Session 17: Infection/amputation

Maria B. D. Nielsen^{1, 2}, Andrea R. Jørgensen^{1, 2}, Maiken Stilling^{1, 2, 3}, Mads K. D. Mikkelsen^{1, 2}, Nis P. Jørgensen⁴, Mats Bue^{1, 2, 3},
1. Department of Clinical Medicine, Aarhus University,; 2. Aarhus Denmark Microdialysis Research (ADMIRE), Orthopedic Research Laboratory, Aarhus University Hospital; 3. Department Of Orthopedic Surgery, Aarhus University Hospital; 4. Departments of Infectious Diseases, Aarhus University Hospital.

Background: Accurate antibiotic treatment is crucial for managing and preventing orthopedic infections due to their complexity and high 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.
Aim: This review aimed to comprehensively summarize the current literature on antibiotic distribution in orthopedically relevant tissues and settings using dynamic sampling.
Materials and Methods: Following 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, with 676 duplicates. 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 presented from various tissues including bone, intervertebral discs, joints, muscles, and subcutaneous tissue. Microdialysis was the predominant sampling method. 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.
Interpretation / Conclusion: 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.

Anna Trier Heiberg Brix^1,2, Katrine Hass Rubin^2,3, Tine Nymark^1,2, Hagen Schmal^1,4, Martin Lindberg-Larsen^1,2
1. Department of Orthopedic Surgery and Traumatology, Odense University Hospital 2. Department of Clinical Research, University of Southern Denmark 3. OPEN - Open Patient Data Explorative Network, Odense University Hospital and University of Southern Denmark 4. Department of Orthopedics and Traumatology, University Medical Center Freiburg

Background: Mortality after major lower extremity amputations (MLEA) is high and many factors contribute when the initial amputation level is decided.
Aim: This study aimed to examine the mortality risk after major lower extremity amputation over time and based on level of amputation.
Materials and Methods: This observational cohort study used data from the Danish Nationwide Health registers. A total of 11,212 first-time MLEAs were included from January 1, 2010, to December 31, 2021, compromising of 3,923 transtibial amputations (TTA) and 7,289 transfemoral amputations (TFA).
Results: The mortality after TTA was 11.2 % (95% confidence interval (CI) 10.2-12.2 ) vs. 23 % (22.0-23.9) after TFA =30 days, 17.4 % (16.2-18.6) vs. 33.9 % (32.8- 35) =90 days, and 29.1 %(27.7-30.5) vs. 47.6% (46.4-48.7) at =1 year. The 30-day and 1-year mortality for TTA declined from 9.7 % and 30.9% in 2010 to 6.8 % and 20.5% in 2021. For TFA the 30-day and 1-year mortality declined from 27% and 54.8% in 2010 to 21.8% and 46.2% in 2021. When adjusting for age, sex and comorbidities the risk of mortality remain increased for TFA compared to TTA; HR 1.8 (1.7-2.1) =30 days, HR 1.8 CI (1.6- 1.9) =90 days and HR 1.6 (1.5-1.7) =1 year.
Interpretation / Conclusion: The mortality after a TFA (23%) was almost twice as high as after a TTA (11.2%) in the first month after amputation. We observed a declining mortality risk over a 12-year period following both TTA and TFA. Additionally, in adjusted analysis, the mortality risk remained higher after TFA compared to TTA, confirming that the TFA procedure as well as the indications to perform a TFA may be associated with increased mortality.

Anna Trier Heiberg Brix^1,2, Katrine Hass Rubin^2,3, Tine Nymark^1,2, Hagen Schmal^1,4, Martin Lindberg-Larsen^1,2
1. Department of Orthopedic Surgery and Traumatology, Odense University Hospital 2. Department of Clinical Research, University of Southern Denmark 3. OPEN - Open Patient Data Explorative Network, Odense University Hospital and University of Southern Denmark 4. Department of Orthopedics and Traumatology, University Medical Center Freiburg

Background: Major lower extremity amputation (MLEA) is a high-risk intervention with significant implications for the patients’ quality of life, as well as pre and post-operative healthcare resource utilization.
Aim: The aim of the study was to examine the length of hospital stay and risk of early readmissions after a major lower extremity amputation in Denmark.
Materials and Methods: This is an observational registry study with data from the Danish National Patient registry. We included first time MLEA patients =50 years with either a primary transtibial amputation (TTA) or transfemoral amputation (TFA). In total, 11,205 MLEAs were included, divided in 3,921 TTAs and 7,284 TFAs. The total length of stay (LOS) was defined as both pre- and postoperative nights. The first readmission =30 days and =90 day were reported and included for analysis if it resulted in =1 overnight stay at any department/hospital in Denmark.
Results: The median total LOS after a TTA was 19 days (Interquartile range, 11-30) vs. 13 days (8-22) after a TFA. The median total LOS for TTA decreased from 28 days (17-41) in 2010 to 14 days (9-23) in 2021. For TFA median total LOS decreased from 16 days (9-27) in 2010 to 11 days (7-18) in 2021. The 30 days post discharge readmission risk was 29.7% (95 % Confidence Interval 28.2- 31.4) % for TTA vs. 27.8% (26.6-28.1) for TFA, whereas the 90 days readmission risk was 44.6 % (42.0-46.3) for TTA vs 41.5 % (40.2-42.7) for TFA. The risk of readmission did not decrease during the study period for both procedures. Stump complications were the main course of readmission for both TTA (42%) and TFA (31 %).
Interpretation / Conclusion: We observed that MLEA surgery was associated with lengthy hospital admissions lasting 2-3 weeks and a high readmission risk (28-30%) within 30 days post-discharge. Although the length of hospital stay decreased over the study period, the risk of readmission remained consistently high. Our findings underscore the significant impact of MLEA patients on hospital resource consumption and highlight the need for improvement in perioperative patient pathways.

