Development of an ex vivo model to study Staphylococcus aureus invasion of the osteocyte lacuno-canalicular network.

Staphylococcus aureus has multiple mechanisms to evade the host's immune system and antibiotic treatment. One such mechanism is the invasion of the osteocyte lacuno-canalicular network (OLCN), which may be particularly important in recurrence of infection after debridement and antibiotic therapy. The aim of this study was to develop an ex vivo model to facilitate further study of S. aureus invasion of the OLCN and early-stage testing of antibacterial strategies against bacteria in this niche. The diameter of the canaliculi of non-infected human, sheep, and mouse bones was measured microscopically on Schmorl's picrothionin stained sections, showing a large overlap in canalicular diameter. S. aureus successfully invaded the OLCN in all species in vitro as revealed by presence in osteocyte lacunae in Brown and Brenn-stained sections and by scanning electron microscopy. Murine bones were then selected for further experiments, and titanium pins with either a wild-type or ΔPBP4 mutant S. aureus USA300 were placed trans-cortically and incubated for 2 weeks in tryptic soy broth. Wild-type S. aureus readily invaded the osteocyte lacunae in mouse bones while the ΔPBP4 showed a significantly lower invasion of the OLCN (p = 0.0005). Bone specimens were then treated with gentamicin, sitafloxacin, R14 bacteriophages, or left untreated. Gentamicin (p = 0.0027) and sitafloxacin (p = 0.0280) significantly reduced the proportion of S. aureus-occupied lacunae, whilst bacteriophage treatment had no effect. This study shows that S. aureus is able to invade the OLCN in an ex vivo model. This ex vivo model can be used for future early-stage studies before proceeding to in vivo studies.

Isolation and Antibiofilm Activity of Bacteriophages against Cutibacterium acnes from Patients with Periprosthetic Joint Infection.

BACKGROUND: Infections following shoulder surgery, particularly periprosthetic joint infection (PJI), are challenging to treat. Cutibacterium acnes is the causative pathogen in 39% to 76% of these cases. This study explores the efficacy of bacteriophage therapy as an alternative to conventional antibiotics for treating such infections. METHODS: Nine phages with lytic activity were isolated from the skin of humans using C. acnes ATCC 6919 as the indicator host. These phages were tested individually or in combination to assess host range and antibiofilm activity against clinical strains of C. acnes associated with PJIs. The phage cocktail was optimized for broad-spectrum activity and tested in vitro against biofilms formed on titanium discs to mimic the prosthetic environment. RESULTS: The isolated phages displayed lytic activity against a range of C. acnes clinical isolates. The phage cocktail significantly reduced the bacterial load of C. acnes strains 183, 184, and GG2A, as compared with untreated controls (p < 0.05). Individual phages, particularly CaJIE7 and CaJIE3, also demonstrated significant reductions in bacterial load with respect to specific strains. Moreover, phages notably disrupted the biofilm structure and reduced biofilm biomass, confirming the potential of phage therapy in targeting biofilm-associated infections. CONCLUSIONS: Our preclinical findings support the potential of phage therapy as a viable adjunct to traditional antibiotics for treating C. acnes infections in orthopedic device-related infections. The ability of phages to disrupt biofilms may be particularly beneficial for managing infections associated with prosthetic implants.

Phage therapy: A primer for orthopaedic trauma surgeons.

Phage therapy (PT) continues to attract interest in the fight against fracture-related infection (FRI), particularly for recurring infections that have not been resolved using conventional therapeutic approaches. The journey PT has taken from early clinical application in the pre-antibiotic era to its recent reintroduction to western clinical practice has been accelerated by the increased prevalence of multi-drug resistant (MDR) pathogens in the clinic. This review will present PT's potential as a precise, adaptable, and effective treatment modality, with a focus on patient and phage selection, as well as the various administration protocols currently applied to patients. The challenges for PT, for example the most optimal application technique and dosing, are also discussed and underscore the importance of personalized approaches and the urgent need for more robust clinical evidence. Future perspectives, including phage engineering and innovative delivery systems will be discussed, as they may broaden the applicability of PT to a point where it may become a standard rather than an option of last resort for orthopedic infection management.

