Introduction. The management of fracture-related infection has undergone radical progress following the development of international guidelines. However, there is limited consideration to the realities of healthcare in low-resource environments due to a lack of available evidence in the literature from these settings. Initial antimicrobial suppression to support fracture union is frequently used in low- and middle-income countries despite the lack of published clinical evidence to support its practice. This study aimed to evaluate the outcomes following initial antimicrobial suppression to support fracture union in the management of fracture-related infection. Materials & Methods. A retrospective review of consecutive patients treated with initial antimicrobial suppression to support fracture healing followed by definitive eradication surgery to manage fracture-related infections following intramedullary fixation was performed. Indications for this approach were; a soft tissue envelope not requiring reconstructive surgery, radiographic evidence of stable fixation with adequate alignment, and progression towards fracture union. Results. This approach was associated with successful treatment in 51/55 (93%) patients. Fracture union was achieved in 52/55 (95%) patients with antimicrobial suppression alone. Remission of infection was achieved in 54/55 (98%) patients following definitive infection eradication surgery. Following antibiotic suppression, 6/46 (13%) pathogens isolated from intra-operative samples demonstrated multi-drug resistance. Conclusions. Initial antimicrobial suppression to support fracture healing followed by definitive infection eradication surgery was associated with successful treatment in 93% of patients. The likelihood of remission of infection increases when eradication surgery is performed in a healed bone. This approach was not associated with an increased risk of developing multi-drug-resistant infections compared to contemporary bone infection cohorts in the published literature

Aim. Current guidelines for the diagnosis of prosthetic joint infection (PJI) recommend collecting 4–5 independent tissue specimens, with isolation of indistinguishable organisms from two or more specimens. The same principle has been applied to other orthopaedic device-related infections (DRI) including fracture-related infections. However there are few published data validating this approach in DRI other than PJI. We evaluated the performance of different diagnostic cutoffs and varying numbers of tissue specimens for microbiological sampling in fracture-related infections. Method. We used standard protocols for tissue sample collection and laboratory processing, and a standard clinical definition of fracture-related infection. We explored how tissue culture sensitivity and specificity varied with the number of tissue specimens obtained; and with the number of specimens from which an identical isolate was required (diagnostic cutoff). To model the effect of the number of specimens taken we randomly sampled n specimens from those obtained at each procedure, excluding procedures from which less than n specimens were collected, and calculated sensitivity and specificity based on this sample. For each value of n we repeated this process 100 times to estimate the mean sensitivity and specificity for n specimens. Results. We analysed data for 246 cases of suspected fracture-related infection. 77 (31%) met the clinical definition of infection. A median of 4 independent tissue samples were obtained from each procedure (IQR 4–5). Culture sensitivity was highest and specificity lowest using a diagnostic cutoff of 1 specimen for isolation of an organism; specificity increased at the expense of sensitivity with diagnostic cutoffs of 2 or 3 specimens. Culture sensitivity increased as the number of tissue specimens obtained increased from 1 to 4. Although there was a corresponding decline in specificity with increasing numbers of tissue specimens obtained, this was negligible when a diagnostic cutoff of 2 or 3 specimens with identical organisms was used. Using a cutoff of 2 specimens with identical organisms, obtaining 4 specimens gave a sensitivity of 68% (55–78%) and a specificity of 95% (86–99%). Small numbers prevented meaningful analysis of the diagnostic performance of five or more specimens. Conclusions. These data are analogous to findings in prosthetic joint infections, and suggest similar principles may be applied to tissue sampling and culture interpretation in other orthopaedic DRI including fracture-related infection. A larger study is underway to evaluate the performance of greater numbers of tissue specimens

Aim. To classify Fracture-related Infection (FRI) allowing comparison of clinical studies and to guide decision-making around the main surgical treatment concepts. Method. An international group of FRI experts met in Lisbon, June 2022 and proposed a new FRI classification. A core group met during the EBJIS Meeting in Graz, 2022 and on-line, to determine the preconditions, purpose, primary factors for inclusion, format and the detailed description of the elements of an FRI Classification. Results. Historically, FRI was classified by time from injury alone (early, delayed or late). Time produces pathophysiological changes which affect the bone, the soft-tissues and the patient general health, over a continuum. No definitive cut-off is therefore possible. Also, in several studies, time was not identified as an independent predictor of outcome. The most important primary factors were characteristics of the fracture (F), relevant systemic co-morbidities of the patient (R) and impairment of the soft-tissue envelope (I). These factors determine FRI severity, choice of treatment method and are predictors of outcome. For the fracture (F), the state of healing, the potential for bone healing and the presence or absence of a bone defect are critical factors. Co-morbidities are listed and the degree of end-organ damage is important (R). The ability to close the wound directly or the need for soft tissue reconstruction determines the impairment of the soft tissue component (I). Hence the FRI Classification was designed. The final proposal of the FRI Classification is presented here. The new classification has five stages; from simple cases of infected healed fractures, in healthy individuals with good soft tissues (Stage 1), through unhealed fractures with variable potential for bone healing (Stages 2, 3 or 4) to Stage 5, with no limb-sparing or reconstructive options. For instance, the need for a free flap (I4), over a well-healed fracture (F1), in a patient with 2 co-morbidities (R2) gives a classification of F1R2I4 for that patient. Conclusions. This novel approach to FRI classification builds on previous work in osteomyelitis, PJI and chronic medical conditions. It focusses attention on the elements of the disease which need treatment. It now requires validation in large patient cohorts. On behalf of the FRI Classification Consensus Group

