Session 5: Tumor, Infection and amputation

16. November
11:00 - 12:00
Lokale: Vingsal 2
Chair: Christina E. Holm and Christen Ravn

37. Rifampicin does not reduce moxifloxacin concentrations at the site of infection or improve treatment outcome of a one-stage exchange surgery protocol of implant-associated osteomyelitis lesions in a porcine model
Sofus Vittrup, Louise Kruse Jensen, Pelle Hanberg, Josefine Slater, Magnus Hvistendahl, Maiken Stilling, Nis Pedersen Jørgensen, Mats Bue
Department of Clinical Medicine, Aarhus University; Aarhus Denmark Microdialysis Research (ADMIRE), Orthopedic Research Laboratory, Aarhus University Hospital; Department of Orthopedic Surgery, Aarhus University Hospital; Department of Infectious Diseases, Aarhus University Hospital; Department of Veterinary and Animal Sciences, University of Copenhagen

Background: Rifampicin has for many years been considered a cornerstone in implant-associated osteomyelitis (IAO) treatment.
Aim: We conducted a randomised, one-stage exchange surgery protocol with either one-week treatment with moxifloxacin alone or co- administered with rifampicin in IAO porcine model to evaluate steady-state moxifloxacin concentrations in infected bone and soft tissue assess and the additive microbiological treatment effect of rifampicin.
Materials and Methods: 16 female pigs were included. On day 0, IAO was induced creating an implant cavity in the right proximal tibia using a moxifloxacin and rifampicin susceptible porcine Staphylococcus aureus strain. On day 7, the pigs underwent one-stage exchange surgery of IAO lesions and were randomly allocated to receive seven days of intravenous antibiotic treatment of either rifampicin 450 mg twice daily combined with moxifloxacin 400 mg once daily (Group RM) or moxifloxacin 400 mg once daily (Group M). Steady state concentrations were presumed for both drugs after seven days. On day 14, microdialysis was applied for continuous sampling of moxifloxacin concentrations during 8 h in five compartments: the implant cavity, cancellous bone in both the right (infected) and left (non-infected) proximal tibia, and adjacent subcutaneous tissue on both the right (infected) and left (non-infected) side. Venous blood samples were collected for reference. Microbiological analyses were performed post- mortem.
Results: Moxifloxacin AUC was lower in plasma in group RM, (mean;95% CI) 407; 315–499 min µg/mL vs Group M, 625; 536–724 min µg/mL (p=0.002). For the implant cavity, there was a trend toward a lower AUC in Group RM, 425; 327–524 min µg/ml vs Group M, 297; 205–389 min µg/ml, but not statistically different (p=0.06). For the other compartments, the remaining calculated pharmacokinetic parameters were similar between the groups. Comparable cure rates (sterilization of both implant and bone) were observed with 5/8 pigs in Group RM compared to 3/7 in Group M (p=0.62).
Interpretation / Conclusion: While moxifloxacin AUC was lower in plasma for animals co-treated with rifampicin, both the moxifloxacin concentrations at the site of infection and treatment outcomes were comparable between groups.

38. Piperacillin Bone Concentrations - a randomized porcine study comparing continuous infusion vs. short-term infusion
Hans Christian Rasmussen¹, Mats Bue¹, Andrea Jørgensen³, Pelle Hanberg4, Sara Tøstesen5, Martin Knudsen6, Maiken Stilling7
Department of Orthopaedic Surgery, Aarhus University Hospital ² 7 Orthopaedic Research Unit, Aarhus University Hospital ¹ ² ³ 4 5 6 7 Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital 4