Optimization of bacteriophage therapy for difficult-to-treat musculoskeletal infections: a bench-to-bedside perspective.

Given the increasing threat of antimicrobial resistance, scientists are urgently seeking adjunct antimicrobial strategies, such as phage therapy (PT). However, despite promising results for the treatment of musculoskeletal infections in our center, crucial knowledge gaps remain. Therefore, a prospective observational study (PHAGEFORCE) and a multidisciplinary approach was set up to achieve and optimize standardized treatment guidelines. At our center, PT is strictly controlled and monitored by a multidisciplinary taskforce. Each phage treatment follows the same pathway to ensure standardization and data quality. Within the PHAGEFORCE framework, we established a testing platform to gain insight in the safety and efficacy of PT, biodistribution, phage kinetics and the molecular interaction between phages and bacteria. The draining fluid is collected to determine the phage titer and bacterial load. In addition, all bacterial isolates are fully characterized by genome sequencing to monitor the emergence of phage resistance. We hereby present a standardized bench-to-bedside protocol to gain more insight in the kinetics and dynamics of PT for musculoskeletal infections.

Management of rotational malalignment following operative treatment of fractures of the lower extremities. A scoping review.

BACKGROUND: Rotational malalignment after operative fracture treatment of the lower extremity may be associated with increased pain and functional impairment. Despite its clinical relevance, there are no uniform management guidelines. The aim of this scoping review is to provide an overview of all available evidence to diagnose and treat rotational deformities of the lower extremity following operative fracture treatment. METHODS: This scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A literature search was carried out on 22 August 2023 by two independent reviewers in the Pubmed (MEDLINE), Embase, Web of Science, and Cochrane library databases. The search strategy was developed with the assistance of a biomedical information specialist. The main search terms were tibial and femoral malrotations. Disagreements were resolved through discussion with a third reviewer. RESULTS: After screening and quality assessment of 3929 unique identified records, 50 articles were included for qualitative synthesis. Most studies were retrospective case reports or case series. Thirty studies focused on the femur, 11 on the tibia and nine included both femur and tibia. Most of the included studies presented cases where malrotation was associated with other limb deformities. Only 18 studies focused solely on the treatment of malrotation of the lower extremities after operative fracture treatment. Regarding diagnosis, bilateral CT-scans were used in 34 studies. Regarding treatment, external fixation was used in two studies, internal fixation (either intramedullary nail or plate) in 45 studies, and in three studies the authors used both. Overall, revision surgery resulted in good clinical outcomes with low complication rates. CONCLUSION: This scoping review reveals that rotational malalignment following operative treatment of lower extremity fractures remains an important complication. Although it occurs frequently and is associated with severe disability for the patient, standardized guidelines regarding the terminology, diagnosis, indications for intervention and treatment are lacking. CT-scan is the most used diagnostic modality in daily clinical practice. Revision surgery, using diverse operative techniques, demonstrated positive results, significantly alleviating patient complaints with few complications. Nevertheless, an international consensus regarding the optimal management pathway is needed, and future prospective clinical studies seem therefore necessary.

The FRI classification - A new classification of fracture-related infections.

AIM: To identify the most relevant factors with respect to the management of fracture-related infection (FRI) and to develop a comprehensive FRI classification that guides decision-making and allows scientific comparison. METHOD: An international group of FRI experts determined the preconditions, purpose, primary factors for inclusion, format and detailed description of the elements of an FRI classification through a consensus driven process. RESULTS: Three major elements were identified and grouped together in the FRI Classification: Fracture (F), Related patient factors (R) and Impairment of soft tissues (I). Each element was divided into five levels of complexity. Fractures can be healed (F1) or unhealed (F2-5). Patients may be fully healthy (R1) or have 4 levels of compromise, with and without end-organ damage (R2-5). Soft tissue condition ranges from well vascularized and easily closed (I1) to major skin defects requiring free flaps (I4). In all three elements, the fifth level (F5, R5 or I5) describes a patient who has an unreconstructible bone, soft tissue envelope or is not fit for surgery. CONCLUSION: The FRI classification, which is based on the three major elements Fracture (F), Related patient factors (R) and Impairment of soft tissues (I) is intended to guide decision-making and improve the quality of scientific reporting for FRIs in the future. The proposed classification is based on expert opinion and therefore an essential next step is clinical validation, in order to realize the ultimate goal of improving outcomes in the management of FRI.