Purpose. Fracture-related infection (FRI) is an important complication related to orthopaedic trauma. Although the scientific interest with respect to the diagnosis and treatment of FRI is increasing, data on the microbiological epidemiology remains limited. Therefore, the primary aim of this study was to evaluate the microbiological epidemiology related to FRI, including the association with clinical symptoms and antimicrobial susceptibility data. The secondary aim was to analyze whether there was a relationship between the time to onset of infection and the microbiological etiology of FRI. Methods. Over a five-year period, FRI patients treated at the University Hospitals of Leuven, Belgium, were retrospectively included. The microbiological etiology and antimicrobial susceptibility data were analyzed. Patients were classified as having an early (<2 weeks after implantation), delayed (2–10 weeks) or late-onset (> 10 weeks) FRI. Results. One hundred ninety-one patients with 194 FRIs, mainly involving the tibia (23.7%) and femur (18.6%), were included. Staphylococcus aureus was the most frequently isolated pathogen, regardless of time to onset (n=61; 31.4%), followed by S. epidermidis (n=50; 25.8%) and non-epidermidis coagulase-negative staphylococci (n=35; 18.0%). Polymicrobial infections (n=49; 25.3%), mainly involving Gram-negative bacilli (n=32; 65.3%), were less common than monomicrobial infections (n=138; 71.1%). Virulent pathogens in monomicrobial FRIs were more likely to cause pus or purulent discharge (n=45;54.9%; p=0.002) and fistulas (n=21;25.6%; p=0.030). Susceptibility to piperacillin/tazobactam for GNB was 75.9%. Vancomycin covered 100% of Gram-positive cocci. Conclusion. The high frequency of polymicrobial infections, including Enterobacterales and enterococci, should be considered when choosing an empirical regimen, especially for early FRI. However, since antibiotic stewardship is the cornerstone of good antibiotic practice, overuse and misuse of broad-spectrum empiric therapy should be avoided at all costs. Large multicenter prospective studies are necessary to gain more insight into the added value of (broad) empirical antibiotic therapy

Aim. 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. Method. 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. Overall, the outcome of patients treated for FRI of the clavicle is good, when management of this complication is performed by using a multidisciplinary team approach. The median healthcare costs of these patients are up to 3.5 times higher compared to non-infected operatively treated clavicle fractures. Expert opinion considers factors such as the size of the bone defect, the condition of the soft tissue, and patient demand to guide surgical decision making

Aim. Ankle fracture surgery comes with a risk of fracture-related infection (FRI). Identifying risk factors are important in preoperative planning, in management of patients, and for information to the individual patient about their risk of complications. In addition, modifiable factors can be addressed prior to surgery. The aim of the current paper was to identify risk factors for FRI in patients operated for ankle fractures. Method. A cohort of 1004 patients surgically treated for ankle fractures at Haukeland University hospital in the period of 2015–2019 was studied retrospectively. Patient charts and radiographs were assessed for the diagnosis of FRI. Binary logistic regression was used in analyses of risk factors. Regression coefficients were used to calculate the probability for FRI based on the patients’ age and presence of one or more risk factors. Results. FRI was confirmed in 87 (9%) of 1004 patients. Higher age at operation (p < 0.001), congestive heart failure (CHF), p = 0.006), peripheral artery disease (PAD, p = 0.001), and current smoking (p = .006) were identified as risk factors for FRI. PAD and CHF were the risk factors displaying the strongest association with FRI with an adjusted odds ratio of 4.2 (95% CI 1.8–10.1) and 4.7 (95% CI 1.6–14.1) respectively. Conclusions. The prevalence of FRI was 9% after surgical treatment of ankle fractures. The combination of risk factors found in this study demonstrate the need for a thorough, multidisciplinary, and careful approach when faced with an elderly or frail patient with an ankle fracture. The results of this study help the treating surgeons to inform their patients of the risk of FRI prior to ankle fracture surgery

