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

Author:

Holger Dana J.1ORCID,El Ghali Amer1,Bhutani Natasha1,Lev Katherine L.1,Stamper Kyle1,Kebriaei Razieh1,Kunz Coyne Ashlan J.1,Morrisette Taylor1,Shah Rahi1,Alexander Jose2,Lehman Susan M.3,Rojas Laura J.456,Marshall Steven H.6,Bonomo Robert A.457,Rybak Michael J.189ORCID

Affiliation:

1. Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , Detroit, Michigan, USA

2. Department of Microbiology, Virology, and Immunology, AdventHealth Central Florida , Orlando, Florida, USA

3. Center for Biologics Evaluation and Research, U.S. Food and Drug Administration , Silver Spring, Maryland, USA

4. Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University , Cleveland, Ohio, USA

5. Center for Antimicrobial Resistance and Epidemiology, Veterans Affairs Medical Center, Case Western Reserve University , Cleveland, Ohio, USA

6. Research Service, Louis Stokes Veterans Affairs Medical Center , Cleveland, Ohio, USA

7. Department of Pharmacology, School of Medicine, Case Western Reserve University , Cleveland, Ohio, USA

8. Department of Pharmacy Services, Detroit Receiving Hospital, Detroit Medical Center , Detroit, Michigan, USA

9. Department of Medicine, Division of Infectious Diseases, Wayne State University , Detroit, Michigan, USA

Abstract

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 log 10 CFU/cm 2 ). 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 log 10 CFU/cm 2 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.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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