Aim. The SOLARIO trial is a randomised controlled non-inferiority trial of antibiotic strategy for bone and joint infection. SOLARIO compares short or long post-operative systemic antibiotic duration, for patients with confirmed infections, who had local antibiotics implanted and no infected metalwork retained when undergoing surgery. This analysis compared systemic antibiotic use in the short (intervention) and long (standard of care) arms of the trial, in the 12 months after index surgery. Method. Data was collected prospectively from study randomisation, within 7 days of index surgery. All systemic antibiotics prescribed for the index infection were recorded, from health records and patient recall, at randomisation, 6 weeks, 3-6 months and 12 months after study entry. Start and end dates for each antibiotic were recorded. Results. 251 patients were randomised to short systemic antibiotics (up to 7 post-operative days) and 249 patients, to long systemic antibiotics. 5 participants in the short group and 2 participants in the long group withdrew from study follow-up. Complete data for all systemic antibiotics taken in the 12 months following surgery, were available for 237 participants in the short group and 236 participants in the long group. 80 participants across both groups were noted as having deviated from their assigned treatment strategy. Both groups received empiric antibiotics, predominantly vancomycin and meropenem, for up to 7 days after surgery. Considering each prescribed antibiotic as a separate duration (even when administered concurrently), participants assigned to standard care received a mean of 74.9 antibiotic-days. Participants assigned to short systemic antibiotics received a mean of 27.5 antibiotic-days in the 12 months after surgery. The most commonly prescribed antibiotics in both treatment groups were vancomycin and meropenem: these antibiotics accounted for 7.1 days prescribed per participant in the long group, and 6.3 days in the short group (p=0.37). Reasons for post-randomisation antibiotic prescribing in the short treatment group included later planned surgery, identification of bacteria requiring additional systemic antibiotics, and treatment of superficial wound infections. WHO AWaRe classification ‘watch’ and ‘reserve’ group antibiotics, such as ciprofloxacin, rifampicin, vancomycin and meropenem, accounted for 39.4 antibiotic-days per long group participant, and 16.5 antibiotic-days per short group participant. Conclusions. Considering the combined duration of all systemic antibiotics prescribed over 12 months, including those co-administered, participants in the short arm of the SOLARIO trial received considerably fewer days of all antibiotic classes, and particularly those antibiotics restricted in the WHO AWaRe classification (2021)

Aim. The current recommendation in Norway is to use four doses of a first-generation cephalosporin (cefazolin or cephalotin) as systemic antibiotic prophylaxis (SAP) the day of surgery in primary joint arthroplasty. Due to shortage of supply, scientific development, changed courses of treatment and improved antibiotic stewardship, this recommendation has been disputed. We therefore wanted to assess if one dose of SAP was non-inferior to four doses in preventing periprosthetic joint infection (PJI) in primary joint arthroplasty. Method. We included patients with primary hip- and knee arthroplasties from the Norwegian Arthroplasty Register and the Norwegian Hip Fracture Register for the period 2005-2023. We included the most used SAPs (cephalotin, cefazolin, cefuroxime, cloxacillin and clindamycin), administered as the only SAP in 1-4 doses, starting preoperatively. Risk of revision (Hazard rate ratio; HRR) for PJI was estimated by Cox regression analyses with adjustment for sex, age, ASA class, duration of surgery, reason for- and type of arthroplasty, and year of primary arthroplasty. The outcome was 1-year reoperation or revision for PJI. Non-inferiority margins were calculated for 1, 2 and 3 doses versus reference of 4 doses of SAP at the day of surgery, against a predetermined limit of 15% increased risk of PJI. Results. In total 274,188 primary arthroplasties (total hip 133,985, hemi hip 51,442, and total knee 88,761) were included. Of these primary arthroplasties, 2,996 (1.1%) had subsequent revisions for PJI during the first postoperative year. One dose of SAP was given in 9,603 arthroplasties, two doses in 10,068, three doses in 18,351, and four doses in 236,166 arthroplasties. With the recommended four doses as reference, the HRR (95% CI) for 1-year revision for infection was 0.9 (0.7-1.1) for one dose, 1.0 (0.8-1.2) for two doses, and 0.9 (0.8-1.1) for three doses. The corresponding adjusted 1-year revision incidences for PJI was 0.9 (0.7-1.1), 1.0 (0.8-1.2), 0.9 (0. 8-1.1) and 1.0 (1.0-1.1) for one, two, three and four doses respectively, and less than four doses was found to be non-inferior. Conclusions. One preoperative dose of SAP in primary joint arthroplasty surgery seems to be non-inferior to the current recommendation of four doses of a first-generation cephalosporin as PJI-prophylaxis. This finding may simplify the course of treatment for arthroplasty patients, save costs, and improve antibiotic stewardship