This study aimed to investigate the outcomes of open tibia shaft fractures at a level one trauma center in a developing world setting. Specific objectives were to determine the association of time delay to antibiotic administration, surgical debridement, definitive skeletal stabilisation and soft tissue reconstruction, and the development of fracture-related infection (FRI). A retrospective cohort study included all adult patients with open tibia shaft fractures from July 2014 to June 2016 and January 2018 to December 2019. Patients who were skeletally immature at the time of injury, those with pathological fractures and who did not complete follow-up of at least three months were excluded. Patients were identified from hospital records. Data was captured in Microsoft Excel and analysed using STATISTICA. A Chi-squared was used to detect significant differences between groups. No association between infection and antibiotic administration was observed when patients were treated within or after 3 hours (p=0.625) or if patients had their first surgical debridement in theatre before or after 24 hours (p=0.259). Patients who waited more than five days for definitive skeletal fixation or soft tissue reconstruction had a significant increase in FRI (OR 4.7, 95% CI 2.0 – 10.9 and OR 4.7, 95% CI 2.0 – 11.0, respectively). Patients who underwent more than two formal debridements had a higher risk of developing FRI (OR 15.6, 95% CI 5.8 – 41.6). Whilst administration of antibiotics within 3 hours of presentation to the emergency unit had no impact on the development of FRI, time delays in managing open tibia shaft fractures are associated with an increased risk for FRI. Definitive soft tissue reconstruction and skeletal stabilization should not be delayed for more than five days

Background. Fracture-related infection (FRI) is treated by adequate debridement, lavage, fracture stabilization (if indicated), adequate soft tissue coverage and systemic antimicrobial therapy. Additional administration of local antibiotics (LA), placed directly in the surgical field, is thought to be beneficial for successful eradication of infection. Aims. 1) To evaluate the effect of local antibiotics on outcome in patients with FRI. 2) To evaluate whether bacterial resistance to the implanted local antibiotics influences its efficacy. Methods. A multinational cross-sectional study was performed in patients with FRI, diagnosed according to the FRI consensus definition, between January 2015 and December 2019. Patients who underwent surgical treatment for FRI at all time points after injury were considered for inclusion. Patients were followed-up for at least 12 months. The primary outcome was the recurrence rate of FRI at follow-up. Inverse Probability for Treatment Weighting (IPTW) modeling and multivariable regression analyses were used to assess the relationship between the application of LA and recurrence rate of FRI at 12 months, 24 months and final follow-up. Results. Overall, 433 FRIs in 429 patients were included. A total of 251 (58.0%) cases were treated with LA. Gentamicin was the most frequently used LA (247/251). Recurrence of infection after surgery occurred in 25/251 (10%) patients who received LA and in 34/182 (18.7%) patients who did not. The use of LA reduced the recurrence rate of FRI at 12 months (HR: 0.69; 95% CI [0.24–1.96]) and 24 months (HR: 0.55; 95% CI [0.22–1.35]). Resistance of cultured microorganisms to the LA was not associated with a higher risk of recurrence of FRI (HR: 0.75, 95% CI [0.32–1.74]). Conclusion. The application of LA in treatment of FRI is likely to reduce the risk of recurrence of FRI as the risk reduction was consistent and clinically relevant but it did not reach statistical significance. High local antibiotic concentrations eradicate most pathogens regardless of susceptibility test results

Aim. This study investigated the management and clinical outcomes of patients treated for confirmed fracture-related infection (FRI) at 3 centres, in the UK and the Netherlands between 2015 and 2019. Method. All patients with FRI, confirmed by the FRI Consensus Definition. 1. and treated surgically, were included. Data were collected on patient characteristics, time from injury to FRI surgery, soft tissue reconstruction, type of stabilization and use of local antibiotics. All patients were followed up for at least one year. The rates of eradication of infection and union were assessed. The associations between treatment methods, time from injury and outcomes were determined. Results. 433 FRIs were treated in patients with mean age 49.7 years (range 14–84). FRI affected the tibia in 226(52.2%), femur in 94(21.7%), pelvis in 26(6%), humerus in 20(4.6%) and foot bones in 19(4.4%). Patients were followed up for a mean of 26 months (range 12–72). Overall, eradication of infection was successful in 86.4% of cases and 86% of unhealed infected fractures were healed at final review. 3.3% required amputation. Successful outcome was not dependent on age, or time from injury (recurrence rate 16.5% in FRI treated at 1–10 weeks after injury; 13.1% at 11–52 weeks; 12.1% at >52 weeks: p=0.52). Method of stabilization had a major affect on outcome. Debridement and retention of a stable infected implant (DAIR) had a failure rate of 22.3%, implant exchange (to new internal fixation) 16.7%, conversion to external fixation 7.4%. DAIR was significantly worse than conversion to external fixation (p=0.01). There was no effect of the time from injury on the outcome of DAIR or any other fixation method. The use of a free flap in the tibia improved the success rate from 80.4% to 92.1% (p=0.044). Outcome was adversely affected by use of a split skin graft alone in soft tissue reconstruction (44% failure) (p=0.006). The use of local antibiotics reduced the recurrence rate from 18.3% to 10.3% (p=0.022). Conclusions. This study is the first to consider outcome for all FRIs, at all-time points, with all treatment modalities. Treatment was mostly successful but may be improved with better directed use of free flaps, local antibiotics, and limitation of DAIR. The results suggest that the division of FRIs into categories based on time from injury, may not be helpful with modern treatment