Combination of bacteriophages and vancomycin in a co-delivery hydrogel for localized treatment of fracture-related infections.

Fracture-related infections (FRIs), particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA), are challenging to treat. This study designed and evaluated a hydrogel loaded with a cocktail of bacteriophages and vancomycin (1.2 mg/mL). The co-delivery hydrogel showed 99.72% reduction in MRSA biofilm in vitro. The hydrogel released 54% of phages and 82% of vancomycin within 72 h and maintained activity for eight days, in vivo the co-delivery hydrogel with systemic antibiotic significantly reduced bacterial load by 0.99 log10 CFU compared to controls, with active phages detected in tissues at euthanasia (2 × 103 PFU/mL). No phage resistance was detected in the phage treatment groups, and serum neutralization resulted in only a 20% reduction in phage count. In this work, we show that a phage-antibiotic co-delivery system via CMC hydrogel is a promising adjunct to systemic antibiotic therapy for MRSA-induced FRI, highlighting its potential for localized, sustained delivery and improved treatment outcomes.

Ureaplasma urealyticum osteomyelitis of the greater trochanter in a patient with multiple sclerosis using ocrelizumab - a case report.

Ocrelizumab - a monoclonal anti-CD20 antibody used in treatment of multiple sclerosis (MS) - marks significant progress in treating autoimmune diseases but raises susceptibility to opportunistic infections due to hypogammaglobulinemia. A young MS patient developed osteomyelitis from persistent Ureaplasma urealyticum urethritis, which was diagnosed with specialized polymerase chain reaction and resolved with targeted antibiotics. A multidisciplinary approach is crucial for managing such infections.

Bacteriophage therapy in musculoskeletal infections: from basic science to clinical application.

The treatment of musculoskeletal infections (MSIs), including periprosthetic joint infection (PJI) and fracture-related infection (FRI), is often complicated by biofilm-related challenges necessitating multiple revision surgeries and incurring substantial costs. The emergence of antimicrobial resistance (AMR) adds to the complexity of the problem, leading to increased morbidity and healthcare expenses. There is an urgent need for novel antibacterial strategies, with the World Health Organization endorsing non-traditional approaches like bacteriophage (phage) therapy. Phage therapy, involving the targeted application of lytic potent phages, shows promise in the treatment of MSIs. Although historical clinical trials and recent case studies present significant milestones in the evolution of phage therapy over the past century, challenges persist, including variability in study designs, administration protocols and phage selection. Efforts to enhance treatment efficacy consist of personalized phage therapy and combination with antibiotics. Future perspectives entail addressing regulatory barriers, standardizing treatment protocols, and conducting high-quality clinical trials to establish phage therapy's efficacy for the treatment of MSIs. Initiatives like the PHAGEFORCE study and the PHAGEinLYON Clinic programme aim to streamline phage therapy, facilitating personalized treatment approaches and systematic data collection to advance its clinical utility in these challenging infections.

Histological analysis of the medial gastrocnemius muscle in young healthy children.

Introduction: Histological data on muscle fiber size and proportion in (very) young typically developing (TD) children is not well documented and data on capillarization and satellite cell content are also lacking. Aims: This study investigated the microscopic properties of the medial gastrocnemius muscle in growing TD children, grouped according to age and gender to provide normal reference values in healthy children. Methods: Microbiopsies of the medial gastrocnemius (MG) muscle were collected in 46 TD boys and girls aged 2-10 years subdivided into 4 age groups (2-4, 4-6, 6-8 and 8-10 years). Sections were immunostained to assess fiber type cross-sectional area (fCSA) and proportion, the number of satellite cells (SC), capillary to fiber ratio (C/F), capillary density for type I and II fiber (CFD), capillary domain, capillary-to-fiber perimeter exchange index (CFPE) and heterogeneity index. fCSA was normalized to fibula length2 and the coefficient of variation (CV) was calculated to reflect fCSA intrasubject variability. Results: Absolute fCSA of all fibers increased with age (r = 0.72, p < 0.001) but more in boys (+112%, p < 0.05) than in girls (+48%, p > 0.05) Normalized fCSA, CV and fiber proportion did not differ between age groups and gender. C/F was strongly correlated with age in boys (r = 0.83, p < 0.001), and to a lesser extent in girls (r = 0.37, p = 0.115), while other capillary parameters as well as the number of SC remained stable with increasing age in boys and girls. Discussion: This study provides reference values of histological measures in MG according to age in normally growing boys and girls. These data may be used as a reference to determine disease impact and efficacy of therapeutic approach on the muscle.

