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Fracture-related infection is a major complication related to musculoskeletal injuries that not only has important clinical consequences, but also a substantial socioeconomic impact. Although fracture-related infection is one of the oldest disease entities known to mankind, it has only recently been defined and, therefore, its global burden is still largely unknown. In this Personal View, we describe the origin of the term fracture-related infection, present the available data on its global impact, and discuss important aspects regarding its prevention and management that could lead to improved outcomes in both high-resource and low-resource settings. We also highlight the need for health-care systems to be adequately compensated for the high cost of human resources (trained staff) and well-equipped facilities required to adequately care for these complex patients. Our aim is to increase awareness among clinicians and policy makers that fracture-related infection is a disease entity that deserves prioritisation in terms of research, with the goal to standardise treatment and improve patient outcomes on a global scale., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: The number of operatively treated clavicle fractures has increased over the past decades. Consequently, this has led to an increase in secondary procedures required to treat complications such as fracture-related infection (FRI). The primary objective of this study was to assess the clinical and functional outcome of patients treated for FRI of the clavicle. The secondary objectives were to evaluate the healthcare costs and propose a standardized protocol for the surgical management of this complication., Methods: All patients with a clavicle fracture who underwent open reduction and internal fixation (ORIF) between 1 January 2015 and 1 March 2022 were retrospectively evaluated. This study included patients with an FRI who were diagnosed and treated according to the recommendations of a multidisciplinary team at the University Hospitals Leuven, Belgium., Results: We evaluated 626 patients with 630 clavicle fractures who underwent ORIF. In total, 28 patients were diagnosed with an FRI. Of these, eight (29%) underwent definitive implant removal, five (18%) underwent debridement, antimicrobial treatment and implant retention, and fourteen patients (50%) had their implant exchanged in either a single-stage procedure, a two-stage procedure or after multiple revisions. One patient (3.6%) underwent resection of the clavicle. Twelve patients (43%) underwent autologous bone grafting (tricortical iliac crest bone graft (n = 6), free vascularized fibular graft (n = 5), cancellous bone graft (n = 1)) to reconstruct the bone defect. The median follow-up was 32.3 (P 25 -P 75 : 23.9-51.1) months. Two patients (7.1%) experienced a recurrence of infection. The functional outcome was satisfactory, with 26 out of 28 patients (93%) having full range of motion. The median healthcare cost was € 11.506 (P 25 -P 75 : € 7.953-23.798) per patient., Conclusion: FRI is a serious complication that can occur after the surgical treatment of clavicle fractures. In our opinion, when treated adequately using a multidisciplinary patient-specific approach, the outcome of patients with an FRI of the clavicle is good. The median healthcare costs of these patients are up to 3.5 times higher compared to non-infected operatively treated clavicle fractures. Although not studied individually, we consider factors such as the size of the bone defect, condition of the soft tissue, and patient demand important when it comes to guiding our surgical decision making in cases of osseous defects., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest with respect to the preparation and writing of this article., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The recently developed fracture-related infection (FRI) consensus definition, which is based on specific diagnostic criteria, has not been fully validated in clinical studies. We aimed to determine the diagnostic performance of the criteria of the FRI consensus definition and evaluated the effect of the combination of certain suggestive and confirmatory criteria on the diagnostic performance., Methods: A multicenter, multi-national, retrospective cohort study was performed. Patients were subdivided into an FRI or a control group, according to the treatment they received and the recommendations from a multidisciplinary team ('intention to treat'). Exclusion criteria were patients with an FRI diagnosed outside the study period, patients younger than 18 years of age, patients with pathological fractures or patients with fractures of the skull, cervical, thoracic and lumbar spine. Minimum follow up for all patients was 18 months., Results: Overall, 637 patients underwent revision surgery for suspicion of FRI. Of these, 480 patients were diagnosed with FRI, treated accordingly, and included in the FRI group. The other 157 patients were included in the control group. The presence of at least one confirmatory sign was associated with a sensitivity of 97.5%, a specificity of 100% and a high discriminatory value (AUROC 0.99, p < 0.001). The presence of a clinical confirmatory criterion or, if not present, at least one positive culture was associated with the highest diagnostic performance (sensitivity: 98.6%, specificity: 100%, AUROC: 0.99 (p < 0.001)). In the subgroup of patients without clinical confirmatory signs at presentation, specificities of at least 95% were found for the clinical suggestive signs of fever, wound drainage, local warmth and redness., Conclusions: The presence of at least one confirmatory criterion identifies the vast majority of patients with an FRI and was associated with an excellent diagnostic discriminatory value. Therefore, our study validates the confirmatory criteria of the FRI consensus definition. Infection is highly likely in case of the presence of a single positive culture with a virulent pathogen. When certain clinical suggestive signs (e.g., wound drainage) are observed (individually or in combination and even without a confirmatory criterion), it is more likely than not, that an infection is present., Competing Interests: Conflict of interest All authors declare no conflict of interest with respect to the preparation and writing of this article., (Copyright © 2022. Published by Elsevier Ltd.)