Aim. This study investigated the effect of the choice of antibiotic regime on outcome of patients treated for fracture-related infection (FRI) at 3 centres, in the UK and the Netherlands between 2015 and 2019. Method. All patients with FRI, confirmed by the FRI Consensus Definition. 1. and treated surgically, were included. Data were collected on patient characteristics, microbial cultures, antibiograms, empiric and definitive systemic antibiotic regimes and local antibiotic use. All patients were followed up for at least one year. The primary outcome was eradication of infection. The chosen antibiotic regimes were compared to the recent guidelines from the FRI Consensus Group. 2. , to assess the correlation with outcome. Results. 433 FRIs were treated in patients with mean age 49.7 years (range 14–84). Patients were followed up for a mean of 26 months (range 12–72). A microbiological diagnosis was obtained in 353 patients (18.5% culture negative rate), with 46% monomicrobial and 35.5% polymicrobial. Staph aureus was present in 51.3% of monomicrobial and 55.2% of polymicrobial infections. Negative cultures were much less likely in FRI within 10 weeks of injury (p=0.00001). Treatment failure with recurrent infection occurred in 13.6% of patients. Failure was more likely in culture positive cases (Polymicrobial; p=0.016, monomicrobial 0.039). Definitive antibiotic regimes were fully compliant with the FRI Guideline in 107 cases (24.7%). In 294 cases (68%) antibiotic regimes outside the guidelines were used. Non-compliance was often due to differences in recommended dosing or overtreatment with extra antimicrobials. 32 cases (7.4%) could not be assessed against the FRI Guidelines as the organisms or regimes were not represented in the guide. Failure rate with FRI Guideline compliant regimes was 12.1% and with non-compliant, 13.2% (p=0.87). Failure in unclassifiable cases was 21.9%. The use of local antibiotics reduced the recurrence rate from 18.3% without local antibiotics to 10.3% with local antibiotics (p=0.022). Conclusions. This study demonstrated that there can be considerable variability in the choice of antimicrobial regimes in FRI. Some deviations from the FRI Guideline did not result in poorer outcomes. These smaller differences in antimicrobial choice may not be major determinants of outcome

Aim. By gaining insight into the Quality of Life (QoL) status and occurrence of complications, critical facets in the care for patients with Fracture-Related Infection (FRI) can be mitigated and measures can be taken to improve their outcome. Therefore, the aims of this study were to 1) determine the QoL in FRI patients in comparison to non-FRI patients and 2) describe the occurrence of complications in both FRI and non-FRI patients. Method. An ambidirectional cohort study was conducted in a level-1 trauma centre between January 1st 2016 and November 1st 2021. All patients who underwent surgical stabilisation of a long bone fracture were eligible for inclusion. Patients with an Injury Severity Score (ISS) ≥16 or incomplete follow-up were excluded. QoL was assessed through the use of five-level EuroQol five-dimension (EQ-5D-5L) questionnaires twelve months post-injury. Results. A total of 134 patients were included, of whom 38 (28%) FRI patients and 96 (72%) non-FRI patients. In comparison to non-FRI patients, FRI patients scored significantly worse on the QoL assessment regarding the index value (p=0.012) and the domains mobility (p<0.001), usual activities (p=0.010) and pain/discomfort (p=0.009). During the median follow-up of 14.5 months (interquartile range (IQR) 9.5–26.5), 25 FRI patients developed a total of 49 distinctive complications besides FRI. The complications nonunion (18%, n=9/49), infection other than FRI (e.g. line infection, urinary tract infection, pneumonia) (18%, n=9/49) and implant failure (14%, n=7/49) were the most frequently described in the FRI group. Conclusions. Patients who suffered from an FRI have a decreased QoL in comparison to those without an FRI. Moreover, patients with an FRI have a higher rate of additional complications. These findings can help in patient counselling regarding the potential physical and mental consequences of having a complicated course of recovery due to an infection

