Echinocandin Resistance in Candida

Abstract

Invasive fungal infections are an important infection concern for patients with underlying immunosuppression. Antifungal therapy is a critical component of patient care, but therapeutic choices are limited due to few drug classes. Antifungal resistance, especially among Candida species, aggravates the problem. The echinocandin drugs (micafungin, anidulafungin, and caspofungin) are the preferred choice to treat a range of candidiasis. They target the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a major cell wall polymer. Therapeutic failure involves acquisition of resistance, although it is a rare event among most Candida species. However, in some settings, higher-level resistance has been reported among Candida glabrata, which is also frequently resistant to azole drugs, resulting in difficult-to-treat multidrug-resistant strains. The mechanism of echinocandin resistance involves amino acid changes in "hot spot" regions of FKSencoded subunits of glucan synthase, which decreases the sensitivity of enzyme to drug, resulting in higher minimum inhibitory concentration values. The cellular processes promoting the formation of resistant FKS strains involve complex stress response pathways that yield a variety of adaptive compensatory genetic responses. Standardized broth microdilution techniques can be used to distinguish FKS mutant strains from wild type, but testing C. glabrata with caspofungin should be approached cautiously. Finally, clinical factors that promote echinocandin resistance include prophylaxis, host reservoirs including biofilms in the gastrointestinal tract, and intra-abdominal infections. An understanding of clinical and molecular factors that promote echinocandin resistance is critical to develop better diagnostic tools and therapeutic strategies to overcome resistance.

Molecular Confirmation of the Relationship between Candida guilliermondii Fks1p Naturally Occurring Amino Acid Substitutions and Its Intrinsic Reduced Echinocandin Susceptibility

“…It is well known that echinocandin clinical resistance is linked to FKS hot spot substitutions (5). The 32-fold increases in echinocandins MICs observed for the seven chimeric S. cerevisiae mutants support the assumption that L633M and T634A polymorphisms at C. guilliermondii Fks1p hot spot 1 are responsible for the observed RES in this species.…”

“…Echinocandin drugs interact with the Fksp subunits of the ␤-1,3-glucan synthase complex, inhibiting the biosynthesis of the principal cell wall glucan. Clinical resistance was linked to hot spot mutations in Fksp (5). It was molecularly confirmed that the C. parapsilosis sensu lato RES phenotype is due to a naturally occurring substitution (P660A) in the hot spot 1 region of Fks1p (8).…”

“…are susceptible to these drugs (1)(2)(3)(4). However, some highly prevalent Candida spp., such as species of the Candida parapsilosis complex and Candida guilliermondii, show natural reduced echinocandin susceptibility (RES) (5)(6)(7). Echinocandin drugs interact with the Fksp subunits of the ␤-1,3-glucan synthase complex, inhibiting the biosynthesis of the principal cell wall glucan.…”

“…It was molecularly confirmed that the C. parapsilosis sensu lato RES phenotype is due to a naturally occurring substitution (P660A) in the hot spot 1 region of Fks1p (8). C. guilliermondii harbors two polymorphisms (L633M and T634A) in the same Fks1p region; it was assumed that the RES in this species is attributable to these amino acid substitutions, but the hypothesis was never confirmed (5).…”

Frequency of the Paradoxical Effect Measured Using the EUCAST Procedure with Micafungin, Anidulafungin, and Caspofungin against Candida Species Isolates Causing Candidemia

“…T reatment with echinocandins, i.e., caspofungin, micafungin, and anidulafungin, is recommended as the primary therapy for patients with candidemia (1,2). Rates of resistance are low (3), but attenuation of activity at high concentrations, known as the paradoxical or Eagle effect, has been reported (4)(5)(6)(7).…”