Aims. With the ageing population, fragility fractures have become one of the most common conditions. The objective of this study was to investigate whether microbiological outcomes and fracture-healing in osteoporotic bone is worse than normal bone with fracture-related infection (FRI). Methods. A total of 120 six-month-old Sprague-Dawley (SD) rats were randomized to six groups: Sham, sham + infection (Sham-Inf), sham with infection + antibiotics (Sham-Inf-A), ovariectomized (OVX), OVX + infection (OVX-Inf), and OVX + infection + antibiotics (OVX-Inf-A). Open femoral diaphysis fractures with Kirschner wire fixation were performed. Staphylococcus aureus at 4 × 10. 4. colony-forming units (CFU)/ml was inoculated. Rats were euthanized at four and eight weeks post-surgery. Radiography, micro-CT, haematoxylin-eosin, mechanical testing, immunohistochemistry (IHC), gram staining, agar plating, crystal violet staining, and scanning electron microscopy were performed. Results. Agar plating analysis revealed a higher bacterial load in bone (p = 0.002), and gram staining showed higher cortical bone colonization (p = 0.039) in OVX-Inf compared to Sham-Inf. OVX-Inf showed significantly increased callus area (p = 0.013), but decreased high-density bone volume (p = 0.023) compared to Sham-Inf. IHC staining showed a significantly increased expression of TNF-α in OVX-Inf compared to OVX (p = 0.049). Significantly reduced bacterial load on bone (p = 0.001), enhanced ultimate load (p = 0.001), and energy to failure were observed in Sham-Inf-A compared to Sham-Inf (p = 0.028), but not in OVX-Inf-A compared to OVX-Inf. Conclusion. In osteoporotic bone with FRI, infection was more severe with more bone lysis and higher bacterial load, and fracture-healing was further delayed. Systemic antibiotics significantly reduced bacterial load and enhanced callus quality and strength in normal bone with FRI, but not in osteoporotic bone. Cite this article: Bone Joint Res 2022;11(2):49–60

Aim. The duration of systemic antibiotic therapy following first-stage surgery is contentious. Our Institution's philosophy is to perform an aggressive debridement, use high concentration targeted antibiotics through cement beads and systemic prophylactic antibiotics alone. In the presence of significant soft tissue infection or microbiological diagnostic uncertainty; systemic antibiotics may be prescribed for 5 days whilst awaiting tissue culture results. The aim of this study was to assess the success of our philosophy in the management of PJI of the hip using our two-stage protocol. Method. A retrospective review of our Institution's prospectively-collected database was performed to identify those patients who were planned to undergo a two-stage hip revision procedure for PJI. All patients had a confirmed diagnosis of PJI as per the major criteria of MSIS 2013, a minimum 5-years follow up and were assessed at the time of review using the MSIS working group outcome-reporting tool (2018). They were then grouped into “successful” or “unsuccessful” (suppressive antibiotics, further revision for infection, death within 1 year). Results. 299 intended two-stage hip revisions in 289 patients (6 repeat ipsilateral two-stage, 4 bilateral two-stage) met our inclusion criteria. 258 (86%) patients proceeded to 2. nd. stage surgery. Median follow up was 10.7 years. 91% success rate was observed for those patients who underwent reimplantation; dropping to 86% when including the patients who did not proceed to second stage surgery. The median duration of post-operative systemic antibiotics following first stage surgery was 5 days (IQR 5–9). No significant difference in outcome was observed in patients who received either; < / = 48 hours (86%; n=70) compared to > 48 hours antibiotics (86%; n=229; p=0.96) or </= 5 days of antibiotics (88%; n=202) compared to > 5 days antibiotics (82%; p=0.38). A significant majority had gram-positive (88%) infection with 30% being polymicrobial. Greater success rates were observed for gram-positive PJI (87%); than for gram-negative PJI (84%) and mixed Gram infection (72%; p=0.098). Conclusion. Aggressive surgical debridement with high concentration, targeted local antibiotic delivery at time of first stage hip surgery, without prolonged systemic antibiotics, provides a high rate of success, responsible antibiotic stewardship and reduced hospital costs