Aim. Surgical treatment of ankle fractures comes with a substantial risk of complications, including infection. An unambiguously definition of fracture-related infections (FRI) has been missing. Recently, FRI has been defined by a consensus group with a diagnostic algorithm containing suggestive and confirmatory criteria. The aim of the current study was to report the prevalence of FRI in patients operated for ankle fractures and to assess the applicability of the diagnostic algorithm from the consensus group. Method. Records of all patients with surgically treated ankle fractures from 2015 to 2019 were retrospectively reviewed for signs of postoperative infections. Patients with suspected infection were stratified according to confirmatory or suggestive criteria of FRI. Rate of FRI among patients with confirmatory and suggestive criteria were calculated. Results. Suspected infection was found in 104 (10%) out of 1004 patients. Among those patients, confirmatory criteria were met in 76/104 (73%) patients and suggestive criteria were met in 28/104 (27%) at first evaluation. Patients with clinical confirmatory criteria (N= 76) were diagnosed with FRI. Patients with suggestive criteria were further examined with either bacterial sampling at the outpatient clinic, revision surgery including bacterial sampling, or a wait-and-see approach. Eleven (39%) of the 28 patients had positive cultures and were therefore diagnosed as having FRI at second evaluation. In total 87 (9%) patients were diagnosed with FRI according to the consensus definition. Only 73 (70%) of the 104 patients with suspected FRI had adequate bacterial sampling. Conclusions. The prevalence of FRI, applying the FRI-consensus criteria, for patients with surgically treated ankle fractures was 9%. Twenty-two percent of patients who met the confirmatory criteria had negative bacterial cultures. The current study shows that we did not have a systematic approach to patients with suspected FRI as recommended by the consensus group. A systematic approach to adequate bacterial sampling when FRI is suspected is paramount. The consensus definition of FRI and its diagnostic algorithm facilitates such an approach

Aim. Fracture-related infection (FRI) is a severe post-traumatic complication which can be accompanied with a soft-tissue defect or an avital soft-tissue envelope. In these cases, a thoroughly planned orthoplastic approach is imperative since a vital soft-tissue envelope is mandatory to achieve fracture union and infection eradication. The aim of our study was to analyse plastic surgical aspects in the management of FRIs, including the type and outcome of soft-tissue reconstruction (STR), and to investigate the long-term outcome of FRI after STR. Method. Patients with a lower leg FRI requiring STR that were treated from 2010 to 2018 at our center were included in this retrospective analysis. STR involved the use of local, pedicled and free flaps. The primary outcome was the success rate of STR, and the secondary outcome was long-term fracture consolidation and cure of infection. Results. Overall, 145 patients with lower leg FRI were identified, of whom 58 (40%) received STR. Muscle flaps were applied in 38, fascio-cutaneous flaps in 19 and a composite osteo-cutaneous flap in one case. All patients underwent successful STR (primary STR in 51/58 patients, 7/58 patients needed secondary STR). A high Charlson Comorbidity Index Score was a significant risk factor for flap failure (p=0.011). Patients with free-flap STR developed significantly more severe complications and needed more surgical interventions (Clavien-Dindo ≥IIIa; p=0.001). Out of the 43 patients that completed long-term follow-up (mean 24 months), fracture consolidation was achieved in 32 and infection eradication in 31. Polymicrobial infection was a significant risk factor for fracture non-union (p=0.002). American Society of Anesthesiologists (ASA) classification of 3 or higher (p=0.040) was a risk factor for persistence or recurrence of infection. Conclusions. In our population, 58/145 patients with FRI required STR. STR was successful in all patients eventually, in 7/58 patients secondary STR was necessary. Therefore, STR should be sought even if primary STR fails. Despite successful STR, the long-term composite outcome showed a high rate of failed fracture consolidation and failed eradication of infection, which was independent of primary STR failure

