Periprosthetic Joint Infection (PJI)

This is a Phase 1/2, randomized, controlled, open-label, proof-of-concept study to evaluate the safety and tolerability, local and systemic PK profiles of TNP-2092 administered via IA injection on the basis of vancomycin IV and oral antibiotics therapy in participants with early (within 1 month of TKA) or acute hematogenous (within 3 weeks of infectious symptoms) PJI requiring or not requiring DAIR therapy after TKA, or requiring long-term antibiotic suppression therapy for PJI (including PJI occurring after various joint replacements and revision surgeries).

Patients with an infected knee replacement will receive their standard of care surgical treatment of the infection, with and without additional ultrasound microbubble treatment (randomly divided 50/50 in the active and control groups). Subjects in the active group will receive a local bolus injection of antibiotics and ultrasound-active microbubbles within 24 hours of their revision surgery. The fundamental hypothesis is that a decrease in re-infection rates of at least 24% can be achieved in the active group relative to controls.

Relevance and Rationale Due to the widespread development of high-tech medical care in traumatology and orthopedics for patients with severe forms of hip and knee osteoarthritis and aseptic necrosis, and the increasing number of knee and hip arthroplasties, there is a proportional increase in serious complications after arthroplasty, the most serious and costly of which is the development of peri-implant infection. Today, the prevalence of peri-implant infection is close to epidemic. It is worth noting that peri-implant infection is not always associated with poor surgical technique or the quality of prostheses. Often, the causes of this life-threatening complication are not fully understood. Currently, no large-scale prospective or retrospective study of the causes of peri-implant infection has been conducted in Russia or in Moscow. The pathogenesis of peri-implant infection remains unexplored, and methodological approaches to its prevention and treatment have not been developed, making this topic relevant and promising. The project's results will establish the key links in the pathogenesis of peri-implant infection, define the risk spectrum for this complication, identify individual patient characteristics that increase the risk of developing this complication, determine the underlying mechanisms underlying its development, and identify alternative treatment options for these patients. Based on the data obtained, diagnostic algorithms and recommendations will be developed for treatment strategies and preoperative preparation for patients with severe forms of hip and knee osteoarthritis, femoral head fractures, and aseptic necrosis. Guidelines for the antemortem and postmortem diagnosis of peri-implant infection will also be developed. These guidelines will be used by general practitioners, rheumatologists, orthopedic traumatologists, pathologists, rehabilitation physicians, general practitioners, and endocrinologists. The program's implementation and implementation of its results are aimed at reducing the share of peri-implant infection in morbidity and mortality. 2. Objective and Tasks Project Objective: To establish the etiopathogenesis and morphological tissue changes following complications of large joint arthroplasty (PJI, aseptic instability, etc.) in patients of different age groups, assessing their somatic and immune status, calcium mineral metabolism, and its metabolism, and to develop guidelines for preoperative examination. List of tasks to be addressed within the Project: 1. Develop a clinical study protocol; 2. Recruit a cohort of at least 600 patients for the study to conduct a comprehensive assessment of the patient's baseline status: assessment of mineral metabolism (total calcium, serum magnesium, inorganic phosphorus, 25OH, vitamin D, osteocalcin, BetaCross laps, P1NP bone matrix formation marker, parathyroid hormone); Immune status assessment (Interleukin 10 (IL-10), Interleukin 1 beta (IL-1beta, IL-1b), Interleukin 6 (IL-6), Interleukin 8 (IL-8), Complement Component C4, TNF (Tumor Necrosis Factor alpha, TNFalpha, sachectin), Lymphocyte phenotyping (main subsets panel): CD3, CD4, CD8, CD19, CD16, 56); Microbiological and PCR testing, as well as somatic status (therapist, rheumatologist) and analysis of the results of instrumental examinations (MRI, CT, densitometry, radiography). 3. The study includes a single, less often twice-time examination of each patient from the group of above-mentioned indicators at the preoperative stage. 4. Conducting a study of each patient with complications of osseointegration of the endoprosthesis from the group of above-mentioned indicators at the postoperative stage. 5. Endoprosthetics/revision endoprosthetics of the knee and hip joint. 6. Collection of tissue samples and metal structures (their fragments) from peri-implant areas for an intravital pathological examination of the patient, scanning electron microscopy, sonication, followed by microbiological examination (at least 5 samples) to characterize the microbiota in patients with developed complications.; 7. Evaluation of the obtained results of the correlation between the patient's somatic, immune, and homeostatic (mineral) status and the development of postoperative complications, statistical analysis of the data, and creation of a database.; 8. Implementation of the results of the work into clinical practice at least at the State Budgetary Healthcare Institution "City Clinical Hospital No. 31 named after Academician G.M. Savelyeva"

High levels of Testosterone causes high amounts of skin bacteria (Cutibacterium Acnes) which can go into the skin during a shoulder replacement surgery and cause a terrible infection. The goal of this experiment is to have participants take Finasteride, a medication that blocks testosterone production, for 2 weeks and evaluate the following: * Blood levels of testosterone * Amount of bacteria on the skin. Participants will: * Be assigned to take Finasteride, or a placebo (a look-alike pill with no active medicine) once daily, for 2 weeks * Have a small sample of their blood collected and their skin swabbed with a Q-tip to determine Testosterone levels and bacteria on the skin * Blood draw and skin testing will take place before starting Finasteride or the placebo (day 0) and at the end of the experiment (day 14).

With the progressive ageing of the population, a significant increase in the incidence of skeletal fractures-particularly of the proximal femur-as well as degenerative conditions such as osteoarthritis has been observed, for which joint arthroplasty represents the treatment of choice. However, this procedure is not free from complications; beyond technical and mechanical issues related to potential implant malpositioning, one of the most feared is periprosthetic joint infection (PJI), which poses a major challenge in terms of clinical management and prognostic impact. Therapeutic strategies for PJI range from debridement with retention of the implant and exchange of modular components (DAIR/DAPRI) to complete implant removal with insertion of an articulating spacer, often followed by a subsequent reimplantation procedure. These approaches require prolonged antibiotic regimens, potentially exerting a negative effect on renal function, particularly in cases of extended exposure to nephrotoxic agents. Despite the clinical relevance of this issue, the current literature still provides limited evidence regarding the identification of inexpensive and readily available biomarkers capable of predicting treatment outcomes in PJI, especially in patients undergoing spacer implantation followed by reimplantation. Recent literature has increasingly explored the use of biomarkers such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic inflammation response index (SIRI), and others to characterize inflammatory and nutritional status, and to investigate possible associations between these markers and the outcomes of selected surgical procedures. The availability of predictive markers could optimize therapeutic management by reducing the risk of infection recurrence and improving postoperative risk stratification.

The goal of this observational study is to measure the diagnostic accuracy of the Multiplex PCR technique in identifying pathogens during the diagnostic stage of resolving pre-implantation infection, in the context of treatment according to two-stage protocol for PJIs. This evaluation will be conducted by comparing the results obtained by Multiplex PCR with those derived from standard culture examination.