Advanced imaging shows extra-articular abscesses in two out of three adult patients with septic arthritis of the native hip joint.

Background: Septic arthritis (SA) of the native adult hip is a rare orthopaedic emergency requiring prompt diagnosis and treatment. As clinical presentation and laboratory findings are frequently atypical, advanced imaging is often requested. This retrospective study aimed to investigate the prevalence and pattern of extra-articular infectious manifestations and their implications for pre-operative advanced imaging in patients with proven SA of the native hip joint. Methods: Out of 41 patients treated surgically for SA of the native hip during a 16-year period at our tertiary referral hospital, 25 received advanced imaging (computed tomography (CT), magnetic resonance imaging (MRI), or fluorodeoxyglucose positron emission tomography (FDG PET-CT)) prior to initial intervention. For each investigation, a specific set of variables was systematically interpreted, and the most suitable surgical approach was determined. The prognostic value was evaluated by comparing specific outcome measures and the extent of extra-articular involvement. Results: It was found that 32 % of patients had an abscess in one anatomical region, 32 % of patients had abscesses in multiple anatomical regions, and only 36 % of patients had no substantial abscess. Gluteal abscesses were especially common in patients with SA due to contiguous spread. Abscesses in the iliopsoas region were more common in patients with SA due to hematogenous seeding. A combination of several different surgical approaches was deemed necessary to adequately deal with the various presentations. No significant prognostic factors could be identified. Conclusion: We recommend performing advanced imaging in patients with suspected or proven septic arthritis of the native hip joint, as extra-articular abscesses are present in 64 % and might require varying anatomical approaches.

The surgical management of fracture-related infection. Surgical strategy selection and the need for early surgical intervention.

The aim of this narrative review is to describe the various surgical management strategies employed in fracture-related infection (FRI), to explore how they are selected and discuss the rationale for early surgical intervention. Surgical treatment options in patients with FRI include debridement, antibiotics and implant retention (DAIR), revision (exchange) or removal. In selecting a treatment strategy, a variety of factors need to be considered, including the condition of the bone, soft tissues, host and causative microorganism. Irrespective of the selected treatment strategy, prompt surgical intervention should be considered in order to confirm the diagnosis of an FRI, to identify the causative organism, remove necrotic or non-viable tissue that can serve as a nidus for ongoing infection, ensure a healthy soft tissue envelope and to prevent the vicious cycle of infection associated with skeletal and/or implant instability. Ultimately, the objective is to prevent the establishment of a persistent infection. Urgent surgery may be indicated in case of active, progressive disease with systemic deterioration, local progression of infection, deterioration of soft tissues, or progressive fracture instability. In case of static disease, the patient should be monitored closely and surgery can be performed on an elective basis, allowing adequate time for optimisation of the host through risk factor modification, optimisation of the soft tissues and careful planning of the surgery.

Key aspects of soft tissue management in fracture-related infection: recommendations from an international expert group.

A judicious, well-planned bone and soft tissue debridement remains one of the cornerstones of state-of-the-art treatment of fracture-related infection (FRI). Meticulous surgical excision of all non-viable tissue can, however, lead to the creation of large soft tissue defects. The management of these defects is complex and numerous factors need to be considered when selecting the most appropriate approach. This narrative review summarizes the current evidence with respect to soft tissue management in patients diagnosed with FRI. Specifically we discuss the optimal timing for tissue closure following debridement in cases of FRI, the need for negative microbiological culture results from the surgical site as a prerequisite for definitive wound closure, the optimal type of flap in case of large soft tissue defects caused by FRI and the role of negative pressure wound therapy (NPWT) in FRI. Finally, recommendations are made with regard to soft tissue management in FRI that should be useful for clinicians in daily clinical practice.Level of evidence Level V.