Aim. Bacteriophages are remerging as alternative and adjunctive therapy for fracture-related infection (FRI). However, current administration protocols involve prolonged retention of a percutaneous draining tube with potential risk of developing superinfection. In this study, we applied a cocktail of in vitro evolved biofilm-targeting phages for Methicillin-resistant Staphylococcus aureus (MRSA) in a hydrogel platform co-delivering vancomycin. In vitro synergy and antibiofilm activity was assessed and a subsequent in vivo study was performed in a mouse FRI model with MRSA. Method. Two evolved bacteriophages (MRSA-R14 and COL-R23) with improved antibiofilm activity against a clinical isolate (MRSA3) were tested in combination with vancomycin and a carboxymethylcellulose (CMC) hydrogel in vitro and in vivo. MRSA3 bacterial biofilms were formed on sterile 4 mm sintered porous glass beads at 37 °C for 24 h. Biofilms were exposed to i-phage cocktail (10. 7. PFU/ml), ii-vancomycin at concentrations of 0.5, 1, 10 and 100 times the MIC, or iii-combination of phage cocktail and vancomycin. Recovered biofilm cells, were quantified by colony counting. The stability and release profiles of phage cocktail and vancomycin in co-delivery hydrogel were assessed in vitro for 8 days and 72 hrs, respectively, and subsequently tested in the treatment of 5-day-old MRSA3 infection of a femoral plate osteotomy in mice. Results. In vitro: The cocktail of evolved phages (10. 7. PFU/ml, 1:1) combined with 0.5 MIC vancomycin achieved 99.72% reduction in MRSA3 biofilm in vitro compared to the growth control. This combination was stable in the co-delivery hydrogel over 8 days. The release profile showed that 57% of phages and 80% of vancomycin were released after 72hrs, which was identical to the performance for gels loaded with phage or antibiotic alone. In the in vivo study, the bacterial load from animals that received co-delivery hydrogel and systemic vancomycin was significantly reduced compared to controls, animals that received systemic vancomycin and animals that received co-delivery hydrogel alone (p<0.05). Conclusions. Our study demonstrates the potential of using evolved phages in combination with vancomycin and hydrogel delivery systems for the treatment of MRSA-related infections. Further research in this area may lead to the development of specific therapies for biofilm-related infection

Aim. The time to onset of symptoms after fracture fixation is still commonly used to classify fracture-related infections (FRI). Early infections (<2 weeks) can often be treated with debridement, systemic antibiotics, irrigation, and implant preservation (DAIR). Late infections (>10 weeks) typically require implant removal as mature, antibiotic-tolerant biofilms have formed. However, the recommendations for delayed infections (2–10 weeks) are not clearly defined. Here, infection healing and bone healing in early and delayed FRI is investigated in a rabbit model with a standardized DAIR procedure. Method. Staphylococcus aureus was inoculated into 17 rabbits after plate osteosynthesis in a humerus osteotomy. The infection developed either one week (early group, n=6) or four weeks (delayed group, n=6) before a standardized DAIR procedure and microbiological analysis were performed. Systemic antibiotics were administered for six weeks (two weeks: Nafcillin+Rifampin, four weeks: Levofloxacin+Rifampin). A control group (n=5) also underwent a revision operation (debridement and irrigation) after four weeks, but received no antibiotic treatment. Rabbits were euthanized seven weeks after the revision operation. Bone healing was assessed using a modified radiographic union score for tibial fractures (mRUST). After euthanasia, a quantitative microbiological examination of the entire humerus, adjacent soft tissues, and implants was performed. Results. All animals were infected at the time of revision surgery, with the bacterial load in the early group (especially in soft tissues) being greater than in the delayed group and control group. This indicates infiltration of bacteria into areas that are more difficult to reach after four weeks of debridement. The infection was eradicated in all animals in both the early and delayed groups at euthanasia, but not in the control group (CFU median (IQR): 2.1×10. 7. (1.3×10. 7. -2.6×10. 7. ). The osteotomy healed in the early group, while bone healing was significantly impaired in both the delayed group and control group (mRUST median (IQR): early group: 16 (14–16), delayed group: 7.5 (6–10), control: 7 (5.5–9); early vs. delayed: p=0.0411, early vs. control p=0.0065). Conclusion. The maturation of the infection between the first and fourth week does not affect the success of infection eradication in this rabbit FRI model. However, bone healing appears to be impaired with increasing duration of infection