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. IMPORTANCE Because of the growing spread of antimicrobial resistance, the use of alternative prevention and treatment strategies is gaining interest. Although the therapeutic potential of bacteriophages has been demonstrated in a number of case reports and series over the past decade, many unanswered questions remain regarding the optimal application protocol. Furthermore, a major concern during phage therapy is the induction of phage neutralizing antibodies. This study aimed at providing a proof-of-concept of phage therapy in a clinically relevant rabbit model of fracture-related infection caused by Staphylococcus aureus. Phage therapy was applied as prophylaxis in a first phase, and as treatment of an established infection in a second phase. The development of phage neutralizing antibodies was evaluated in the treatment study. This study demonstrates that phage therapy can be useful in targeting orthopedic device-related infection, especially as prophylaxis; however, further research and improvements of these application methods are required.

Objectives: Fracture-related infection (FRI) is a feared complication with substantial clinical and economic consequences. The main objective of this study was to compare direct and indirect healthcare costs related to long bone fractures in patients with and without FRI and to assess its impact on the patient's quality of life (QoL)., Patients and Methods: Between January 2015 and March 2019, 175 patients with FRI were treated at the University Hospitals Leuven (Belgium). Using a matched-pair analysis, patients with an FRI were matched by age, sex, and fracture location (humeral, femoral, or tibial shaft) to a non-FRI cohort treated during the same time period. Clinical and process-related variables, direct hospital-related healthcare costs, and indirect costs due to absenteeism were compared between the two groups. Furthermore, the patient's QoL was evaluated using Patient-Reported Outcomes Measurement Information System (PROMIS) physical function and pain interference., Results: After matched-pair analysis, 15 patients in both the FRI and non-FRI group were included. FRI was associated with direct hospital-related costs being eight times that of non-FRI patients (€ 47,845 [€ 43,072-€ 82,548] vs. € 5,983 [€ 4,519-€ 8,428], p < 0.001). Furthermore, FRI was associated with prolonged absenteeism (340 [340-676] vs. 86 [65-216] days, p = 0.007) and a median indirect cost that was nearly four times that of patients without FRI (€ 77,909 vs. € 19,706). Lastly, FRI patients showed significantly poorer outcomes on both physical function (35.6 vs. 48.4, p < 0.001) and pain interference (60.4 vs. 46.3, p < 0.001) PROMIS scales., Conclusion: Direct hospital-related healthcare costs of FRI are eight times that of non-FRI long bone fractures. Total healthcare costs are mainly driven by hospitalisation costs, wherein FRI is associated with prolonged length of stay. To the best of our knowledge, this study is the first to demonstrate that FRI is also associated with substantial absenteeism, which is almost four times higher compared to non-FRI patients. In addition to this economic impact, FRI significantly deteriorates QoL. Generalizing the outcome of this study should be done cautiously due to the small sample size of 15 patients in both the FRI and non-FRI group after matched-pair analysis., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest with respect to the preparation and writing of this article., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Fracture-related infection (FRI) remains one of the most challenging complications in orthopaedic trauma surgery. An early diagnosis is of paramount importance to guide treatment. The primary aim of this study was to compare the Centers for Disease Control and Prevention (CDC) criteria for the diagnosis of organ/space surgical site infection (SSI) to the recently developed diagnostic criteria of the FRI consensus definition in operatively treated fracture patients., Methods: This international multicenter retrospective cohort study evaluated 257 patients with 261 infections after operative fracture treatment. All patients included in this study were considered to have an FRI and treated accordingly ('intention to treat'). The minimum follow-up was one year. Infections were scored according to the CDC criteria for organ/space SSI and the diagnostic criteria of the FRI consensus definition., Results: Overall, 130 (49.8%) FRIs were captured when applying the CDC criteria for organ/space SSI, whereas 258 (98.9%) FRIs were captured when applying the FRI consensus criteria. Patients could not be classified as having an infection according to the CDC criteria mainly due to a lack of symptoms within 90 days after the surgical procedure (n = 96; 36.8%) and due to the fact that the surgery was performed at an anatomical localization not listed in the National Healthcare Safety Network (NHSN) operative procedure code mapping (n = 37; 14.2%)., Conclusion: This study confirms the importance of standardization with respect to the diagnosis of FRI. The results endorse the recently developed FRI consensus definition. When applying these diagnostic criteria, 98.9% of the infections that occured after operative fracture treatment could be captured. The CDC criteria for organ/space SSI captured less than half of the patients with an FRI requiring treatment, and seemed to have less diagnostic value in this patient population., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest with respect to the preparation and writing of this article., (Copyright © 2021. Published by Elsevier Ltd.)