Charlotte Abrahamsen^1,2, Inge Hansen-Bruun^2,3, Chelina Deleuran-Evers¹, Dorte Dall-Hansen¹, Ines Willerslev Jorgensen¹, Ane Simony^1,2
1. Department of Orthopedics and Traumatology, Hospital Lillebelt, Kolding 2. Institute for Regional Health Services, University of Southern Denmark 3. Department for occupational and physiotherapy, Hospital Lillebelt, Kolding

Background: It is well known, that patients discharged after a Major Lower Extremity Amputations are in high risk for readmissions and that 1 year mortality is high. The patients are fragile and suffering from a variety of comorbidities like diabetes, arteriosclerosis, cardiovascular disease and the majority are receiving anticoagulation therapy. The Safe Journey Program was implemented at hospital Lillebelt in 2019, an integrated care program offering the patients to be followed home, by the hospital nurse, daily visits from the home care nurses the first week and additional visits from the acute team members for objective evaluation of the patient de first 2 weeks after discharge.
Aim: In this study we will explore the readmission rate and mortality, before and after implementation of the Safe Journey Program for Major Lower Extremity Amputation patients.
Materials and Methods: Medical charts from amputee patients was reviewed from 2015-2016 and compared to the data from the Safe Journey database. 142 patients was included in the study, and 81 patients received the Safe Journey intervention, in the study period. Patient demographics, amputation levels, comorbidities, readmission and mortality were evaluated and data was analyzed using STATA.
Results: 130 patients was discharged after a Major Lower Extremity Amputation from 2015-2016. 142 patients was discharged after a Major Lower Extremity Amputation from 2019-2021 and 81 of them received the Safe Journey Intervention. Patient demographics, including the indication for surgery was similar, from the 2 periods. The 30 days readmission rate before the program was 14% and during the program 16%. Mortality rates was also found to be similar.
Interpretation / Conclusion: Patients discharged after a Major Lower Extremity Amputation are complex patients, with a high need observation. Implementing the Safe Journey program at discharge was costly, but beneficial to the patients, on a psychological level. The program was unable to reduce the 30-day readmissions rate and reduce mortality, compared to a data-set from 2015.

Jeppe Marinus Mortensen^{1, 2}, Anna Trier Heiberg Brix^{1, 2}, Kristine Bollerup Arndt³, Tine Nymark^{1, 2}, Martin Lindberg-Larsen^{1, 2}
1. Department of Orthopedic Surgery and Traumatology, Odense University Hospital 2. Department of Clinical Research, University of Southern Denmark 3. Department of Orthopedic Surgery, Kolding Hospital

Background: Major lower extremity amputations (MLEA) in Denmark are often performed with the indication of ischemic pain relief.
Aim: This study aims to investigate analgesic consumption before and after MLEA and identify predictors for postoperative long- term opioid use.
Materials and Methods: Data from the Danish National Patient registry was used to identify 7,069 first-time MLEA patients =50 years, divided in 3,120 below knee amputations (BKA) and 3,949 above knee amputations (AKA). The patient had to be alive 1 year post-operatively to be included. Prescription reimbursement data served as a surrogate marker for analgesic consumption, and patients with one or more redeemed prescription of opioids in all quarters post-surgery were defined as long- term opioid users. Patients who did not have a long-term use pre-surgery, but a long-term use post-surgery were defined as new long-term users.
Results: The amount of long-term opioid users increased after MLEA. In the year prior to surgery, 17.0% of the BKAs and 22.8% of the AKAs were long-term opioid users compared to 23.7% and 32.6% postoperatively. The use of analgesics for nerve pain also increased in the first two quarters after surgery. 23.1% of the BKAs and 31.2% of the AKAs used nerve pain analgesics before surgery compared to 45.6% and 57.6% postoperatively. The use of the other analgesics was stable for both groups before and after surgery. 13.2% and 18.4% became new long-term opioid users after BKA and AKA, respectively. Risk factors for postoperative new long-term opioid use were index AKA surgery Odds ratio (OR) 1.6 CI(1.4; 1.7), female sex 1.7 (1.6; 1.9), or a Charlson Comorbidity Index score =3 1.3 (1.2; 1.5).
Interpretation / Conclusion: An increased number of long-term opioid users was observed in the year following MLEA and over 50 % reimbursed prescriptions for nerve pain postoperatively. Risk factors for becoming a new long-term opioid user after MLEA was initial AKA, female sex, and a Charlson Comorbidity Index score of 3 or more. This indicates that analgesics consumption increases rather than declines after MLEA, and should be considered, when possible, in a shared decision-making process prior to amputation.