Background: Osteoarticular infections caused by Pseudomonas aeruginosa have seen an increase in recent years. A central antimicrobial choice in the treatment of pseudomonal orthopaedic infections is piperacillin. Studies have indicated higher cure rate of pseudomonal infections with continuous infusion (CI) of piperacillin compared to intermitted short-term infusion (STI). However, due to practical reasons STI is still commonly used.
Aim: The aim was to assess time above the minimal inhibitory free concentration (f(T>MIC)) for piperacillin at steady state in tibial cortical bone, cancellous bone, the knee joint, and subcutaneous tissue following STI and CI using microdialysis in a porcine model.
Materials and Methods: 16 female Danish landrace pigs were randomized to either CI or STI of piperacillin/ tazobactam. Group STI received a bolus of 4g/0.5g every 6h and Group CI received 16g/2g daily. Microdialysis catheters were placed for sampling in the tibial cortical bone, cancellous bone, the knee joint, and subcutaneous tissue. Steady state was assumed at 12h and data collection of dialysates and blood samples preceded for the following 6h. The piperacillin f(T>MIC) was evaluated at MIC targets of 4 µg/mL, 8 µg/mL and 16 µg/mL.
Results: At steady state, with exclusion of cortical bone, CI resulted in a mean f(T>MIC) (4 µg/mL) target attainment of =99% across all compartments compared to =67% for group STI. Similar results were found for targets of 8 µg/mL (=93%, =53%) and 16 µg/mL (=64%, =35%). Mean f(T>MIC) in cortical bone was generally lower in group CI compared to group STI for all targets, but only statistically significant for the 8 µg/mL target (p=0.049).
Interpretation / Conclusion: For all tissue targets, except cortical bone, CI administration resulted in higher steady state piperacillin concentrations compared to STI administration. To obtain sufficient piperacillin concentrations in cortical bone, higher or more frequent dosing is needed.

39. Surgical offloading procedures for patients with non-healing diabetic foot ulcers. A National Clinical Guideline
Tue Smith Jørgensen
Department of Orthopedics, Amager and Hvidovre University Hospital

Background: Patients with diabetes have a higher risk of developing a foot deformity or malposition in the foot due to bone collapse, neuropathy, tendon contracture and insufficient muscle strength. Deformities and misalignments can result in an increased local pressure load on the foot, and significantly increased risk of developing a diabetic foot ulcer. To promote wound healing, it is essential to offload the wound with insoles, footwear or a offloading bandage. If the external offloading (standard treatment) does not have an effect, or the misalignment of the foot and toes is too extensive, offloading surgery may be appropriate.
Aim: To review the litterature on surgical offloading procedures for patients with foot or toe malalignment and non-healing diabetic foot ulcers.
Materials and Methods: The study is a systematic review and metaanalysis, and the systematic litterature search was performed the 31. Of january 2020. The evidens consists of three randomised clinical trials (4 publications), one non randomised controlled trial and 4 case control studies. The intervention in the studies consisted of achilles tendon lengthening or metatarsal osteotomy. Patients in the control groups were treated with a non-removable cast or a specially made foot orthosis.
Results: Nine out of 63 patients in the surgical offloading group had a recurrent ulcer compared with 29 out of 60 patients who received standard wound care. The meta-analysis showed a lower risk of recurrence of wounds in patients who received offloading surgery, the relative risk was 0.30 (95% CI: 0.15, 0.58). None of the 52 patients in the group who received surgical offloading had a lower extremity amputation, whereas 2 out of 53 patients had an amputation in the group that received standard wound treatment. The meta-analysis showed a relative risk of 0.34 (95% CI: 0.04, 3.12)
Interpretation / Conclusion: Clinicians should consider surgical offloading with achilles tendon lengthening or metatarsal osteotomy in patients with foot or toe malalignment and non- healing diabetic foot ulcers.

40. Role of Sonication in Diagnosis of Orthopaedic Implant Associated Infections
Diana Salomi Ponraj¹, Thomas Falstie-Jensen², Nis Pedersen Jørgensen³ , Christen Ravn², Holger Brüggemann4, Jeppe Lange ¹,5
Department of Clinical Medicine, Aarhus University¹; Department of Orthopaedic surgery, Aarhus University Hospital²; Department of Infectious diseases, Aarhus University Hospital³; Department of Biomedicine, Aarhus University4; Department of Orthopaedic surgery, Horsens Regional Hospital5

