Although several studies have shown promising clinical outcomes of phage therapy in patients with orthopedic device-related infections, questions remain regarding the optimal application protocol, systemic effects, and the impact of the immune response. This study provides a proof-of-concept of phage therapy in a clinically relevant rabbit model of fracture-related infection (FRI) caused by Staphylococcus aureus. In a prevention setting, phage in saline (without any biomaterial-based carrier) was highly effective in the prevention of FRI, compared to systemic antibiotic prophylaxis alone. In the subsequent study involving treatment of established infection, daily administration of phage in saline through a subcutaneous access tube was compared to a single intraoperative application of a phage-loaded hydrogel and a control group receiving antibiotics only. In this setting, although a possible trend of bacterial load reduction on the implant was observed with the phage-loaded hydrogel, no superior effect of phage therapy was found compared to antibiotic treatment alone. The application of phage in saline through a subcutaneous access tube was, however, complicated by superinfection and the development of neutralizing antibodies. The latter was not found in the animals that received the phage-loaded hydrogel, which may indicate that encapsulation of phages into a carrier such as a hydrogel limits their exposure to the adaptive immune system. These studies show phage therapy can be useful in targeting orthopedic device-related infection, however, further research and improvements of these application methods are required for this complex clinical setting.
Bibliographical noteFunding Information:
This work was supported by the AOTrauma Technical Commission as part of the Anti-infective Global Expert Committee of the AO Foundation. The labs of W-.J.M. and R.L. are supported by the ID-N grant PHAGEFORCE from the KU Leuven (IDN/20/024) and the Research Foundation Flanders (FWO) (ERA-NET JPI-EC-AMR grant). We thank Andrew Foster (AO) for his help during sampling and dissections. The authors would also like to acknowledge the Eliava Institute (Tbilisi, Georgia) for granting access to phage ISP.
© 2021 Onsea et al.