Diagnostic Performance of a telephone questionnaire for fracture-related infections (FRIs) in open tibia fracture patients in Tanzania.

INTRODUCTION: Fracture-related infections (FRIs) are a major cause of trauma-associated morbidity worldwide. In 2018, an expert group supported by the AO Foundation, European Bone and Joint Infection Society developed a consensus definition of FRI. Still, there is limited knowledge on the applicability of this definition in low- and middle-income countries (LMICs). Given the unique barriers that cause low follow-up rates for orthopaedic trauma patients in LMICs, this study aims to evaluate the diagnostic performance of a telephone questionnaire in identifying patients with FRIs after open tibia fracture fixation in Tanzania. MATERIALS AND METHODS: Patients from a randomized controlled trial investigating the infection prevention benefit of locally applied gentamycin for open tibial fractures were included. Patients completed FRI based telephone questionnaires 7-10 days prior to scheduled follow-ups at 6 weeks, 3 months, 6 months, 9 months, and 1 year. The questionnaire included two "confirmatory" criteria questions for FRI (i.e., open wound and purulent drainage) and three "suggestive" criteria questions (i.e., wound drainage, fever, and warmth). Contingency tests were performed to identify the sensitivity and specificity between answers and adjudicated FRI diagnoses at the corresponding in-person follow-up. Data was analysed using STATA version 15.0 and MedCalc's online diagnostic test calculator. RESULTS: There were a total of 234 complete questionnaires and 85 unique patients included. The sensitivity and specificity of having any positive answer in the questionnaire was highest at 6 months (100 % and 92.5 %, respectively). For all time-points pooled, sensitivity was 71.4 % and specificity was 93.0 %. Drainage had the highest sensitivity (71.4 %) while fever had the highest specificity (99.6 %). For confirmatory criteria, sensitivity was 14.3 % and specificity was 96.0 %. Contrastingly, the sensitivity for suggestive criteria was higher (71.4 %), with a similar specificity (93.8 %). CONCLUSION: Our study indicates that telephone questionnaires have adequate diagnostic performance when assessing FRIs. The presence of drainage identified the majority of patients with FRI, and specificities were high across confirmatory and suggestive criteria. Our study is one of the first to evaluate telephone questionnaires as a diagnostic tool for FRIs in patients with open tibia fractures in a LMIC hospital and validates the FRI consensus definition criteria.

Should treatment decisions in septic arthritis of the native hip joint be based on the route of infection?

Background: Surgical management of septic arthritis (SA) of the hip aims at treating the infection by either preserving, resecting or replacing the joint. In some cases, joint preservation should be attempted, whereas other cases would benefit from immediate joint resection or replacement. Prognostic factors have been proposed to guide decision-making. We hypothesized that most of these factors can be simplified to three subgroups based on the route of infection: contiguous spreading, direct inoculation or hematogenous seeding. Methods: A total of 41 patients have been treated surgically for SA of the native hip at our tertiary hospital during the last 16 years. Medical records were studied, and various patient and disease characteristics were collated. Results: Significant differences between (1) level of fitness, (2) condition of the hip joint, (3) micro-organisms and (4) chance of femoral head preservation were found for patients with SA of the native hip resulting from the three aforementioned subgroups. Femoral head resection was necessary at one point in 85 % of patients. Patients with hematogenous infections of undamaged hips had a reasonable chance (53 %) of avoiding joint resection or replacement. Hip arthroplasty was performed on 46.3 % of patients, with an infection rate of 10.5 %. Conclusion: Patients with SA of the native hip resulting from contiguous spreading, hematogenous seeding or direct inoculation differ significantly and should be considered distinct clinical entities. Route of infection is directly related to the chance of femoral head preservation and should, therefore, guide decision-making. Only patients with hematogenous infection to a previously healthy hip had the possibility of femoral head preservation.

The global burden of fracture-related infection: can we do better?

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.

Bedside check of medication appropriateness (BED-CMA) as a risk-based tool for bedside clinical pharmacy services: A proof-of-concept study at the trauma surgery ward.