The duration of systemic antibiotics following first-stage surgery is contentious. Our Institution's philosophy is to perform an aggressive debridement, high concentration of targeted antibiotics through cement beads and systemic prophylactic antibiotics alone. In the presence of significant soft tissue infection or microbiological diagnostic uncertainty; systemic antibiotics may be prescribed for 5 days whilst awaiting tissue culture results. The aim of this study was to assess the success of our philosophy for two-stage hip revision. A retrospective review of our Institution's prospective database was performed to identify all intended two-stage hip revision procedures for PJI. All patients had a confirmed PJI as per MSIS 2013 criteria, minimum 5-years follow up and outcomes according to the MSIS working group outcome-reporting tool; then grouped into “successful” or “unsuccessful” (suppressive antibiotics, further revision for infection, death within 1 year). 383 intended two-stage hip revisions were identified; of which 299 met our inclusion criteria, in 289 patients (6 repeat ipsilateral two-stage, 4 bilateral two-stage). Median follow up was 10.7 years (IQR 6.3 – 15.0). 258 (86%) patients proceeded to 2. nd. stage surgery. 91% success rate was observed for those patients who underwent reimplantation, although dropping to 86% when including the patients who did not proceed to second stage. The median duration of post-operative systemic antibiotics was 5 days (IQR 5–9). No significant difference was observed in patients who received either; < / = 48 hours (86%; n=70) compared to > 48 hours antibiotics (86%; n=229; p=0.96) or </= 5 days of antibiotics (88%; n=202) compared to > 5 days antibiotics (82%; p=0.38). A significant majority had gram-positive (88%) infection with 30% being polymicrobial. Greater success rates were observed with two-stage exchange or gram-positive PJI (86%); than for gram-negative PJI (81%) and polymicrobial infection (74%) (p=0.36). Fungal PJI was observed to have a significantly reduced rate of success (n=3; 33%; p=0.03). Aggressive surgical debridement with high concentration, targeted local antibiotic delivery at time of first stage to manage PJI of the hip provides a high rate of success, responsible antibiotic stewardship and reduced hospital costs

Aims. Excision of chronic osteomyelitic bone creates a dead space which must be managed to avoid early recurrence of infection. Systemic antibiotics cannot penetrate this space in high concentrations, so local treatment has become an attractive adjunct to surgery. The aim of this study was to present the mid- to long-term results of local treatment with gentamicin in a bioabsorbable ceramic carrier. Methods. A prospective series of 100 patients with Cierny-Mader Types III and IV chronic ostemyelitis, affecting 105 bones, were treated with a single-stage procedure including debridement, deep tissue sampling, local and systemic antibiotics, stabilization, and immediate skin closure. Chronic osteomyelitis was confirmed using strict diagnostic criteria. The mean follow-up was 6.05 years (4.2 to 8.4). Results. At final follow-up, six patients (six bones) had recurrent infection; thus 94% were infection-free. Three infections recurred in the first year, two in the second year, and one 4.5 years postoperatively. Recurrence was not significantly related to the physiological class of the patient (1/20 Class A (5%) vs 5/80 Class B (6.25%); p = 0.833), nor was it significantly related to the aetiology of the infection, the organisms which were cultured or the presence of nonunion before surgery (1/10 with nonunion (10%) vs 5/90 without nonunion (5.6%); p = 0.570). Organisms with intermediate or high-grade resistance to gentamicin were significantly more likely in polymicrobial infections (9/21; 42.8%) compared with monobacterial osteomyelitis (7/79 (8.9%); p < 0.001). However, recurrence was not significantly more frequent when a resistant organism was present (1/16 for resistant cases (6.25%) vs 5/84 in those with a microbiologically sensitive infection (5.95%); p = 0.958). Conclusion. We found that a single-stage protocol, including the use of a high-delivery local antibiotic ceramic carrier, was effective over a period of several years. The method can be used in a wide range of patients, including those with significant comorbidities and an infected nonunion. Cite this article: Bone Joint J 2022;104-B(9):1095–1100