Aims. Fracture-Related Infection (FRI) is a severe complication caused by microbial infection of bone. It is imperative to gain more insight into the potentials and limitations of Debridement, Antibiotics and Implant Retention (DAIR) to improve future FRI treatment. The aims of this study were to: 1) determine how time to surgery affects the success rate of DAIR procedures of the lower leg performed within 12 weeks after the initial fracture fixation operation and 2) evaluate whether appropriate systemic antimicrobial therapy affects the success rate of a DAIR procedure. Methods. This multinational retrospective cohort study included patients of at least 18-years of age who developed an FRI of the lower leg within 12 weeks after the initial fracture fixation operation, between January 1st 2015 to July 1st 2020. DAIR success was defined by the absence of recurrence of infection, preservation of the affected limb and retention of implants during the initial treatment. The antimicrobial regimen was considered appropriate if the pathogen(s) was susceptible to the given treatment at the correct dose as per guideline. Logistic regression modelling was used to assess factors that could contribute to the DAIR success rate. Results. A total of 120 patients were included, of whom 70 DAIR patients and 50 non-DAIR patients. Within a median follow-up of 35.5 months, 21.4% of DAIR patients developed a recurrent FRI compared to 12.0% of non-DAIR patients. The DAIR procedure was successful in 45 patients (64.3%). According to the Willenegger and Roth classification, DAIR success was achieved in 66.7% (n=16/24) of patients with an early infection (<2 weeks), 64.4% (n=29/45) of patients with a delayed infection (2–10 weeks) and 0.0% (0/1) of patients with a late infection (>10 weeks). Univariate analysis showed that the duration of infection was not associated with DAIR success in this cohort (p=0.136; OR: 0.977; 95%CI: [0.947–1.007]). However, an appropriate antimicrobial regimen was associated with success of DAIR (p=0.029; OR: 3.231; 95%CI: [1.138–9.506]). Conclusions. Although the results should be interpreted with caution, an increased duration of infection was not associated with a decreased success rate of a DAIR procedure in patients with FRI of the lower leg. The results of this study highlight the multifactorial contribution to the success of a DAIR procedure and emphasize the importance of adequate antimicrobial treatment. Therefore, time to surgery should not be the only key-factor when considering a DAIR procedure to treat FRI

Aim. Staphylococcus aureus is the leading pathogen in fracture-related infection (FRI). Virulence factors vary between different strains, which may have a decisive influence on the course of infection. Previous in vitro experiments, in vivo testing in wax moth larvae, and genomic analysis of S. aureus isolates from FRI identified a low- and high-virulent strain. These findings correlated with the acute course of FRI induced by the high-virulent pathogen, whereas the low-virulent strain caused a chronic FRI in its human host. However, the role of bacterial virulence in FRI is not completely understood. Therefore, the present study aimed to compare the identified high- and low-virulent S. aureus isolates in a murine FRI model. Method. Skeletally mature C57Bl/6N mice received a femoral osteotomy stabilized by titanium locking plates. FRI was established by inoculation of either high-virulent S. aureus EDCC 5458 or low-virulent S. aureus EDCC 5464 in the fracture gap. Mice were euthanized 4 and 14 days after surgery, respectively. Severity and progression of infection were assessed in terms of clinical presentation, quantitative bacteriology, semiquantitative histopathologic evaluation, and serum cytokine profile. Results. Quantitative bacteriological results 4 days after surgery revealed a higher bacterial load in soft tissue samples in high-virulent infected animals (p =0.026). Mice infected with the high-virulent strain also displayed higher rates of organ dissemination (24/36 organs in high-virulent, versus 5/36 organs in low-virulent infected animals; p <0.0001). In the histopathological assessment, bacterial agglomerations at the fracture ends were present to a greater extent in the high-virulent cohort and barely detectable in low-virulent infected mice. In both cohorts, no bone healing was observed after 4 days. On day 14, bone healing at the fracture site was visible in low-virulent infected animals, whereas callus formation was observed in only one animal from the high-virulent infected cohort. Furthermore, osteonecrosis and osteolysis were increased in high-virulent infected animals. Regarding serum cytokines, innate immune markers were elevated in both groups at day 4. By day 14, a more pronounced proinflammatory response indicated by increased serum cytokine levels of IFN-γ, IL-1β, and IL-6 was observed in high-virulent infected animals. Conclusions. The present study demonstrated distinct bacteriological and histopathological differences between two different virulent S. aureus strains previously shown to have different courses in human patients. While host physiology is often considered to have a major impact on the course of FRI, this study highlights the critical influence of the invading pathogen and its virulence characteristics

Aim. Duration of perioperative antimicrobial prophylaxis (PAP) remains controversial in prevention of fracture-related infection (FRI) – with rates up to 30% - in open fracture (OF) management. Objectives were to investigate the impact of the PAP duration exclusively in or related to long bone OF trauma patients and the influence of augmented renal clearance (ARC), a known phenomenon in trauma patients, as PAP consists of predominantly renally eliminated antibiotics. Method. Trauma patients with operatively treated OF, admitted between January 2003 and January 2017 at the University Hospitals Leuven, were retrospectively evaluated. FRI was defined following the criteria of the consensus definition of FRI. A logistic regression model was conducted with FRI as outcome. Results were considered statistically significant when p< 0.05. Results. Forty (8%) from the 502 patients developed a FRI, with 20% FRIs in Gustilo-Anderson (GA) III OFs. Higher GA grade and polytrauma were independently associated with the occurrence of FRI. The heterogeneity in OF management, especially with regard to the applied PAP regimens and duration, was striking and consequently hampering the investigation on the impact of PAP duration. To overcome this issue, a subgroup analysis was performed in patients treated with the two PAP regimens as defined in the hospitals' guidelines – i.e. cefazolin, with metronidazole and tobramycine when extensive contamination was present -, revealing flap coverage and relative duration of augmented renal ARC as independently associated factors. Conclusions. For the first time, a definition based on diagnostic criteria was used to objectively include patients with a FRI. In order to support clinicians in establishing strategies to prevent FRI in long bone OFs, further prospective large randomized controlled trials with clearly predefined PAP regimens are needed to provide reliable recommendations regarding the impact of duration of PAP and ARC

