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

Author

Listed:
  • Hattie Chung

    (Harvard Medical School
    The Broad Institute of MIT and Harvard)

  • Christina Merakou

    (Boston Children’s Hospital
    Harvard Medical School)

  • Matthew M. Schaefers

    (Boston Children’s Hospital
    Harvard Medical School)

  • Kelly B. Flett

    (Boston Children’s Hospital
    Novant Health Eastover Pediatrics)

  • Sarah Martini

    (Boston Children’s Hospital)

  • Roger Lu

    (Boston Children’s Hospital)

  • Jennifer A. Blumenthal

    (Boston Children’s Hospital
    Harvard Medical School)

  • 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
    Winchester Hospital)

  • Michelle Anderson

    (Boston Children’s Hospital
    Becton Dickinson)

  • 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
    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
    Technion—Israel Institute of Technology)

  • Gregory P. Priebe

    (Boston Children’s Hospital
    Harvard Medical School)

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.

Suggested Citation

  • 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 & Miche, 2022. "Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28188-w
    DOI: 10.1038/s41467-022-28188-w
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    References listed on IDEAS

    as
    1. Rachel Wheatley & Julio Diaz Caballero & Natalia Kapel & Fien H. R. Winter & Pramod Jangir & Angus Quinn & Ester Barrio-Tofiño & Carla López-Causapé & Jessica Hedge & Gabriel Torrens & Thomas Schalk &, 2021. "Rapid evolution and host immunity drive the rise and fall of carbapenem resistance during an acute Pseudomonas aeruginosa infection," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Hattie Chung & Tami D. Lieberman & Sara O. Vargas & Kelly B. Flett & Alexander J. McAdam & Gregory P. Priebe & Roy Kishony, 2017. "Global and local selection acting on the pathogen Stenotrophomonas maltophilia in the human lung," Nature Communications, Nature, vol. 8(1), pages 1-7, April.
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    Cited by:

    1. Julio Diaz Caballero & Rachel M. Wheatley & Natalia Kapel & Carla López-Causapé & Thomas Van der Schalk & Angus Quinn & Liam P. Shaw & Lois Ogunlana & Claudia Recanatini & Basil Britto Xavier & Leen T, 2023. "Mixed strain pathogen populations accelerate the evolution of antibiotic resistance in patients," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Rachel M. Wheatley & Julio Diaz Caballero & Thomas E. Schalk & Fien H. R. Winter & Liam P. Shaw & Natalia Kapel & Claudia Recanatini & Leen Timbermont & Jan Kluytmans & Mark Esser & Alicia Lacoma & Cr, 2022. "Gut to lung translocation and antibiotic mediated selection shape the dynamics of Pseudomonas aeruginosa in an ICU patient," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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