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

Aim. Periprosthetic joint infection (PJI) is a complication of total joint arthroplasty that typically requires revision surgery for treatment. Systemic antibiotics are usually held prior to surgery to improve yield of intraoperative cultures. However, recent studies suggest that preoperative aspirations have a high concordance with intraoperative cultures, which may allow surgeons to initiate antibiotic treatment earlier. The purpose of the study was to investigate the effect of Pre-surgical systemic antibiotic therapy on the bacterial burden within the periprosthetic space and systemic immune reaction. Method. PJI was induced with MSSA (Xen36) S. aureus in the right knee of 16-week old, female, C57BL6 mice using a previously validated murine model. Mice were randomized to three groups (n=8, each): control; Vanc, receiving systemic vancomycin (110mg/kg, SQ, twice daily); or VancRif receiving vancomycin same as in Vanc group, plus rifampin (12mg/kg dose, IV, once daily). Following 2 weeks of treatment, mice were euthanized and periprosthetic bone, soft tissue and the implant were harvested. Bacterial burden, colony forming units (CFUs), was quantified in soft tissue, tibial bone, and on the implant. Specifically, tissues were homogenized and serially plated for CFUs, while the implant was sonicated and then plated for CFUs. The host immune response was analysed through weighing inguinal and iliac lymph nodes and through measuring serum amyloid A (SAA). Non-parametric pairwise group comparisons of the three outcome measures were performed using a Mann-Whitney U test. Results. VancRif, the combined treatment significantly reduced bacterial burden in the periprosthetic soft tissue, bone, and implant compared to control (p<0.001) and Vanc alone (p<0.001). While not significant, Vanc alone did reduce bacterial load as compared to control. The ipsilateral weight of the iliac lymph nodes was significantly reduced in Vanc and VancRif mice compared to controls (p<0.001), was well as in VancRif versus Vanc alone (p<0.001). Interestingly, SAA levels did not significantly differ among all groups. During tissue harvesting, minimal purulence was observed in antibiotic treatment groups, unlike controls. Conclusions. Treating active PJI with vancomycin alone decreases periprosthetic bacterial loads and reduces the local immunological response. This effect is significantly enhanced with the combined rifampin use. These findings could suggest that when culture positive PJI is diagnosed, pre-surgical treatment with antibiotics may decrease immunosuppression and soft tissue infiltration, leading to a better chance of infection cure with subsequent surgical debridement. Histological investigations and repeat experiments involving subsequent surgical treatment are underway. Acknowledgements. Funding comes from internal institutional grants

Chronic osteomyelitis (OM) is a progressive, inflammatory infection of bone caused predominantly by S. aureus and requires treatment through surgical debridement and systemic antibiotic administration. We have previously reported the fabrication of an antibiotic-eluting scaffold which is responsive to microbial activity for the treatment of OM. Herein, we ventured to assess the capacity of this antibiotic-eluting scaffold to treat infection in a rabbit model of chronic OM. Infections were established in the radii of New Zealand White rabbits using inoculations of 2×10. 6. CFUs S. aureus JAR 060131 over a period of 4 weeks. Following surgical debridement (6mm), rabbits underwent treatment for a period of 8 weeks until euthanasia. The treatment groups were; 1) empty, 2) antibiotic-eluting scaffold (collagen/hydroxyapatite scaffold loaded with vancomycin) and 3) commercially available antibiotic-eluting fleece (Septocoll E®, collagen fleece loaded with gentamicin). During the treatment period, all groups received systemic antibiotics (Cefazolin 25mg/kg) administered subcutaneously twice daily for 4 weeks. Inoculation of the radius resulted in the development of a sequestrum containing S. aureus, demonstrating the successful establishment of OM. After the 8-week treatment period, 4/5 rabbits in the empty group were still infected, indicating that systemic antibiotic administration following debridement was insufficient to treat the infection. Fewer rabbits in both the antibiotic-eluting scaffold group (2/4) and the antibiotic-eluting fleece group (1/3) were infected. This work demonstrates that the implantation of an antibiotic-eluting biomaterial into a defect following debridement enhances bacterial clearance in conditions of chronic OM

Local antimicrobial therapy is an integral aspect of treating orthopaedic device related infection (ODRI), which is conventionally administered via polymethylmethacrylate (PMMA) bone cement. PMMA, however, is limited by a suboptimal antibiotic release profile and a lack of biodegradability. In this study, we compare the efficacy of PMMA versus an antibioticloaded hydrogel in a single- stage revision for chronic methicillin-resistant Staphylococcus aureus (MRSA) ODRI in. sheep. Antibiofilm activity of the antibiotic combination (gentamicin and vancomycin) was determined in vitro. Swiss alpine sheep underwent a single-stage revision of a tibial intramedullary nail with MRSA infection. Local gentamicin and vancomycin therapy was delivered via hydrogel or PMMA (n = 5 per group), in conjunction with systemic antibiotic therapy. In vivo observations included: local antibiotic tissue concentration, renal and liver function tests, and quantitative microbiology on tissues and hardware post-mortem. There was a nonsignificant reduction in biofilm with an increasing antibiotic concentration in vitro (p = 0.12), confirming the antibiotic tolerance of the MRSA biofilm. In the in vivo study, four out of five sheep from each treatment group were culture negative. Antibiotic delivery via hydrogel resulted in 10–100 times greater local concentrations for the first 2–3 days compared with PMMA and were comparable thereafter. Systemic concentrations of gentamicin were minimal or undetectable in both groups, while renal and liver function tests were within normal limits. This study shows that a single-stage revision with hydrogel or PMMA is equally effective, although the hydrogel offers certain practical benefits over PMMA, which make it an attractive proposition for clinical use