Fracture-related infection (FRI) is a serious complication following musculoskeletal trauma. Accurate diagnosis and appropriate treatment depend on retrieving adequate deep tissue biopsies for bacterial culture. The aim of this cohort study was to compare intraoperative tissue cultures obtained by the Reamer-Irrigator-Aspirator system (RIA)-system against standard tissue cultures obtained during the same surgical procedure. All patients had long bone fractures of the lower limbs and were assigned to the FRI or Control group based on the FRI consensus definition. The FRI group consisted of 24 patients with confirmed FRI and the Control group consisted of 21 patients with aseptic nonunion or chronic pain (in the absence of other suggestive/confirmatory criteria). Standard tissue cultures and cultures harvested by the RIA-system showed similar results. In the FRI group, standard tissue cultures and RIA cultures revealed relevant pathogens in 67% and 71% of patients, respectively. Furthermore, in four FRI patients, cultures obtained by the RIA-system revealed additional relevant pathogens that were not found by standard tissue culturing, which contributed to the optimization of the treatment plan. In the Control group, there were no false-positive RIA culture results. As a proof-of-concept, this cohort study showed that the RIA-system could have a role in the diagnosis of FRI as an adjunct to standard tissue cultures. Since scientific evidence on the added value of the RIA-system in the management of FRI is currently limited, further research on this topic is required before its routine application in clinical practice., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Fracture-related infection (FRI) remains a challenging complication that creates a heavy burden for orthopaedic trauma patients, their families and treating physicians, as well as for healthcare systems. Standardization of the diagnosis of FRI has been poor, which made the undertaking and comparison of studies difficult. Recently, a consensus definition based on diagnostic criteria for FRI was published. As a well-established diagnosis is the first step in the treatment process of FRI, such a definition should not only improve the quality of published reports but also daily clinical practice. The FRI consensus group recently developed guidelines to standardize treatment pathways and outcome measures. At the center of these recommendations was the implementation of a multidisciplinary team (MDT) approach. If such a team is not available, it is recommended to refer complex cases to specialized centers where a MDT is available and physicians are experienced with the treatment of FRI. This should lead to appropriate use of antimicrobials and standardization of surgical strategies. Furthermore, an MDT could play an important role in host optimization. Overall two main surgical concepts are considered, based on the fact that fracture fixation devices primarily target fracture consolidation and can be removed after healing, in contrast to periprosthetic joint infection were the implant is permanent. The first concept consists of implant retention and the second consists of implant removal (healed fracture) or implant exchange (unhealed fracture). In both cases, deep tissue sampling for microbiological examination is mandatory. Key aspects of the surgical management of FRI are a thorough debridement, irrigation with normal saline, fracture stability, dead space management and adequate soft tissue coverage. The use of local antimicrobials needs to be strongly considered. In case of FRI, empiric broad-spectrum antibiotic therapy should be started after tissue sampling. Thereafter, this needs to be adapted according to culture results as soon as possible. Finally, a minimum follow-up of 12 months after cessation of therapy is recommended. Standardized patient outcome measures purely focusing on FRI are currently not available but the patient-reported outcomes measurement information system (PROMIS) seems to be the preferred tool to assess the patients' short and long-term outcome. This review summarizes the current general principles which should be considered during the whole treatment process of patients with FRI based on recommendations from the FRI Consensus Group.Level of evidence: Level V.

Fracture-related infection (FRI) remains a challenging complication. It may result in permanent functional loss or even amputation in otherwise healthy patients. For these reasons, it is important to focus attention on prevention. In treatment algorithms for FRI, antibiotic stewardship programmes have already proved their use by means of a multidisciplinary collaboration between microbiologists, surgeons, pharmacists, infectious disease physicians and nursing staff. A similar approach, however, has not been described for infection prevention. As a first step towards achieving a multidisciplinary care package for infection prevention, this review summarises the most recent guidelines published by the World Health Organization (WHO) and US National Institutes of Health Centers for Disease Control and Prevention (CDC), primarily focusing on the musculoskeletal trauma patient. The implementation of these guidelines, together with close collaboration between infection control physicians, surgeons, anaesthesiologists and nursing staff, can potentially have a beneficial effect on the rate of FRI after musculoskeletal trauma surgery. It must be stated that most evidence presented here in support of these guidelines was not obtained from musculoskeletal trauma research. Although most preventive measures described in these studies can be generalised to the musculoskeletal trauma patient, there are still important differences with nontrauma patients that require further attention. Future research should therefore focus more on this very defined patient population and more specifically on FRI prevention.