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Echinocandin Resistance

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Antimicrobial Drug Resistance
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Abstract

Fungal diseases cause life-threatening illnesses such as meningitis and pneumonias, chronic asthma, other respiratory diseases, and recurrent diseases like oral and vaginal thrush. Invasive fungal infections are a consequence of underlying health problems often associated with immunosuppression [1]. Fungal infections often carry high mortality and successful patient management requires antifungal therapy. Yet, treatment options remain extremely limited due to limited classes of antifungal agents and by the emergence of prominent antifungal drug resistance. Currently registered antifungal drugs represented by polyenes and azoles, flucytosine, and echinocandins target the cell membrane, nucleic acid biosynthesis, and cell wall, respectively [2]. The latter and most recently approved class, the echinocandins, are now recommended as primary therapy for non-neutropenic patients with invasive candidiasis [3]. It is estimated that 60 % of candidemia patients now receive an echinocandin for treatment or prophylaxis [4]. As worldwide use of echinocandins broadens, clinical failures due to resistant organisms are a concern, especially among certain Candida species. The development of echinocandin resistance among most susceptible organisms like Candida albicans is an uncommon event. Yet, there is a disturbing trend of increased resistance among strains of Candida glabrata, which are frequently cross-resistant to azole drugs. Echinocandin resistance is acquired during therapy and its mechanism is firmly established to involve amino acid changes in “hot-spot” regions of the Fks subunits of the target glucan synthase. These changes significantly decrease the sensitivity of the enzyme to drug resulting in higher MIC values and reduced pharmacodynamic responses. Biological factors that promote selection of Fks-resistant strains involve complex cellular stress response pathways. The use of broth microdilution assays to assess susceptibility can be problematic with some drug- and species-related variability among clinical microbiology laboratories. Clinical factors promoting resistance include expanding use of echinocandins for therapy and prophylaxis, and localized reservoirs such as those in the gastrointestinal tract or intra-abdominal infections, which can seed emergence of resistant organisms. A basic understanding of the resistance mechanism, along with cellular and clinical factors promoting resistance, will promote better strategies to overcome and prevent echinocandin resistance.

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Acknowledgments

David S. Perlin is supported by grants from National Institutes of Health (AI069397 and AI109025) and Astellas Pharma.

Disclosures 

Dr. Perlin serves on scientific advisory boards for Merck, Astellas, Amplyx, Cidara,and Synexis and he receives grant support from Astellas, Cidara and Amplyx. He is an inventor in US patent 8,753,819 entitled “Assays for Resistance to Echinocandin-Class Drugs.”

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Perlin, D.S. (2017). Echinocandin Resistance. In: Mayers, D., Sobel, J., Ouellette, M., Kaye, K., Marchaim, D. (eds) Antimicrobial Drug Resistance. Springer, Cham. https://doi.org/10.1007/978-3-319-46718-4_29

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