Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
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
_version_ 1784665615629287424
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
work_keys_str_mv AT chunghattie rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT merakouchristina rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT schaefersmatthewm rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT flettkellyb rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT martinisarah rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT luroger rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT blumenthaljennifera rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT webstershanices rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT crossashleyr rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT alahmarroy rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT halpinerin rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT andersonmichelle rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT moorenicholass rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT snesrudericc rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT yuhongweid rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT goldbergjoannab rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT otoolegeorgea rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT mcgannpatrick rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT stamjasona rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT hinklemary rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT mcadamalexanderj rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT kishonyroy rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections
AT priebegregoryp rapidexpansionandextinctionofantibioticresistancemutationsduringtreatmentofacutebacterialrespiratoryinfections