Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections

Hattie Chung, Christina Merakou, Matthew M. Schaefers, Kelly B. Flett, Sarah Martini, Roger Lu, Jennifer A. Blumenthal, Shanice S. Webster, Ashley R. Cross, Roy Al Ahmar, Erin Halpin, Michelle Anderson, Nicholas S. Moore, Eric C. Snesrud, Hongwei D. Yu, Joanna B. Goldberg, George A. O’Toole, Patrick McGann, Jason A. Stam, Mary Hinkle, Alexander J. McAdam, Roy Kishony () and Gregory P. Priebe ()
Additional contact information
Hattie Chung: Harvard Medical School
Christina Merakou: Boston Children’s Hospital
Matthew M. Schaefers: Boston Children’s Hospital
Kelly B. Flett: Boston Children’s Hospital
Sarah Martini: Boston Children’s Hospital
Roger Lu: Boston Children’s Hospital
Jennifer A. Blumenthal: Boston Children’s Hospital
Shanice S. Webster: Geisel School of Medicine at Dartmouth
Ashley R. Cross: Emory University School of Medicine
Roy Al Ahmar: Joan C. Edwards School of Medicine at Marshall University
Erin Halpin: Boston Children’s Hospital
Michelle Anderson: Boston Children’s Hospital
Nicholas S. Moore: Harvard Medical School
Eric C. Snesrud: Walter Reed Army Institute of Research
Hongwei D. Yu: Joan C. Edwards School of Medicine at Marshall University
Joanna B. Goldberg: Emory University School of Medicine
George A. O’Toole: Geisel School of Medicine at Dartmouth
Patrick McGann: Walter Reed Army Institute of Research
Jason A. Stam: Walter Reed Army Institute of Research
Mary Hinkle: Walter Reed Army Institute of Research
Alexander J. McAdam: Boston Children’s Hospital
Roy Kishony: Harvard Medical School
Gregory P. Priebe: Boston Children’s Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-28188-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28188-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-28188-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().