Phage activity againstStaphylococcus aureusis impaired in plasma and synovial fluid

Abstract

AbstractS. aureus is a pathogen that frequently causes severe morbidity and phage therapy is being discussed as an alternative to antibiotics for the treatment of S. aureus infections. In this in vitro and animal study, we demonstrated that the activity of anti-staphylococcal phages is severely impaired in plasma and synovial fluid. Despite phage replication in these matrices, lysis of the bacteria was slower than phage propagation, and no reduction of the bacterial population was observed. This phage inhibition is due to a 99% reduction of phage adsorption, already at 10% plasma concentration. Coagulation factors bind S. aureus resulting in the formation of aggregates and blood clots that protect the bacterium from the phages. This was confirmed by the finding that purified fibrinogen is sufficient to impair phage activity. In contrast, dissolution of the clots by tissue plasminogen activator (tPA) partially restored phage activity. Consistent with these in vitro findings, phage treatment did not reduce bacterial burdens in a neutropenic mouse S. aureus thigh infection model. In summary, phage treatment of S. aureus infections may be fundamentally challenging, and more investigation is needed prior to proceeding to in-human trials.