Introduction. Debridement, Antibiotics and Implant Retention (DAIR) remains the norm for the treatment of acute periprosthetic joint infection (PJI) despite less than optimal success rates. Intraosseous (IO) administration of vancomycin has been shown to have significantly increased local bone and tissue concentrations compared to systemic antibiotics, with lower systemic antibiotic levels compared to intravenous. The purpose of this study was to evaluate if the addition of IO regional antibiotics to our protocol at the time of DAIR would improve outcomes. Methods. A retrospective review of 35 PJI TKA patients who underwent DAIR combined with IO vancomycin (500mg) was performed with minimum 12-month follow-up. 26 patients were treated for acute perioperative or acute hematogenous infections following primary TKA. Nine were treated for chronic infections with components that were considered unresectable (ie) constructs with ingrown cones, sleeves, or long cemented stems in elderly comorbid patients. Primary outcome was defined by no reoperations for infection nor clinical signs or symptoms of PJI. Results. The average follow up for acute infection was 16.5 months (range 12.1–24.2) and 15.8 months (range 12–24.8) for chronic infections with unresectable components. Overall eradication rates for acute infection was 93.1% while only 44.4% for chronic infections with unresectable components. MSIS host grade was a significant indicator of failure (p<0.001). Conclusion. The use of IO vancomycin at the time of DAIR yielded improved results compared to standard irrigation and debridement in acute periprosthetic infections. Its use in chronic infections should remain cautious. While these results are encouraging, this technique requires longer follow-up before widespread adoption

Diabetic foot problems are a common cause for hospitalisation in this group and up to 25% of diabetic patients will be affected. Prevalence of diabetes is rising, currently affecting 680000000 people worldwide. The enormity of this problem mandates any strategy that shortens therapeutic period and enhances success rates. Cerament G has been used in our unit as a treatment adjunct in diabetic foot treatment. Successful treatment is viewed as eradication of infection and a functional foot. Retrospective review of 40 months practice with 115 patients. Inclusion: all diabetic feet requiring surgery Cerament G used, protocol driven Microbiology pathway. Exclusion: Primary closure not possible. Cerament G not used. Outcome assessed in three groups: Total failure (further surgery required); slow to heal (healing by secondary intention); healed without problems. Healed 99 (eradication of infection and return to function), failure to heal 16 (success rate: 86.1%). Infection was the cause of failure in only in 2.6% (13 failures due to patient noncompliance or poor vascularity). Accepted success rate in treating osteomyelitis in diabetic feet is 68% (medical treatment only), combination of surgery and medical is 86%. Eradication of infection is the only end point return to function is not addressed. This study shows Cerament G with surgery/systemic antibiotics provides a 97.4% success rate. Therapeutic drivers in this field have been determined traditionally by Physicians and Vascular Surgeons (resection rather than reconstructive surgery.) Our assertion is that eradicating infection in a functionally useless foot is a waste of health resources. Our strategy is always the delivery of an intact functional foot residuum. Cerament G as an adjunct allows this goal in a cost-effective manner

