Phage-antibiotic combinations against multidrug-resistant Pseudomonas aeruginosa in in vitro static and dynamic biofilm models

Dana J. Holger, Amer El Ghali, Natasha Bhutani, Katherine L. Lev, Kyle Stamper, Razieh Kebriaei, Ashlan J. Kunz Coyne, Taylor Morrisette, Rahi Shah, Jose Alexander, Susan M. Lehman, Laura J. Rojas, Steven H. Marshall, Robert A. Bonomo, Michael J. Rybak

Research output: Contribution to journalArticlepeer-review

Abstract

Biofilm-producing Pseudomonas aeruginosa infections pose a severe threat to public health and are responsible for high morbidity and mortality. Phage-antibiotic combinations (PACs) are a promising strategy for combatting multidrug-resistant (MDR), extensively drug-resistant (XDR), and difficult-to-treat P. aeruginosa infections. Ten MDR/XDR P. aeruginosa strains and five P. aeruginosa-specific phages were genetically characterized and evaluated based upon their antibiotic susceptibilities and phage sensitivities. Two selected strains, AR351 (XDR) and I0003-1 (MDR), were treated singly and in combination with either a broad-spectrum or narrow-spectrum phage, phage EM-T3762627-2_AH (EM), or 14207, respectively, and bactericidal antibiotics of five classes in biofilm time-kill analyses. Synergy and/or bactericidal activity was demonstrated with all PACs against one or both drug-resistant P. aeruginosa strains (average reduction: −Δ3.32 log10 CFU/cm2). Slightly improved ciprofloxacin susceptibility was observed in both strains after exposure to phages (EM and 14207) in combination with ciprofloxacin and colistin. Based on phage cocktail optimization with four phages (EM, 14207, E20050-C (EC), and 109), we identified several effective phage-antibiotic cocktails for further analysis in a 4-day pharmacokinetic/pharmacodynamic in vitro biofilm model. Three-phage cocktail, EM + EC + 109, in combination with ciprofloxacin demonstrated the greatest biofilm reduction against AR351 (−Δ4.70 log10 CFU/cm2 from baseline). Of remarkable interest, the addition of phage 109 prevented phage resistance development to EM and EC in the biofilm model. PACs can demonstrate synergy and offer enhanced eradication of biofilm against drug-resistant P. aeruginosa while preventing the emergence of resistance.

Original languageEnglish
JournalAntimicrobial Agents and Chemotherapy
Volume67
Issue number11
DOIs
StatePublished - Nov 2023

Bibliographical note

Publisher Copyright:
© 2023 American Society for Microbiology. All Rights Reserved.

Keywords

  • MDR
  • Pseudomonas aeruginosa
  • antibiotics
  • antimicrobial combinations
  • antimicrobial resistance
  • bacteriophage
  • biofilms
  • cocktail
  • phage
  • synergy

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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