The effects of different doses of inhaled bacteriophage therapy for Pseudomonas aeruginosa pulmonary infections in mice

Rachel Yoon Kyung Chang, Michael Y.T. Chow, Yuncheng Wang, Chengxi Liu, Qixuan Hong, Sandra Morales, Andrew J. McLachlan, Elizabeth Kutter, Jian Li, Hak Kim Chan

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Abstract

Objectives: Inhaled phage therapy has been revisited as a potential treatment option for respiratory infections caused by multidrug-resistant Pseudomonas aeruginosa; however, there is a distinct gap in understanding the dose–response effect. The aim of this study was to investigate the dose–response effect of Pseudomonas-targeting phage PEV31 delivered by the pulmonary route in a mouse lung infection model. Methods: Neutropenic BALB/c mice were infected with multidrug-resistant P. aeruginosa (2 × 104 colony-forming units) through the intratracheal route and then treated with PEV31 at three different doses of 7.5 × 104 (Group A), 5 × 106 (Group B), and 5 × 108 (Group C) plaque-forming units, or phosphate-buffered saline at 2 hours postinoculation. Mice (n = 5–7) were euthanized at 2 hours and 24 hours postinfection, and lungs, kidneys, spleen, liver, bronchoalveolar lavage fluid, and blood were collected for bacteria and phage enumeration. Results: At 24 hours postinfection, all phage-treated groups exhibited a significant reduction in pulmonary bacterial load by 1.3–1.9 log10, independent of the delivered phage dose. The extent of phage replication was negatively correlated with the dose administered, with log10 titre increases of 6.2, 2.7, and 9 for Groups A, B, and C, respectively. Phage-resistant bacterial subpopulations in the lung homogenate samples harvested at 24 hours postinfection increased with the treatment dose (i.e. 30%, 74%, and 91% in respective Groups A–C). However, the mutants showed increased susceptibility to ciprofloxacin, impaired twitching motility, and reduced blue-green pigment production. The expression of the inflammatory cytokines (IL-1ß and IL-6, and TNF-α) was suppressed with increasing PEV31 treatment dose. Discussion: This study provides the dose–response effect of inhaled phage therapy that may guide dose selection for treating P. aeruginosa respiratory infections in humans.

Original languageEnglish
Pages (from-to)983-989
Number of pages7
JournalClinical Microbiology and Infection
Volume28
Issue number7
DOIs
Publication statusPublished - Jul 2022

Keywords

  • Bacteriophage (or phage)
  • Dose–response
  • Inhaled therapy
  • Intratracheal administration
  • Pseudomonas aeruginosa
  • Pulmonary infection

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