Synergistic Interaction Between Phage Therapy and Antibiotics Clears Pseudomonas Aeruginosa Infection in Endocarditis and Reduces Virulence

BACKGROUND 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. METHODS In vitro fibrin-clots and rats with aortic EE were treated with an anti-pseudomonas phage cocktail alone or combined with ciprofloxacin. Phage pharmacology, therapeutic efficacy, and resistance were determined. RESULTS In vitro, single-dose phage-therapy killed 7 log CFU/g of fibrin-clots in 6 h. Phage-resistant mutants regrew after 24 h, but were prevented by combination with ciprofloxacin (2.5xMIC). In vivo, single-dose phage-therapy killed 2.5 log CFU/g of vegetations in 6 h (P 6 log CFU/g of vegetations in 6 h and successfully treating 64% (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 (e.g. the pilT and galU genes involved in pilus motility and LPS formation). CONCLUSION 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.