title: Synergistic Interaction Between Phage Therapy and Antibiotics Clears Pseudomonas Aeruginosa Infection in Endocarditis and Reduces Virulence.
abstract: Increasing antibiotic resistance warrants therapeutic alternatives. Here we investigated the efficacy of bacteriophage-therapy (phage) alone or combined with antibiotics against experimental endocarditis (EE) due to Pseudomonas aeruginosa, an archetype of difficult-to-treat infection.
  
  
  
  In vitro fibrin clots and rats with aortic EE were treated with an antipseudomonas phage cocktail alone or combined with ciprofloxacin. Phage pharmacology, therapeutic efficacy, and resistance were determined.
  
  
  
  In vitro, single-dose phage therapy killed 7 log colony-forming units (CFUs)/g of fibrin clots in 6 hours. Phage-resistant mutants regrew after 24 hours but were prevented by combination with ciprofloxacin (2.5 × minimum inhibitory concentration). In vivo, single-dose phage therapy killed 2.5 log CFUs/g of vegetations in 6 hours (P < .001 vs untreated controls) and was comparable with ciprofloxacin monotherapy. Moreover, phage/ciprofloxacin combinations were highly synergistic, killing >6 log CFUs/g of vegetations in 6 hours and successfully treating 64% (n = 7/11) of rats. Phage-resistant mutants emerged in vitro but not in vivo, most likely because resistant mutations affected bacterial surface determinants important for infectivity (eg, the pilT and galU genes involved in pilus motility and LPS formation).
  
  
  
  Single-dose phage therapy was active against P. aeruginosa EE and highly synergistic with ciprofloxacin. Phage-resistant mutants had impaired infectivity. Phage-therapy alone or combined with antibiotics merits further clinical consideration.
authors.affiliation: Department of Fundamental Microbiology, University of Lausanne, Switzerland
authors.forename: Frank
authors.initials: F
authors.lastname: Oechslin
authors.affiliation: Department of Fundamental Microbiology, University of Lausanne, Switzerland
authors.forename: Philippe
authors.initials: P
authors.lastname: Piccardi
authors.affiliation: Department of Fundamental Microbiology, University of Lausanne, Switzerland
authors.forename: Stefano
authors.initials: S
authors.lastname: Mancini
authors.affiliation: Pherecydes Pharma, Romainville, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Gabard
authors.affiliation: Department of Fundamental Microbiology, University of Lausanne, Switzerland
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreillon
authors.affiliation: Department of Fundamental Microbiology, University of Lausanne, Switzerland
authors.forename: José M
authors.initials: JM
authors.lastname: Entenza
authors.affiliation: Department of Fundamental Microbiology, University of Lausanne, Switzerland
authors.forename: Gregory
authors.initials: G
authors.lastname: Resch
authors.affiliation: Department of Intensive Care Medicine, Bern University Hospital, Switzerland.
authors.forename: Yok-Ai
authors.initials: YA
authors.lastname: Que
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D004696:Endocarditis / Q000382:microbiology / Q000628:therapy*; D005260:Female; D008826:Microbial Sensitivity Tests; D000071059:Phage Therapy / Q000379:methods*; D011552:Pseudomonas Infections / Q000628:therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000472:pathogenicity; D051381:Rats; D017208:Rats, Wistar; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin
keywords: Pseudomonas aeruginosa; bacteriophage; endocarditis; phage therapy; resistance; antibiotic