Background: Bedside clinical pharmacy prevents drug-related problems, but is not feasible in many countries due to limited resources. Hence, clinical rules using structural information in the electronic health record can help identifying potentially inappropriate prescriptions (PIPs). We aimed to develop and implement a risk-based clinical pharmacy service and evaluate its impact on prescribing at the trauma surgery ward. Methods: The proportion of residual PIPs per day, i.e. the number of PIPs that persisted up to 24 h after pharmacist intervention divided by the number of PIPs at T0, was evaluated before and after implementation of the intervention in an interrupted time series analysis. The pre-intervention cohort received usual pharmacy services, i.e. a 0.3 FTE clinical pharmacist trainee. Fifteen clinical rules, targeting antimicrobial, anticoagulant and analgesic therapy were implemented in the post-intervention period. The pre-intervention period was compared to two post-intervention scenarios: A) clinical rule alerts reviewed by a 0.3 FTE clinical pharmacist trainee; and B) clinical rule alerts reviewed daily for approximately 1 h by a clinical pharmacist trainee. Results: Pre-intervention, a median proportion of 67% (range 0%-100%) residual PIPs per day was observed. Scenario A showed an immediate relative reduction of 14% (p = 0.72) and scenario B a significant immediate relative reduction of 85% (p = 0.0015) in residual PIPs per day. In scenario A, recommendations were provided for 19% of clinical rule alerts, of which 67% was accepted by the surgeon within 24 h. In scenario B, recommendations were given for 56% of alerts, of which 84% was accepted. Conclusions: Using clinical rules is an effective approach to organize bedside clinical pharmacy services and improves prescribing at the trauma surgery ward. Advanced training and daily follow-up of the clinical rules are two requirements to be considered.

Stability of magistral phage preparations before therapeutic application in patients with chronic rhinosinusitis, sepsis, pulmonary, and musculoskeletal infections.

IMPORTANCE: As antimicrobial resistance becomes more prevalent, the application of (bacterio)phage therapy as an alternative treatment for difficult-to-treat infections is (re)gaining popularity. Over the past decade, numerous promising case reports and series have been published demonstrating the therapeutic potential of phage therapy. However, important questions remain regarding the optimal treatment protocol and, unlike for medicinal products, there are currently no predefined quality standards for the stability of phage preparations. Phage titers can be influenced by several factors which could lead to reduced titers after preparation and storage and, ultimately, subtherapeutic applications. Determining the stability of different phages in different recipients according to the route of administration is therefore one of the first important steps in establishing a standardized protocol for phage therapy.

Alginate microbeads and hydrogels delivering meropenem and bacteriophages to treat Pseudomonas aeruginosa fracture-related infections.

Bacteriophage (phage) therapy has shown promise in treating fracture-related infection (FRI); however, questions remain regarding phage efficacy against biofilms, phage-antibiotic interaction, administration routes and dosing, and the development of phage resistance. The goal of this study was to develop a dual antibiotic-phage delivery system containing hydrogel and alginate microbeads loaded with a phage cocktail plus meropenem and evaluate efficacy against muti-drug resistant Pseudomonas aeruginosa. Two phages (FJK.R9-30 and MK.R3-15) displayed enhanced antibiotic activity against P. aeruginosa biofilms when tested in combination with meropenem. The antimicrobial activity of both antibiotic and phage was retained for eight days at 37 °C in dual phage and antibiotic loaded hydrogel with microbeads (PA-HM). In a mouse FRI model, phages were recovered from all tissues within all treatment groups receiving dual PA-HM. Moreover, animals that received the dual PA-HM either with or without systemic antibiotics had less incidence of phage resistance and less serum neutralization compared to phages in saline. The dual PA-HM could reduce bacterial load in soft tissue when combined with systemic antibiotics, although the infection was not eradicated. The use of alginate microbeads and injectable hydrogel for controlled release of phages and antibiotics, leads to the reduced development of phage resistance and lower exposure to the adaptive immune system, which highlights the translational potential of the dual PA-HM. However, further optimization of phage therapy and its delivery system is necessary to achieve higher bacterial killing activity in vivo in the future.

Treatment and outcome of fracture-related infection of the clavicle.

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 (P25-P75: 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 (P25-P75: € 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.