An increasing elderly population means joint replacement surgery numbers are projected to increase, with associated complications such as periprosthetic joint infections (PJI) also rising. PJI are particularly challenging due to antimicrobial resistant biofilm development on implant surfaces and surrounding tissues, with treatment typically involving invasive surgeries and systemic antibiotic delivery. Consequently, functionalisation of implant surfaces to prevent biofilm formation is a major research focus. This study characterises clinically relevant antimicrobials including gentamicin, clindamycin, daptomycin, vancomycin and caspofungin within a silica-based, biodegradable sol-gel coating for prosthetic devices. Antimicrobial activity of the coatings against clinically relevant microorganisms was assessed via disc diffusion assays, broth microdilution culture methods and the MBEC assay used to determine anti-biofilm activity. Human and bovine cells were cultured in presence of antimicrobial sol-gel to determine cytotoxicity using Alamar blue and antibiotic release was measured by LC-MS. Biodegradability in physiological conditions was assayed by FT-IR, ICP-MS and measuring mass change. Effect of degradation products on osteogenesis were studied by culturing mesenchymal stem cells in the presence of media in which sol-gel samples had been immersed. Antimicrobial-loaded coatings showed strong activity against a wide range of clinically relevant bacterial and fungal pathogens with no loss of activity from antibiotic alone. The sol-gel coating demonstrated controlled release of antimicrobials and initial sol-gel coatings showed no loss of viability on MSCs with gentamicin containing coatings. Current work is underway investigating cytotoxicity of sol-gel compositions against MG-63 cells and primary osteoblasts. This research forms part of an extended study into a promising antimicrobial delivery strategy to prevent PJI. The implant coating has potential to advance PJI infection prevention, reducing future burden upon healthcare costs and patient wellbeing

Fracture related infection remains a major challenge in musculoskeletal trauma surgery. Despite best practice, treatment strategies suffer from high failure rates due to antibiotic resistance and tolerance. Bacteriophages represent a promising alternative as they retain activity against such bacteria. However, optimal phage administration protocols remain unknown, although injectable hydrogels, loaded with phage and conventional antibiotics, may support conventional therapy. In this study we tested the activity of meropenem, and two newly isolated bacteriophages (ϕ9 and ϕ3) embedded within alginate-chitosan microbeads and a hydrogel. Antibiotic and phage stability and activity were monitored in vitro, over a period of 10 days. In vivo, the same material was tested in treatment of a 5-day old Pseudomonas aeruginosa infection of a tibial plate osteotomy in mice. Treatment involved debridement and 5 days of systemic antibiotic therapy plus: i- saline, ii-phages in saline, iii-phages and antibiotics loaded into a hydrogel (n=7 mice/group). To assess the efficacy of the treatments, the infection load was monitored during revision surgery with debridement of the infected tissue after 5,10 and 13 days (euthanasia) by CFU and PFU quantification. In vitro testing confirmed that the stability of meropenem and activity of ϕ9 and ϕ3, was not affected within the alginate beads or hydrogel over 10 days. The in vivo study showed that all mice receiving phages and antibiotics loaded into a hydrogel survived the infection with a reduction of the bacterial load in the soft tissue. Active phages could be recovered from the infected site at euthanasia (10. 4. PFU/g). The hydrogel loaded with bacteriophages and meropenem showed a positive result in locally reducing the infection load indicating a synergistic effect of the selected antimicrobials. Overall, our new strategy shows encouraging results for improving the treatment of antibiotic-resistant biofilm infections that are related to medical implants

Treatment of bone infection often includes a burdensome two-stage revision. After debridement, contaminated implants are removed and replaced with a non-absorbable cement spacer loaded with antibiotics. Weeks later, the spacer is exchanged with a bone graft aiding bone healing. However, even with this two-stage approach infection persists. In this study, we investigated whether a novel 3D-printed, antibiotic-loaded, osteoinductive calcium phosphate scaffold (CPS) is effective in single-stage revision of an infected non-union with segmental bone loss in rabbits. A 5 mm defect was created in the radius of female New Zealand White rabbits. The bone fragment was replaced, stabilized with cerclage wire and inoculated with Staphylococcus aureus (MSSA). After 4 weeks, the infected bone fragment was removed, the site debrided and a spacer implanted. Depending on group allocation, rabbits received: 1) PMMA spacer with gentamycin; 2) CPS loaded with rifampin and vancomycin and 3) Non-loaded CPS. These groups received systemic cefazolin for 4 weeks after revision. Group 4 received a loaded CPS without any adjunctive systemic therapy (n=12 group1-3, n=11 group 4). All animals were euthanized 8 weeks after revision and assessed by quantitative bacteriology or histology. Covariance analysis (ANCOVA) and multiple regression were performed. All animals were culture positive at revision surgery. Half of the animals in all groups had eliminated the infection by end of study. In a historical control group with empty defect and no systemic antibiotic treatment, all animals were infected at euthanasia. There was no significant difference in CFU counts between groups at euthanasia. Our results show that treating an osteomyelitis with segmental bone loss either with CPS or PMMA has a similar cure rate of infection. However, by not requiring a second surgery, the use of CPS may offer advantages over non-resorbable equivalents such as PMMA

