Evaluation of bacteriophage as an adjunct therapy for treatment of peri-prosthetic joint infection caused by Staphylococcus aureus

Abstract

Phage therapy offers a potential alternate strategy for the treatment of peri-prosthetic joint infection (PJI), particularly where limited effective antibiotics are available. We undertook preclinical trials to investigate the therapeutic efficacy of a phage cocktail, alone and in combination with vancomycin, to reduce bacterial numbers within the infected joint using a clinically-relevant model of Staphylococcus aureus-induced PJI. Infected animals were randomised to 4 treatment groups, with treatment commencing 21-days post-surgery: bacteriophage alone, vancomycin alone, bacteriophage and vancomycin, and sham. At day 28 post-surgery, animals were euthanised for microbiological and immunological assessment of implanted joints. Treatment with phage alone or vancomycin alone, led to 5-fold and 6.2-fold reductions, respectively in bacterial load within peri-implant tissue compared to sham-treated animals. Compared to sham-treated animals, a 22.5-fold reduction in S. aureus burden was observed within joint tissue of animals that were administered phage in combination with vancomycin, corresponding with decreased swelling in the implanted knee. Microbiological data were supported by evidence of decreased inflammation within the joints of animals administered phage in combination with vancomycin, compared to sham-treated animals. Our findings provide further support for phage therapy as a tolerable and effective adjunct treatment for PJI.

Phage Therapy as Adjuvant to Conservative Surgery and Antibiotics to Salvage Patients With Relapsing S. aureus Prosthetic Knee Infection

“…In patients with chronic infection, if getting rid of the biofilm by prosthesis exchange is not feasible, DAIR followed by SAT is usually proposed, but the success rate remains low (1)(2)(3)(4). By using phage therapy as adjunctive therapy, the aim is to act locally on bacteria embedded in biofilm stuck on the implant surface into the joint cavity, as demonstrated recently in an animal model (11). The anti-S. aureus phages used to treat our patients demonstrated dose-dependent anti-biofilm activity in vitro.…”

Bacteriophage Treatment: Critical Evaluation of Its Application on World Health Organization Priority Pathogens

“…However, no side effects were reported in the reviewed study here. In 34.5% of the studies included in this review, intraperitoneal phages administration was commonly used, but limited data is available on the applicability, practicality, and safety of this approach in humans [ 17 , 20 , 26 , 29 , 30 , 32 , 37 , 41 , 44 ]. Intranasal administration showed significant improvement of pneumonia in all five studies [ 18 , 19 , 24 , 27 , 31 ].…”

“…In this systematic review, five studies were included in which combined therapy of antibiotics and phage therapy were tested [ 21 , 35 , 37 , 39 , 43 ]. All five studies dealt with S. aureus infections, with one of the studies, also including P. aeruginosa .…”

“…The S. aureus studies included systemic and localized burn wound infection model [ 21 ], in vitro biofilm [ 35 ], peri-prosthetic joint infection model [ 37 ], ventilator-associated pneumonia [ 39 ], and implant-related osteomyelitis model [ 43 ], and phages and antibiotics were simply added in cased in vitro model [ 35 ]. In vivo studies saw phages being administered subcutaneously/through the skin in two studies [ 21 , 43 ], intraperitonially and intravenously in one study each, respectively [ 37 , 39 ]. Antibiotics were administered in the animal studies either orally [ 21 ], intraperitonially [ 37 , 43 ], or intravenously [ 39 ].…”

“…In vivo studies saw phages being administered subcutaneously/through the skin in two studies [ 21 , 43 ], intraperitonially and intravenously in one study each, respectively [ 37 , 39 ]. Antibiotics were administered in the animal studies either orally [ 21 ], intraperitonially [ 37 , 43 ], or intravenously [ 39 ]. The results of combination therapy were mostly synergistic, reducing bacterial concentration significantly.…”