Aim. The aim of this systematic review was to determine the reported treatment strategies, their individual success rates, and other outcome parameters in the management of critical-sized bone defects in Fracture-Related Infection (FRI) patients between 1990 and 2018. Method. We performed a systematic literature search on treatment and outcome of critical-sized bone defects in FRI. Treatment strategies identified were, autologous cancellous grafts, autologous cancellous grafts combined with local antibiotics, the induced membrane technique, vascularized grafts, bone transport, and bone transport combined with local antibiotics. Studies describing bone defects of 1 cm or greater were included. Outcomes were bone healing and infection eradication after primary surgical protocol and recurrence of FRI and amputations at the end of study period. Results. Fifty studies were included, describing 1,530 patients, of which the tibia was affected in 82%. The mean age was 40 years (range 6–80), with predominantly male subjects (79%). Mean duration of infection was 17 months (range 1–624) and mean follow-up lasted 51 months (range 6–126). Four studies (8%) described treatment using vascularized grafts, 18 (36%) cancellous grafts, 8 (16%) the induced membrane technique, and 20 (40%) bone transport. A total of 1063 grafts were used of which 30% were vascularized and 60% were cancellous bone. After initial protocolized treatment, FRI was cured in 83% (95% CI 79–87) of all cases, increasing to 94% (95% CI 92–96) at the end of each individual study. Recurrence of infection was seen in 8% (95% CI 6–11) and amputation in 3% (95% CI 2–3). Conclusions. This is the first extensive review of bone defect treatment protocols in chronic/late-onset FRI. Overall published work showed a high success rate of 94% and low amputation rate of only 3%. However, data did not allow a reliable comparison across treatments. The results should thus be interpreted with caution due to the retrospective and observational design of most studies, the lack of clear classification systems, incomplete data reports, potential underreporting of adverse outcomes, and heterogeneity in patient series. A consensus on classification, treatment protocols, and outcome is needed in order to improve reliability of future studies

Aim. Focused high energy extracorporeal shockwave therapy (fhESWT) is used to support fracture healing in non-union cases and has been shown to have antibacterial effects. We trialed fhESWT as an adjunct to conventional treatment in a clinically relevant rabbit model of fracture related infection. Method. A complete humeral osteotomy was performed in 31 rabbits and fixed with a 7-hole-LCP. A fracture-related infection (FRI) was established with Staphylococcus aureus. After two weeks, a revision surgery was performed with debridement, irrigation and implant retention. Rabbits then received: no further treatment (controls); shockwaves (at day 2 and 6 after revision, 4'000 Impulses each time with 23kV); systemic antibiotics (rifampin and nafcillin) over one week in weight adjusted dosages; or the combination of antibiotics and shockwaves. Treatments were applied over one week. Blood cultures were taken before and after shockwave sessions. After an additional week without treatment, rabbits were euthanized, and quantitative bacteriology was performed on implants and tissues to determine infection burden. Indicator organs (brain, heart, liver, lungs, kidneys and spleen) were cultured to assess possible bacteraemia due to fhESWT. Results. All rabbits were infected at revision surgery as determined by bacteriological culture of debrided materials. fhESWT in combination with antibiotic treatment lowered the bacterial burden at euthanasia hundredfold compared to antibiotic treatment alone in all samples (p=0.38). This effect was most prevalent for the implant sample (p=0.08). No significant effect was seen for fhESWT alone compared to untreated controls. No signs of bacteraemia occurred. Conclusions. The additon of systemic antibiotics had the biggest effect on reduction of bacteria. Although further lowering the bacterial burden in our model the effect of fhESWT as an adjunct was not big enough to be statistically secured in this in vivo rabbit model. In certain difficult-to-treat infections the addition of fhESWT might be beneficial. The method appears to be safe in this model of acute FRI as no signs of bacteremia occurred despite the high energy and impulse number. Further investigations are needed to identify the correct indication