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Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections
Acute bacterial infections are often treated empirically, with the choice of antibiotic therapy updated during treatment. The effects of such rapid antibiotic switching on the evolution of antibiotic resistance in individual patients are poorly understood. Here we find that low-frequency antibiotic...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8907320/ https://www.ncbi.nlm.nih.gov/pubmed/35264582 http://dx.doi.org/10.1038/s41467-022-28188-w |
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author | Chung, Hattie Merakou, Christina Schaefers, Matthew M. Flett, Kelly B. Martini, Sarah Lu, Roger Blumenthal, Jennifer A. Webster, Shanice S. Cross, Ashley R. Al Ahmar, Roy Halpin, Erin Anderson, Michelle Moore, Nicholas S. Snesrud, Eric C. Yu, Hongwei D. Goldberg, Joanna B. O’Toole, George A. McGann, Patrick Stam, Jason A. Hinkle, Mary McAdam, Alexander J. Kishony, Roy Priebe, Gregory P. |
author_facet | Chung, Hattie Merakou, Christina Schaefers, Matthew M. Flett, Kelly B. Martini, Sarah Lu, Roger Blumenthal, Jennifer A. Webster, Shanice S. Cross, Ashley R. Al Ahmar, Roy Halpin, Erin Anderson, Michelle Moore, Nicholas S. Snesrud, Eric C. Yu, Hongwei D. Goldberg, Joanna B. O’Toole, George A. McGann, Patrick Stam, Jason A. Hinkle, Mary McAdam, Alexander J. Kishony, Roy Priebe, Gregory P. |
author_sort | Chung, Hattie |
collection | PubMed |
description | Acute bacterial infections are often treated empirically, with the choice of antibiotic therapy updated during treatment. The effects of such rapid antibiotic switching on the evolution of antibiotic resistance in individual patients are poorly understood. Here we find that low-frequency antibiotic resistance mutations emerge, contract, and even go to extinction within days of changes in therapy. We analyzed Pseudomonas aeruginosa populations in sputum samples collected serially from 7 mechanically ventilated patients at the onset of respiratory infection. Combining short- and long-read sequencing and resistance phenotyping of 420 isolates revealed that while new infections are near-clonal, reflecting a recent colonization bottleneck, resistance mutations could emerge at low frequencies within days of therapy. We then measured the in vivo frequencies of select resistance mutations in intact sputum samples with resistance-targeted deep amplicon sequencing (RETRA-Seq), which revealed that rare resistance mutations not detected by clinically used culture-based methods can increase by nearly 40-fold over 5–12 days in response to antibiotic changes. Conversely, mutations conferring resistance to antibiotics not administered diminish and even go to extinction. Our results underscore how therapy choice shapes the dynamics of low-frequency resistance mutations at short time scales, and the findings provide a possibility for driving resistance mutations to extinction during early stages of infection by designing patient-specific antibiotic cycling strategies informed by deep genomic surveillance. |
format | Online Article Text |
id | pubmed-8907320 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-89073202022-03-23 Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections Chung, Hattie Merakou, Christina Schaefers, Matthew M. Flett, Kelly B. Martini, Sarah Lu, Roger Blumenthal, Jennifer A. Webster, Shanice S. Cross, Ashley R. Al Ahmar, Roy Halpin, Erin Anderson, Michelle Moore, Nicholas S. Snesrud, Eric C. Yu, Hongwei D. Goldberg, Joanna B. O’Toole, George A. McGann, Patrick Stam, Jason A. Hinkle, Mary McAdam, Alexander J. Kishony, Roy Priebe, Gregory P. Nat Commun Article Acute bacterial infections are often treated empirically, with the choice of antibiotic therapy updated during treatment. The effects of such rapid antibiotic switching on the evolution of antibiotic resistance in individual patients are poorly understood. Here we find that low-frequency antibiotic resistance mutations emerge, contract, and even go to extinction within days of changes in therapy. We analyzed Pseudomonas aeruginosa populations in sputum samples collected serially from 7 mechanically ventilated patients at the onset of respiratory infection. Combining short- and long-read sequencing and resistance phenotyping of 420 isolates revealed that while new infections are near-clonal, reflecting a recent colonization bottleneck, resistance mutations could emerge at low frequencies within days of therapy. We then measured the in vivo frequencies of select resistance mutations in intact sputum samples with resistance-targeted deep amplicon sequencing (RETRA-Seq), which revealed that rare resistance mutations not detected by clinically used culture-based methods can increase by nearly 40-fold over 5–12 days in response to antibiotic changes. Conversely, mutations conferring resistance to antibiotics not administered diminish and even go to extinction. Our results underscore how therapy choice shapes the dynamics of low-frequency resistance mutations at short time scales, and the findings provide a possibility for driving resistance mutations to extinction during early stages of infection by designing patient-specific antibiotic cycling strategies informed by deep genomic surveillance. Nature Publishing Group UK 2022-03-09 /pmc/articles/PMC8907320/ /pubmed/35264582 http://dx.doi.org/10.1038/s41467-022-28188-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Chung, Hattie Merakou, Christina Schaefers, Matthew M. Flett, Kelly B. Martini, Sarah Lu, Roger Blumenthal, Jennifer A. Webster, Shanice S. Cross, Ashley R. Al Ahmar, Roy Halpin, Erin Anderson, Michelle Moore, Nicholas S. Snesrud, Eric C. Yu, Hongwei D. Goldberg, Joanna B. O’Toole, George A. McGann, Patrick Stam, Jason A. Hinkle, Mary McAdam, Alexander J. Kishony, Roy Priebe, Gregory P. Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections |
title | Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections |
title_full | Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections |
title_fullStr | Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections |
title_full_unstemmed | Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections |
title_short | Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections |
title_sort | rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8907320/ https://www.ncbi.nlm.nih.gov/pubmed/35264582 http://dx.doi.org/10.1038/s41467-022-28188-w |
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