Fatal Breakthrough Candidemia in an Immunocompromised Patient in Kuwait Due to Candida auris Exhibiting Reduced Susceptibility to Echinocandins and Carrying a Novel Mutation in Hotspot-1 of FKS1

Abstract

Candida auris is an emerging yeast pathogen that has recently caused major outbreaks in healthcare facilities worldwide. Clinical C. auris isolates are usually resistant to fluconazole and readily develop resistance to echinocandins and amphotericin B (AMB) during treatment. We describe here an interesting case of C. auris infection in an immunocompromised patient who had previously received AMB and caspofungin treatment. Subsequently, C. auris was isolated from tracheal (tracheostomy) secretions and twice from urine and all three isolates were susceptible to AMB and micafungin. The patient received a combination therapy with AMB and caspofungin. Although the C. auris was cleared from the urine, the patient subsequently developed breakthrough candidemia and the bloodstream isolate exhibited a reduced susceptibility to micafungin and also showed the presence of a novel (S639T) mutation in hotspot-1 of FKS1. Interestingly, C. auris from the tracheal (tracheostomy) secretions recovered one and four days later exhibited a reduced susceptibility to micafungin and S639Y and S639T mutations in hotspot-1 of FKS1, respectively. Although the treatment was changed to voriconazole, the patient expired. Our case highlights a novel FKS1 mutation and the problems clinicians are facing to treat invasive C. auris infections due to inherent or developing resistance to multiple antifungal drugs and limited antifungal armamentarium.

Synergistic Interaction of Caspofungin Combined with Posaconazole against FKS Wild-Type and Mutant Candida auris Planktonic Cells and Biofilms

“…The FKS point mutations described in our study were detected previously (S639Y, S639P, and R1354H). Al-Obaid et al (2022) reported that isolates containing the S639Y or S639P mutation in hot-spot 1 of FKS1 exhibited reduced susceptibility to echinocandins, especially against micafungin [ 36 ]. Asadzadeh et al (2022) also described isolates with decreased sensitivity to echinocandins carrying an R1354H mutation in hot-spot 2 of FKS1 [ 37 ].…”

Synergistic interaction of caspofungin combined with posaconazole against FKS wild-type and mutant Candida auris planktonic cells and biofilms

“…The FKS point mutations described in our study were detected previously (S639Y, S639P and R1354H). Al-Obaid et al (2022) reported that isolates containing the S639Y or S639P mutation in hot spot 1 of FKS1 exhibited reduced susceptibility to echinocandins, especially against micafungin. Asadzadeh et al (2022) also described isolates with decreased sensitivity to echinocandins carrying a R1354H mutation in hot spot 2 of FKS1.…”

Strategies to Prevent Transmission of Candida auris in Healthcare Settings

“…Echinocandin resistance in C. auris mainly involves nonsynonymous mutations in the hotspot-1 (HS-1) and HS-2 regions of FKS1 encoding 1,3 β-D-glucan synthase. Most genetic alterations occur at codon 639 in HS-1 of FKS1 gene (Table 1 ) [ 43 , 60 , 71 , 78 , 79 ]. Two nonsynonymous mutations (F635L and F635Y) as well as deletion of codon F635 and D642Y mutation within HS-1 of FKS1 have been detected in some echinocandin-resistant C. auris [ 40 , 43 , 78 , 79 ].…”

“…Most genetic alterations occur at codon 639 in HS-1 of FKS1 gene (Table 1 ) [ 43 , 60 , 71 , 78 , 79 ]. Two nonsynonymous mutations (F635L and F635Y) as well as deletion of codon F635 and D642Y mutation within HS-1 of FKS1 have been detected in some echinocandin-resistant C. auris [ 40 , 43 , 78 , 79 ]. Two nonsynonymous mutations (R1354S and R1354H) have also been found within HS-2 of FKS1 (Table 1 ) [ 43 , 79 ].…”

“…Two nonsynonymous mutations (R1354S and R1354H) have also been found within HS-2 of FKS1 (Table 1 ) [ 43 , 79 ]. Clinical C. auris isolates with identical FKS1 mutations exhibit variable susceptibility to echinocandins (different MIC values) likely due to differences in their genetic background [ 35 •, 43 , 78 , 79 ]. Also, patients infected with C. auris strains carrying different FKS1 mutations show variable in vivo response to treatment with antifungal drugs suggesting differences in fitness cost associated with these mutations [ 43 , 78 , 80 ].…”