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An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen

A key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and on...

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Autores principales: Morley, Valerie J, Kinnear, Clare L, Sim, Derek G, Olson, Samantha N, Jackson, Lindsey M, Hansen, Elsa, Usher, Grace A, Showalter, Scott A, Pai, Manjunath P, Woods, Robert J, Read, Andrew F
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707840/
https://www.ncbi.nlm.nih.gov/pubmed/33258450
http://dx.doi.org/10.7554/eLife.58147
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author Morley, Valerie J
Kinnear, Clare L
Sim, Derek G
Olson, Samantha N
Jackson, Lindsey M
Hansen, Elsa
Usher, Grace A
Showalter, Scott A
Pai, Manjunath P
Woods, Robert J
Read, Andrew F
author_facet Morley, Valerie J
Kinnear, Clare L
Sim, Derek G
Olson, Samantha N
Jackson, Lindsey M
Hansen, Elsa
Usher, Grace A
Showalter, Scott A
Pai, Manjunath P
Woods, Robert J
Read, Andrew F
author_sort Morley, Valerie J
collection PubMed
description A key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile acid sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an ‘anti-antibiotic’ to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model of Enterococcus faecium gastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistant E. faecium by up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens.
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spelling pubmed-77078402020-12-02 An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen Morley, Valerie J Kinnear, Clare L Sim, Derek G Olson, Samantha N Jackson, Lindsey M Hansen, Elsa Usher, Grace A Showalter, Scott A Pai, Manjunath P Woods, Robert J Read, Andrew F eLife Evolutionary Biology A key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile acid sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an ‘anti-antibiotic’ to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model of Enterococcus faecium gastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistant E. faecium by up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens. eLife Sciences Publications, Ltd 2020-12-01 /pmc/articles/PMC7707840/ /pubmed/33258450 http://dx.doi.org/10.7554/eLife.58147 Text en © 2020, Morley et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Evolutionary Biology
Morley, Valerie J
Kinnear, Clare L
Sim, Derek G
Olson, Samantha N
Jackson, Lindsey M
Hansen, Elsa
Usher, Grace A
Showalter, Scott A
Pai, Manjunath P
Woods, Robert J
Read, Andrew F
An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen
title An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen
title_full An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen
title_fullStr An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen
title_full_unstemmed An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen
title_short An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen
title_sort adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen
topic Evolutionary Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707840/
https://www.ncbi.nlm.nih.gov/pubmed/33258450
http://dx.doi.org/10.7554/eLife.58147
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