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The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Candida glabrata Colonization Mouse Model

BACKGROUND: Gastrointestinal (GI) Candida commensals may be a major source of invasive candidiasis and a hidden reservoir of antifungal resistance. Candida glabrata resistance rates have increased greater than those of other species. Here, we present a C. glabrata GI colonization model to explore ho...

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Autores principales: Healey, Kelley, Zhao, Yanan, Nagasaki, Yoji, Park, Steven, Perlin, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5631610/
http://dx.doi.org/10.1093/ofid/ofx163.180
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author Healey, Kelley
Zhao, Yanan
Nagasaki, Yoji
Park, Steven
Perlin, David
author_facet Healey, Kelley
Zhao, Yanan
Nagasaki, Yoji
Park, Steven
Perlin, David
author_sort Healey, Kelley
collection PubMed
description BACKGROUND: Gastrointestinal (GI) Candida commensals may be a major source of invasive candidiasis and a hidden reservoir of antifungal resistance. Candida glabrata resistance rates have increased greater than those of other species. Here, we present a C. glabrata GI colonization model to explore how antifungal drugs affect resistance acquisition and systemic breakthrough infections. METHODS: Immunocompetent mice were treated with antibiotics to clear native GI bacteria and then inoculated via oral gavage with C. glabrata. Fecal samples were collected throughout the study to assess fungal GI colonization. Daily administration of caspofungin (CSF; 5 or 20 mg/kg i.p.), chitin synthase inhibitor nikkomycin Z (Nz; 100 mg/kg oral), or saline was initiated on day 3 post inoculation. CSF-resistant colony frequencies were determined through selection of fecal samples on CSF-supplemented media, and FKS mutations were identified using the newly developed molecular beacon diagnostic assays. Dexamethasone was administered to induce immunosuppression. Upon completion of the experiment, blood, and organs were harvested and yeast burden levels determined. RESULTS: Daily therapeutic dosing (5 mg/kg) of CSF resulted in no reduction in fecal burdens, little resistance (0–10%), and organ breakthrough rates similar to control groups. Treatment with high dose (20 mg/kg) CSF caused a 2.5-log decrease in average burden, yet high levels (10/10 mice) of resistance (fks1/2 mutants) were observed following 5–9 days of treatment. Although breakthrough rates decreased in this group, yeast recovered from organs contained fks mutations. The largest reduction (3 log) in GI burdens was obtained within 3–5 days of high dose CSF plus Nz (100 mg/kg; oral) treatment. However, echinocandin resistance was again observed from all mice (10/10) following 5–7 days of treatment. Treatment with the therapeutic dose plus Nz left GI burdens unchanged, but did significantly reduce organ breakthrough rates (20%; P < 0.05). CONCLUSION: We have developed a C. glabrata GI colonization and dissemination model. Systemic breakthrough depends on both gut C. glabrata population composition and serum/tissue drug level. DISCLOSURES: D. Perlin, Merck: Grant Investigator and Scientific Advisor, Research support Pfizer: Grant Investigator, Research support. Astellas: Consultant and Grant Investigator, Research support and Speaker honorarium. F2G: Consultant, Consulting fee
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spelling pubmed-56316102017-11-07 The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Candida glabrata Colonization Mouse Model Healey, Kelley Zhao, Yanan Nagasaki, Yoji Park, Steven Perlin, David Open Forum Infect Dis Abstracts BACKGROUND: Gastrointestinal (GI) Candida commensals may be a major source of invasive candidiasis and a hidden reservoir of antifungal resistance. Candida glabrata resistance rates have increased greater than those of other species. Here, we present a C. glabrata GI colonization model to explore how antifungal drugs affect resistance acquisition and systemic breakthrough infections. METHODS: Immunocompetent mice were treated with antibiotics to clear native GI bacteria and then inoculated via oral gavage with C. glabrata. Fecal samples were collected throughout the study to assess fungal GI colonization. Daily administration of caspofungin (CSF; 5 or 20 mg/kg i.p.), chitin synthase inhibitor nikkomycin Z (Nz; 100 mg/kg oral), or saline was initiated on day 3 post inoculation. CSF-resistant colony frequencies were determined through selection of fecal samples on CSF-supplemented media, and FKS mutations were identified using the newly developed molecular beacon diagnostic assays. Dexamethasone was administered to induce immunosuppression. Upon completion of the experiment, blood, and organs were harvested and yeast burden levels determined. RESULTS: Daily therapeutic dosing (5 mg/kg) of CSF resulted in no reduction in fecal burdens, little resistance (0–10%), and organ breakthrough rates similar to control groups. Treatment with high dose (20 mg/kg) CSF caused a 2.5-log decrease in average burden, yet high levels (10/10 mice) of resistance (fks1/2 mutants) were observed following 5–9 days of treatment. Although breakthrough rates decreased in this group, yeast recovered from organs contained fks mutations. The largest reduction (3 log) in GI burdens was obtained within 3–5 days of high dose CSF plus Nz (100 mg/kg; oral) treatment. However, echinocandin resistance was again observed from all mice (10/10) following 5–7 days of treatment. Treatment with the therapeutic dose plus Nz left GI burdens unchanged, but did significantly reduce organ breakthrough rates (20%; P < 0.05). CONCLUSION: We have developed a C. glabrata GI colonization and dissemination model. Systemic breakthrough depends on both gut C. glabrata population composition and serum/tissue drug level. DISCLOSURES: D. Perlin, Merck: Grant Investigator and Scientific Advisor, Research support Pfizer: Grant Investigator, Research support. Astellas: Consultant and Grant Investigator, Research support and Speaker honorarium. F2G: Consultant, Consulting fee Oxford University Press 2017-10-04 /pmc/articles/PMC5631610/ http://dx.doi.org/10.1093/ofid/ofx163.180 Text en © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America. http://creativecommons.org/licenses/by-nc-nd/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Abstracts
Healey, Kelley
Zhao, Yanan
Nagasaki, Yoji
Park, Steven
Perlin, David
The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Candida glabrata Colonization Mouse Model
title The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Candida glabrata Colonization Mouse Model
title_full The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Candida glabrata Colonization Mouse Model
title_fullStr The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Candida glabrata Colonization Mouse Model
title_full_unstemmed The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Candida glabrata Colonization Mouse Model
title_short The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Candida glabrata Colonization Mouse Model
title_sort gastrointestinal tract is a major source of echinocandin drug resistance in a candida glabrata colonization mouse model
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5631610/
http://dx.doi.org/10.1093/ofid/ofx163.180
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