Background: Orthopaedic implant associated infections (OIAI) have high morbidity and mortality. In addition to aerobic bacteria like Staphylococcus aureus, slow growing Gram- positive anaerobic bacteria (SGAB) like Cutibacterium acnes are increasingly associated with OIAI. SGAB infections are difficult to diagnose because of their prolonged cultivation times as well as non- specific clinical, laboratory and radiologic features. Sonication of implants can help in the diagnosis of SGAB infections.
Aim: To identify the different bacteria, especially SGAB, isolated from sonication fluid of orthopaedic implants removed during revision surgeries.
Materials and Methods: Between August 2019 and September 2020, 100 implants that were removed during revision surgery at the Department of Orthopaedic surgery, Aarhus university hospital were collected and processed by the vortex-sonication method. The resultant sonication fluid (SF) was cultured aerobically and anaerobically. All isolated bacteria were identified by 16S rRNA sequencing. Bacterial growth >50 or >200 CFU/ml of uncentrifuged or centrifuged SF respectively was considered significant. In case of C. acnes, significance of the isolates was based on whole genome sequencing and amplicon based next generation sequencing. Relevant clinical details including tissue culture results were obtained from patients’ records.
Results: SF from 21 implants showed significant bacterial growth. Only 11 of these implants had a prior diagnosis or suspicion of infection. C. acnes (n=8), S. aureus (n=4) and Staphylococcus epidermidis (n=2) were the most commonly isolated bacteria. Tissue culture were either not sent or had no bacterial growth in 33% (7/21) of implants.
Interpretation / Conclusion: Routine sonication of orthopaedic implants removed during revision surgeries can help to identify cases of OIAI that might otherwise be overlooked.

41. Hip Joint Stability After Hip Replacement Surgery due to Metastatic Bone Disease - A retrospective cohort study evaluating different hip joint options
Afrim Iljazi¹, Michala Skovlund Sørensen¹, Thea Hovgaard Ladegaard, Michael Mørk Petersen¹
¹Musculoskeletal Tumor Section, Department of Orthopedic Surgery, Rigshospitalet, Denmark

Background: Joint stability after hip replacement in patients with metastatic bone disease (MBD) is of special importance. Dislocation is the second leading cause of all-time implant revision. Expected survival after surgery among these patients is very poor, why avoidance of hospital re- admissions has a significant impact on end-of-life quality. Selecting the right joint solution is therefore paramount. Few studies have investigated the dislocation rate across different hip joint options in MBD patients. We therefore conducted a retrospective study on primary hip replacements for patients with MBD conducted at Rigshospitalet.
Aim: To evaluate the 1-year post-operative joint dislocation rate by type of hip joint.
Materials and Methods: We included patients =18 years with MBD who received hemiarthroplasty (HA), regular total hip arthroplasty (THA) or THA with a constrained liner (CL) at Rigshospitalet in 2014-2020. We excluded patients with dual mobility joints, partial pelvic reconstruction, total femoral replacement and endoprosthesis revision surgeries. Risk of dislocation was assessed by competing risk analysis (cumulative incidence function) with death and implant removal as competing risks. Only the first surgery was included in the analysis in case of bilateral surgery. The Kaplan- Meier estimator was used to assess the probability of survival.
Results: We identified 266 patients who received 277 joint replacements. Mean age was 68(SD:11) years. Median follow-up was 176(IQR: 54-503) days. The patients were treated with 101(36%) HA, 88(32%) THA and 88(32%) CL. Major bone resection (MBR) was performed in 75% of THAs, 64% of CLs and 55% of HAs. The 1-year patient survival was 44% (CI-95: 33-55) for THA, 29% (CI-95: 20-38) for HA and 38% (CI-95: 27-48) for CL. The 1-year dislocation risk was 8% (CI-95: 2-14) for THA, 5% (CI-95: 1-10) for HA and 6% (CI-95: 1-11) for CL (p=0.19). The 1-year dislocation rate by MBR was 5% (CI-95: 1-10) for non-resection and 7% (3-11) for resection (p=0.33).
Interpretation / Conclusion: Our study suggests a higher tendency for dislocation in THA. However, the finding was not statistically significant. Interpretation might be confounded by MBR and lower survival for HA. Further studies are needed.

42. Solitary vs. Multiple Bone Metastases in The Extremities: Are There Any Differences?
Thea Hovgaard Ladegaard, Michala Skovlund Sørensen, Michael Mørk Petersen
Musculoskeletal Tumor Section, Department of Orthopedic Surgery, Rigshospitalet, University of Copenhagen

