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Original research
Maintenance tobramycin primarily affects untargeted bacteria in the CF sputum microbiome
  1. Maria T Nelson1,2,3,
  2. Daniel J Wolter1,4,
  3. Alexander Eng5,
  4. Eli J Weiss6,
  5. Anh T Vo6,
  6. Mitchell J Brittnacher6,
  7. Hillary S Hayden6,
  8. Sumedha Ravishankar6,
  9. Gilbert Bautista6,
  10. Anina Ratjen6,
  11. Marcella Blackledge4,
  12. Sharon McNamara4,
  13. Laura Nay4,
  14. Cheryl Majors7,
  15. Samuel I Miller5,6,8,
  16. Elhanan Borenstein5,9,10,
  17. Richard H Simon7,
  18. John J LiPuma11,
  19. Luke R Hoffman1,4,6
  1. 1Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA
  2. 2Medical Scientist Training Program, University of Washington School of Medicine, Seattle, Washington, United States
  3. 3Molecular and Cellular Biology, University of Washington School of Medicine, Seattle, Washington, United States
  4. 4Pediatrics, Seattle Children's Hospital, Seattle, Washington, USA
  5. 5Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA
  6. 6Microbiology, University of Washington School of Medicine, Seattle, Washington, USA
  7. 7Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  8. 8Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States
  9. 9Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel
  10. 10Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  11. 11Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Luke R Hoffman, Pediatrics, University of Washington, Seattle, WA 98195-0005, USA; lhoffm{at}uw.edu

Abstract

Rationale The most common antibiotic used to treat people with cystic fibrosis (PWCF) is inhaled tobramycin, administered as maintenance therapy for chronic Pseudomonas aeruginosa lung infections. While the effects of inhaled tobramycin on P. aeruginosa abundance and lung function diminish with continued therapy, this maintenance treatment is known to improve long-term outcomes, underscoring how little is known about why antibiotics work in CF infections, what their effects are on complex CF sputum microbiomes and how to improve these treatments.

Objectives To rigorously define the effect of maintenance tobramycin on CF sputum microbiome characteristics.

Methods and measurements We collected sputum from 30 PWCF at standardised times before, during and after a single month-long course of maintenance inhaled tobramycin. We used traditional culture, quantitative PCR and metagenomic sequencing to define the dynamic effects of this treatment on sputum microbiomes, including abundance changes in both clinically targeted and untargeted bacteria, as well as functional gene categories.

Main results CF sputum microbiota changed most markedly by 1 week of antibiotic therapy and plateaued thereafter, and this shift was largely driven by changes in non-dominant taxa. The genetically conferred functional capacities (ie, metagenomes) of subjects’ sputum communities changed little with antibiotic perturbation, despite taxonomic shifts, suggesting functional redundancy within the CF sputum microbiome.

Conclusions Maintenance treatment with inhaled tobramycin, an antibiotic with demonstrated long-term mortality benefit, primarily impacted clinically untargeted bacteria in CF sputum, highlighting the importance of monitoring the non-canonical effects of antibiotics and other treatments to accurately define and improve their clinical impact.

  • cystic fibrosis
  • respiratory infection
  • bacterial infection
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Footnotes

  • Contributors MTN, JJL, RHS, DJW and LRH performed conceptualisation and design of the study. MTN, DJW, ATV, SR, GB, AR, MB, SN, LN and CM helped in data collection. MTN, AE, EJW, MJB, EB and LRH performed the data analysis and interpretation. Resources were collected by MJB, HSH, SIM, MB, SN, LN and CM. MTN and LRH helped in writing the original draft. All authors helped in writing, review and editing of the article. MTN helped in visualisation, DJW, EB, JJL, RHS and LRH helped in supervision and LRH, JJL and RHS helped in acquisition of funds.

  • Funding This work was supported by grants from the NIH (DK089507), from the Cystic Fibrosis Foundation (SINGH15R0), an institutional training grant (T32AI55396), and an unrestricted grant from Novartis.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. The accession number for all metagenomic sequencing and 16S amplicon sequencing data reported in this paper is NCBI Bioproject: PRJNA516442.

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