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Background The potential of phage therapy for the treatment of endovascularStaphylococcus aureus infections remains to be evaluated.Methods and Results The efficacy of a phage cocktail combiningHerelleviridae phage vB_SauH_2002 andPodoviriae phage 66 was evaluated against a methicillin‐sensitiveS. aureus strain in vitro and in vivo in a rodent model of experimental endocarditis. Six hours after bacterial challenge, animals were treated with (1) the phage cocktail. (2) subtherapeutic flucloxacillin dosage, (3) combination of the phage cocktail and flucloxacillin, or (4) saline. Bacterial loads in cardiac vegetations at 30 hours were the primary outcome. Secondary outcomes were phage loads at 30 hours in cardiac vegetations, blood, spleen, liver, and kidneys. We evaluated phage resistance 30 hours post infection in vegetations of rats under combination treatment. In vitro, phages synergized againstS. aureus planktonic cells and the cocktail synergized with flucloxacillin to eradicated biofilms. In infected animals, the phage cocktail achieved bacteriostatic effect. The addition of low‐dose flucloxacillin elevated bacterial suppression (∆ of −5.25 log10 colony forming unit/g [CFU/g] versus treatment onset,P &lt;0.0001) and synergism was confirmed (∆ of −2.15 log10 CFU/g versus low‐dose flucloxacillin alone,P &lt;0.01). Importantly, 9/12 rats given the combination treatment had sterile vegetations at 30 hours. In vivo phage replication was partially suppressed by the antibiotic and selection of resistance to thePodoviridae component of the phage cocktail occurred. Plasma‐mediated inhibition of phage killing activity was observed in vitro.Conclusions Combining phages with a low‐dose standard of care antibiotic represents a promising strategy for the treatment ofS. aureus infective endocarditis.

journal of the american heart association. cardiovascular and cerebrovascular disease

Bacteriophages Combined With Subtherapeutic Doses of Flucloxacillin Act Synergistically Against <i>Staphylococcus aureus</i> Experimental Infective Endocarditis

Bacteriophages Combined With Subtherapeutic Doses of Flucloxacillin Act Synergistically Against Staphylococcus aureus Experimental Infective Endocarditis