The goal of this clinical trial is to evaluate whether the investigational drug PLG0206 can help reduce recurrence of infection in adults who have undergone total knee replacement and are receiving a DAIR (Debridement, Antibiotics, and Implant Retention) surgical procedure to treat a Prosthetic Joint Infection (PJI). The study will also assess the safety of PLG0206 when used as an irrigation solution during the DAIR procedure.

Participants will receive either PLG0206 or a placebo (an inactive substance that looks like the investigational drug), in addition to standard of care treatments. All participants will be monitored for approximately one year following their DAIR procedure.

This study is designed to assess the efficacy and safety of PLG0206 administered intraoperatively by local irrigation to participants undergoing a DAIR procedure for treatment of Prosthetic Joint Infection (PJI) occurring after total knee arthroplasty (TKA), also known as knee joint replacement.

Eligible participants will undergo a DAIR procedure according to the treating hospital's standard of care (SOC). Participant eligibility will be based on clinical and diagnostic assessments, including laboratory results.

Once debridement during DAIR is complete, the Investigator will follow a standardized irrigation protocol, with the final irrigation step being administration of a single dose of blinded study drug (PLG0206 or matching placebo). The study drug will be administered as a single intra-articular irrigation.

Following study drug administration, all participants will receive standard post-operative care per institutional guidelines and will be discharged from the hospital in accordance with local standards. Participants may receive IV/oral antimicrobial therapy, as part of post-operative SOC.

Participants will be monitored for safety and signs of PJI recurrence or persistent infection for 365 days post study drug administration. After hospital discharge, study visits will occur in-clinic on Days 14, 90, and 365, and on Days 30, 180, and 270 via a telephone or virtual visit.

Inclusion Criteria:

• Male or female participants age between 18 and <80 years
• Able to provide informed consent, geographically stable, and able to comply with the required follow-up visits
• Suspected or confirmed PJI of the knee
• Well-fixed and positioned prosthesis and good condition of surrounding soft tissue (no sinus tract)
• A single DAIR procedure is indicated as treatment of PJI
• Agree to use contraceptives if of childbearing potential

Exclusion Criteria:

• Loose prosthesis or surgical treatment planned for removal of well-fixed, nonmodular implants
• Anticipated to require antibiotic therapy for >6 months after DAIR procedure
• Infection spread beyond the affected knee joint (e.g., osteomyelitis)
• History of a prior PJI of the affected knee
• Two or more prior revisions in the affected joint
• Epithelialized sinus tract with evidence of communication to the joint or visualization of prosthesis
• Diabetes mellitus and with an A1c ≥9%
• History of malignant disease and having received immunosuppressive therapy, radiation therapy, or chemotherapy within the past year
• Known immunodeficiency (e.g., splenectomy; sickle cell anemia; human immunodeficiency virus [HIV] with recent CD4 count <200 cells/mm3; or primary humoral, bone marrow, or other transplantation)