Background: Patients with solitary metastatic bone disease in the extremities (MBDex) is believed to have better survival than patients with multiple MBDex. Metastasectomy is known to improve patient survival for renal cell cancer and maybe breast cancer in selected cohorts.
Aim: To evaluate 1-year survival for metastasectomy in patients treated surgically for MBDex.
Materials and Methods: We conducted a retrospective study including all MBDex-lesions treated surgically at orthopedic departments in the Capital Region (CR) 2014- 2016. We excluded patients with unknown status of bone metastases and unknown resection margin. Patients were followed until end of study (30 September 2021) or death. Kaplan-Meier analysis (with log-rank test) evaluated patient survival.
Results: We identified 506 MBDex-surgeries (459 patients), 22 surgeries were revisions. 122 surgeries (118 patients) were oligo metastatic and 384 surgeries (343 patients) were known with multiple metastases. Of the 122 surgeries, 72 surgeries (71 patients) had no/unknown status of visceral metastases (solitary-group) and 50 surgeries had visceral metastases. In the solitary-group, 44 surgeries had wide resection (44 patients).The most common primary cancer in this group was renal (15) and breast (9). 24 patients in the group had intralesional resection (24 patients). The most common primary cancer in this group was breast (6), lung (5), lymphoma (5) and myelomatosis (5). The 1-year patient survival was 48% (CI-95: 40-58) for the oligo MBDex and 34% (CI-95: 29-38) for the multiple MBDex (p<0.001). The 1-year patient survival was 65% (CI-95: 55- 77) for solitary MBDex without/unknown visceral metastases and 23% (CI-95: 14-39) for solitary MBDex with visceral metastases (p<0.001). The 1-year patients survival was 75% (CI-95: 63-89) for the solitary-group with wide resection and 42% (95% CI: 26-67) for the solitary-group with intralesional resection (p<0.001).
Interpretation / Conclusion: Our study suggests that aggressive treatment of solitary MBDex-lesions with wide resection improve patient survival regardless of primary tumor. Further, surgical treatment of patients with oligo metastatic disease results in better 1-year survival than patients with multiple metastatic disease.

43. Surgical treatment of metastatic bone disease in the extremities: a population-based epidemiologic study
Thea Hovgaard Ladegaard¹, Celine Sørensen¹, Rasmus Nielsen², Anders Troelsen³, Dhergam AA. Al-Mousawi4, Rikke Bielefeldt5, Michael Mørk Petersen¹, Michala Skovlund Sørensen¹
Musculoskeletal Tumor Section, Department of Orthopedic Surgery, Rigshospitalet, University of Copenhagen¹; Department of Orthopedic Surgery, Herlev and Gentofte Hospital²; Department of Orthopedic Surgery, Amager and Hvidovre Hospital³; Department of Orthopedic Surgery, Nordsjællands Hospital4; Department of Orthopedic Surgery, Frederiksberg and Bispebjerg Hospital5

Background: Population-based studies of patients with metastatic bone disease in the extremities (MBDex) requiring surgery for complete or impending fracture is meagerly known.
Aim: We sought to determine possible time-related changes of the incidence of MBDex-surgery and examine differences between patients treated at different centers in a population-based cohort.
Materials and Methods: We examined a population-based cohort consisting of all MBDex patients treated in the Capital Region (CR) 2014–2019. Procedures were performed at 5 secondary surgical centers (SSC) or 1 tertiary referral Musculoskeletal Tumor Center (MTC). Patients were followed until end of study (Sep 30 2021) or death. No patients were lost to follow-up. Logistic regression was used to describe associations. Kaplan-Meier analysis was used for survival analysis.
Results: Four-hundred-fifty-seven patients (493 primary MBDex lesions, 482 procedures) were included. Annual incidence of MBDex-surgery was 46 MBDex lesions/million inhabitants/year. MTC- patients had a significant better preoperative status than SSC-patients considering factors known for survival. Patients with complete fracture experienced longer surgical delay when treated at MTC compared to SSC: 4 (1-9) and 1 (1-3) days (p<0.001), respectively. Overall survival for the entire cohort was 37% and 11% at 1 and 5 years (MTC and SSC 1- and 5-year respectively: 44% and 15% vs. 29% and 5%, p<0.001). In patients with debut or relapse of cancer, 8% and 9% had insufficient biopsies, and 21% and 12% had no biopsy, respectively. The majority of patients with insufficient/no biopsies were treated at SSC. Comparison showed no change over time.
Interpretation / Conclusion: Current study highlights the low awareness on treating MBDex at SSC and emphasizes the importance of caution in interpretation of studies not representing an entire population thus introducing selection bias. A need for more awareness of atypical fractures, concern of MBD and securing proper biopsies for histopathological examinations is essential, especially at SSC, since the majority of lesions without any biopsy were found here. Biopsies are valuable to exclude a second malignancy and as material for targeted oncological treatment postoperatively.