Aim. Efficacious antibiotic treatment is crucial for managing and preventing orthopedic infections due to their complexity and associated risk of treatment failure. Previous reviews on antibiotic target tissue concentrations have primarily focused on static measurements, which may not accurately reflect the dynamic pharmacokinetic/pharmacodynamic (PK/PD) changes encountered in clinical settings. This review aimed to summarize the current literature on antibiotic distribution in orthopedically relevant tissues and settings using dynamic sampling methods. Method. In accordance with PRISMA guidelines, a literature search was conducted with a scientific librarian's assistance. PubMed and Embase databases were systematically searched using relevant MeSH terms, entries, and keywords. English-published studies between 2004 and 2023 involving systemic antibiotic administration and dynamic measurements were included. 4467 titles were identified. After title and abstract screening, 77 eligible studies remained. Results. The studies covered clinical and pre-clinical studies on both healthy and infected tissue. Dynamic measurements were obtained from various tissues including bone, intervertebral discs, joints, muscles, and subcutaneous tissue. Microdialysis was the predominant sampling method (98.70%, 76/77). Antibiotics like cefuroxime, linezolid, and vancomycin were extensively studied. Fluoroquinolones, tetracyclines, and most beta-lactams typically presented good tissue penetration in relation to relevant PK/PD-targets. In contrast, glycopeptides, macrolides, and flucloxacillin exhibited poorer penetration. Conclusions. This review provides valuable insights of antibiotic distribution in orthopedically relevant target tissues and settings, which may help improve dosing recommendations and treatment outcomes. Our findings are limited to the investigated dosing regimens and administration methods and depend on the chosen PK/PD target. Many antibiotics still require further research to address the significant knowledge gaps, such as the lack of dynamic evaluations for certain antibiotic types and further investigation across various orthopedic settings and tissues

Despite the routine use of systemic antibiotic prophylaxis, postoperative infection following fracture surgery remains a persistent issue with substantial morbidity. The use of additional local antibiotic prophylaxis may have a protective effect and some orthopaedic surgeons have adopted their use in recent years, despite limited evidence of its beneficial effect. The purpose of this systematic review and meta-analysis was to evaluate the current literature regarding the effect of prophylactic local antibiotics on the rate of infection in fracture surgery in both open and closed fractures. A comprehensive search of Medline, EMBASE, and PubMed was performed. Cohort studies were eligible if they investigated the effect on infection rate of additional local antibiotic prophylaxis compared with systemic prophylaxis alone following fracture surgery. The data were pooled in a meta-analysis. In total, four randomized controlled trials and 11 retrospective cohort studies with a total of 6161 fractures from various anatomical locations were eligible for inclusion. The majority of the included studies were Level 3 evidence and had a moderate risk of bias. When all fractures were pooled, the risk of infection was significantly reduced when local antibiotics were applied compared with the control group receiving systemic prophylaxis only (OR = 0.39; 95%CI: 0.26 to 0.53, P < 0.001). In particular, there was a significant reduction in deep infections (OR = 0.59; 95%CI: 0.38 to 0.91, P = 0.017). The beneficial effect of local antibiotics for preventing total infection was seen in both open fractures (OR = 0.35; 95%CI: 0.23 to 0.53, P < 0.001) and closed fractures (OR = 0.58; 95%CI: 0.35 to 0.95, P = 0.029) when analyzed separately. This meta-analysis suggests a significant risk reduction for postoperative infection following fracture surgery when local antibiotics were added to standard systemic prophylaxis, with a protective effect present in both open and closed fractures

Aim. In trauma surgery, the development of biomaterial-associated infections (BAI) is one of the most common complications affecting trauma patients, requiring prolonged hospitalization and the intensive use of antibiotics. Following the attachment of bacteria on the surface of the biomaterial, the biofilm-forming bacteria could initiate a chronic implant-related infection. Despite the use of conventional local and systemic antibiotic therapies, persistent biofilms involve various resistance mechanisms that contribute to therapeutic failures. The development of in vivo chronic BAI models to optimize antibiofilm treatments is a major challenge. Indeed, the biofilm pathogenicity and the host response need to be finely regulated, and compatible with the animal lifestyle. Previously, a Galleria mellonella larvae model for the formation of an early-stage biofilm on the surface of a Kirschner (K)-wire was established. In the present study, two models of mature biofilm using clinical Staphylococcus aureus strains were assessed: one related to contaminated K-wires (in vitro biofilm maturation) and the second to hematogenous infections (in vivo biofilm maturation). Rifampicin was used as a standard drug for antibiofilm treatment. Method. In the first model, biofilms were formed following an incubation period (up to 7 days) in the CDC Biofilm Reactor (CBR, BioSurface Technologies). Then, after implantation of the pre-incubated K-wire in the larvae, rifampicin (80 mg/kg) was injected and the survival of the larvae was monitored. In the second model, biofilm formation was achieved after an incubation period (up to 7 days) inside the larvae and then, after removing the K-wires from the host, in vitro rifampicin susceptibility assays were performed (according to EUCAST). Results. The first model indicate that in vitro biofilm maturation affects the bacterial pathogenicity in the host, depending on the S. aureus strain used. Furthermore, the more the biofilm is matured, the more the rifampicin treatment efficiency is compromised. The second model shows that, despite the fast in vivo biofilm formation in the host, the number of bacteria, either attached to the surface of the K-wire surface or in surrounding tissue of the larvae, was not increased over time. Conclusions. Altogether, these results allow the establishment of biofilm models using G. mellonella larvae in order to understand the impact of biofilm maturation on both the bacterial pathogenicity and the efficiency of antibiofilm treatments

