild type by applying WTULs, whereas the most prominent effect was seen in C. albicans [48% (30/63) vs 70% (44/63)]. IBX shows in vitro activity against echinocandin-resistant Candida and thus is an addition to the antifungal armory. However, our data suggest that this effect is more pronounced in C. albicans and strains harboring mutations, affecting the HS-center.

Keywords: Candida; anidulafungin; antifungal agents; antifungal susceptibility testing; echinocandin resistance; ibrexafungerp; invasive candidiasis; new antifungals.

Fig 1

IBX vs AND in vitro activity in the four most prevalent mutations affecting Candida glabrata (F659, S663) and Candida albicans (F641, S645). (A) Grouped bar diagram: MIC distribution and MIC 50/90 values of AND (purple) vs IBX (green) in C. glabrata F659 mutated strains. Scatter plot: AND vs IBX MIC-values in unique F659 alterations. All isolates sharing the same AND MIC-values share the same color (i.e., isolates with 4 mg/L and 2 mg/L are illustrated as purple dots and blue dots, respectively). Scattered lines indicate geometrical means. (B) Grouped bar diagram: MIC distribution and MIC 50/90 values of AND (purple) vs IBX (green) in C. glabrata S663 mutated strains. Scatter plot: AND vs IBX MIC-values in unique S663 alterations. All isolates sharing the same AND MIC-values share the same color. Scattered lines indicate geometrical means. (C) Grouped bar diagram: MIC distribution and MIC 50/90 values of AND (purple) vs IBX (green) in C. albicans F641 mutated strains. Scatter plot: AND vs IBX MIC-values in unique F641 alterations. All isolates sharing the same AND MIC-values share the same color. Scattered lines indicate geometrical means. (D) Grouped bar diagram: MIC distribution and MIC 50/90 values of AND (purple) vs IBX (green) in C. albicans S645 mutated strains. Scatter plot: AND vs IBX MIC-values in unique S645 alterations. All isolates sharing the same AND MIC-values share the same color. Scattered lines indicate geometrical means. Abbreviations: Anidulafungin (AND), Ibrexafungerp (IBX), Minimum inhibitory concentrations (MIC).

Fig 2

Comparison of anidulafungin and ibrexafungerp in vitro activity in FKS HS-mutated C. glabrata isolates. Hotspot (HS). Calculating geometrical mean values beyond 4 mg/L: >4 mg/L values were defined as 8 mg/L and listed in brackets. HS were categorized as follows: (i) start sequence: first two AA with red background, (ii) center sequence with green background, and (iii) end sequence: last two AA with yellow background.

Fig 3

Comparison of anidulafungin and ibrexafungerp in vitro activity in FKS HS-mutated C. albicans isolates. Hotspot (HS). Calculating geometrical mean values beyond 4 mg/L: >4 mg/L values were defined as 8 mg/L and listed in brackets. HS were categorized as follows: (i) start sequence: first two AA with red background, (ii) center sequence with green background, and (iii) end sequence: last two AA with yellow background. Outside the known hotspots (Out of HS). D1337 described by Arendrup et al. (24). One strain with a double center mutation was found in S645P and R1361G.

Fig 4

Comparison of anidulafungin and ibrexafungerp in vitro activity in less-abundant Candida isolates, harboring FKS HS alternations. Hotspot (HS). Calculating geometrical mean values beyond 4 mg/L: >4 mg/L values were defined as 8 mg/L and listed in brackets. HS were categorized as follows: (i) start sequence: first two AA with red background, (ii) center sequence with green background, and (iii) end sequence: last two AA with yellow background. One C. tropicalis strain harbored a start (L642Y) and end (D648Y) mutation.