Lauritz Walsøe¹, Rehne Lessmann Hansen¹, Anette Marianne Fedder², Mikala Wang³, Per Hviid Gundtoft¹
1. Department of Orthopaedics, Aarhus University Hospital 2. Emergency Medicine, Aarhus University Hospital, Denmark 3. Department of Clinical Microbiology, Aarhus University Hospital, Denmark

Background: Necrotizing Soft Tissue Infections (NSTI) are rapidly progressing infections with high mortality. Patients with NSTI undergo multiple surgeries and are often discharged in a weakened state.
Aim: To estimate the one-year mortality of NSTI.
Materials and Methods: In this retrospective study, we used data from the Aarhus University Hospital NSTI database, where all inpatients with NSTI are recorded. A NSTI diagnosis is always made by a consultant at the hospital, and the diagnoses in the database have been validated through a review of the medical record. To identify the one-year mortality we used data from medical records, which is linked to the Danish Civil Registration System. Furthermore, clinical, laboratory, and surgical data were collected and analysed using the electronic medical record.
Results: A total of 130 patients (77 men and 53 women) with a mean age of 59 were included. 32 of the patients had uncomplicated diabetes and 9 patients had diabetes with complications. The in-hospital mortality was 17% (n=22), which increased to 19.2% (n=25) after 3 months and the 1-year mortality at 23.1% (n=30). When surgery included amputation, we found an increased in-hospital mortality of 40% at 3 months and 50% at 1 year. Patients infected with Group A Streptococcal (GAS) were grouped into two groups depending on Intravenous Immunoglobulin G (IVIG) treatment: IVIG treated patients (n=14) had an in-hospital mortality of 14% and no additional deaths after one year, whereas patients not treated with IVIG (n=21) had a higher mortality of 19% (n=4), which increased to 29% n(=6) after one year. The bacteria most prevalent were GAS and anaerobes (Bacteroides spp., Fusobacterium spp., Prevotella spp. and Peptostreptococci).
Interpretation / Conclusion: We found a high in-hospital mortality, which increased by 6% at 1-year follow-up. Diabetes was a high-risk factor for in-hospital and 1-year mortality. IVIG treatment was a protective factor for in-hospital mortality and 1-year mortality if NSTI with GAS was identified. Amputation was a major risk factor for in-hospital death and 1- year mortality.

Johanne Gade Lilleøre^1,2,3, Andrea René Jørgensen^1,2,3, Mads K. D. Mikkelsen^1,2,3, Elisabeth Krogsgaard Petersen^1,4, Hans Christian Rasmussen^1,2, Slater Josefine^1,2,3, Alex Soriano^1,5, Maiken Stilling^1,2,3, Nis Pedersen Jørgensen^1,3,6, Mats Bue^1,2,3
1. Aarhus Denmark Microdialysis Research Group (ADMIRE), Aarhus University Hospital, Aarhus N, Denmark 2. Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus, Denmark 3. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark 4. Department of Internal Medicine, Gødstrup Hospital, Herning, Denmark 5. Department of Infectious Diseases, Hospital Clínic of Barcelona, University of Barcelona, Barcelona, Spain 6. Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark

Background: Gram-positive bacteria remain the primary aetiology of prosthetic joint infections (PJI). Dalbavancin may be a valuable future antibiotic for treating PJI due to its uniquely long half-life and bactericidal activity against most Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Currently, no long-term target tissue pharmacokinetic data exists for PJI treatment settings.
Aim: We aimed to investigate dalbavancin concentrations in a 5-week setup in tibial cancellous and cortical bone, subcutaneous tissue, and synovial fluid of the knee joint in pigs using microdialysis.
Materials and Methods: 21 female pigs (Danish landrace, weight 72-95 kg) were included. A bolus of 1.5 g of dalbavancin was administered intravenously over 30 minutes on day 1 and day 8. In groups of 3, the pigs were allocated to surgery on days 1, 3, 5, 7, 10, 26, and 35 followed by euthanasia. Microdialysis catheters were placed to sample dalbavancin concentrations in tibial cancellous and cortical bone, subcutaneous tissue, and synovial fluid of the knee joint. Microdialysis samples were obtained for 4 hours, and blood samples were taken for reference.
Results: All pigs completed the study. The full data-set analysis is incomplete upon the abstract deadline. Data based on the 5-week protocol in relation to dalbavancin minimal inhibitory concentrations (MIC) for three strains of Staphylococcus aureus: 0.03 µg/mL (low), 0.06 µg/mL (intermediary), and 0.125 µg/mL (high) will be presented at the conference.
Interpretation / Conclusion: This study is the first to establish dalbavancin concentrations measured over a 5 week period. This much-needed insight can potentially guide and optimize future gram-positive PJI treatment regimens.