Aim. One of the most severe complications of primary total knee arthroplasty (TKA) is periprosthetic joint infection (PJI). Nowadays, the use of antibiotic-loaded cement for prevention of infection is still controversial. The aim of the present study is to evaluate the use of an antibiotic-loaded cement to reduce the infection rate in primary total knee arthroplasty. Method. Prospective randomized study, with 2893 cemented total knee arthroplasties performed between 2005 and 2010 in our institution. Two different groups were formed depending on which bone cement was used, without antibiotic (the control group) or loaded with erythromycin and colistin (the study group). All patients received the same systemic prophylactic antibiotics. The patients were followed for a minimum of twelve months. The rate of infection was analyzed according to the criteria of the Centers for Disease Control and Prevention (CDC). Results. In 1452 patients the prosthetic components were fixed using bone cement without antibiotic and in 1441 patients bone cement loaded with erythromycin and colistin was used. There were no differences between both groups in terms of demographic data (age, sex and BMI), either in operating time (p>0,05). The rate of infection was similar in both groups, being 2,0% (n=29) in the control group and 1,7% in the study group (p=0,58) at 8,7 years (SD 5,1) of follow up. In terms of prosthetic revision due to any cause (infected or aseptic), there wasn't differences between groups, performing a total of 61 revision arthroplasties in control group and 68 in study group (p>0,05). Moreover, we analyzed the erythromycin resistance rate, being no differences between both groups (p=0.6). Conclusions. The use of erythromycin and colistin-loaded bone cement in total knee arthroplasty did not lead to a decrease in the rate of infection when systemic prophylactic antibiotics were used, a finding that suggests that its use would not be indicated in the general population

The need for an artificial scaffold in very large bone defects is clear, not only to limit the risk of graft harvesting, but also to improve clinical success. The use of custom osteoconductive scaffolds made from biodegradable polyester and ceramics can be a valuable patient friendly option, especially in case of a concomitant infection. Multiple types of scaffolds for the Masquelet procedure (MP) are available, however these frequently demonstrate central graft involution when defects exceed a certain size and the complication rates remains high. This paper describes three infected tibial defect nonunions with a segmental defect over ten centimeters long treated with a customized 3D printed polycaprolactone-tricalcium phosphate (PCL-TCP) cage in combination with biological adjuncts. Three male patients, between the age of 37 and 47, were treated for an infected tibial defect nonunion after sustaining Gustilo grade 3 open fractures. All had a segmental midshaft bone defect of more than ten centimeters (range 11–15cm). First stage MPs consisted of extensive debridement, external fixation and placement of anterior lateral thigh flaps (ALT). Positive cultures were obtained from all patients during this first stage, that were treated with specific systemic antibiotics during 12 weeks. The second stage MP was carried out at least two months after the first stage. CT scans were obtained after the first stage to manufacture defect-specific cages. In the final procedure a custom 3D printed PCL-TCP cage (Osteopore, Singapore) was placed in the defect in combination with biological adjuncts (BMAC, RIA derived autograft, iFactor and BioActive Glass). Bridging of the defect, assessed at six months by CT, was achieved in all cases. SPECT-scans 6 months post-operatively demonstrated active bone regeneration, also involving the central part of the scaffold. All three patients regained function and reported less pain with full weight-bearing. This case report shows that 3D printed PCL-TCP cages in combination with biological adjuncts is a novel addition to the surgical treatment of very large bone defects in (infected) posttraumatic nonunion of the tibia. This combination could overcome some of the current drawbacks in this challenging indication