Synergistic interaction between phage therapy and antibiotics clears Pseudomonas aeruginosa infection in endocarditis and reduces virulence.

Oechslin, Frank; Piccardi, Philippe; Mancini, Stefano; Gabard, Jérôme; Moreillon, Philippe; Entenza, José M; Resch, Gregory; Que, Yok-Ai (2016). Synergistic interaction between phage therapy and antibiotics clears Pseudomonas aeruginosa infection in endocarditis and reduces virulence. Journal of infectious diseases, 215(5), pp. 703-712. Oxford University Press 10.1093/infdis/jiw632

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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 < 0.001 versus untreated controls) and was comparable to ciprofloxacin monotherapy. Moreover, phage-ciprofloxacin combinations were highly synergistic, killing >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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Intensive Care, Emergency Medicine and Anaesthesiology (DINA) > Clinic of Intensive Care

UniBE Contributor:

Que, Yok-Ai

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0022-1899

Publisher:

Oxford University Press

Language:

English

Submitter:

Mirella Aeberhard

Date Deposited:

19 Apr 2017 12:34

Last Modified:

01 Jan 2020 02:30

Publisher DOI:

10.1093/infdis/jiw632

PubMed ID:

28007922

Uncontrolled Keywords:

Pseudomonas aeruginosa; antibiotic; bacteriophage; endocarditis; phage therapy; resistance

BORIS DOI:

10.7892/boris.94058

URI:

https://boris.unibe.ch/id/eprint/94058

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