The State of Local Antibiotic Use in Orthopedic Trauma.

Fracture-related infections are a challenging complication in orthopedic trauma that often necessitates multiple surgeries. Early administration of systemic antibiotics and surgical intervention remains the gold standard of care, but despite these measures, treatment failures can be as high as 35%. For these reasons, the introduction of local antibiotics at the site of at-risk fractures has increased over the past decade. This review looks at the various measures being used clinically including local antibiotic powder, polymethylmethacrylate, biodegradable substances, antibiotic-coated implants, and novel methods such as hydrogels and nanoparticles that have the potential for use in the future.

Defining the shelf-life of calcium sulfate beads embedded with tobramycin and vancomycin.

Background: Antibiotic-laden calcium sulfate beads are gaining popularity in the treatment of orthopaedic infections such as fracture-related infection and osteomyelitis. Calcium sulfate beads have several advantages over polymethylmethacrylate (PMMA) beads as they are bioabsorbable, have demonstrated improved elution characteristics, and have lower peak polymerization temperatures than seen in PMMA. The ability to make and store antibiotic beads for later use has the potential to standardize dosing and decrease operating room times and healthcare costs. This study aims to determine the antibiotic efficacy of premade, antibiotic-laden calcium sulfate beads. Methods: Calcium sulfate beads containing vancomycin or tobramycin were molded to 4.8 mm in diameter and stored for shelf-life durations of three and six months at 20 °C. A subset of beads was tested immediately after creation. At the designated time points, beads were placed into a buffer solution and incubated at 37 °C with agitation. Antibiotic eluent was collected at 1-hour, 4-hour, 24-hour, and 48-hour timepoints. Eluent concentrations were inferred from a prior study implementing the same calcium sulfate bead model. Eluent was used in microbroth dilution assays to determine its minimum inhibitory concentration (MIC) against methicillin-sensitive Staphylococcus aureus. Results: MIC assays for tobramycin and vancomycin against S. aureus yielded concentrations consistent with previously reported ranges. MIC results across different bead shelf lives also remained consistent without an increase in MIC with increasing shelf life for either antibiotic. Conclusions: Shelf life up to six months does not impact the efficacy of tobramycin or vancomycin eluent from calcium sulfate beads in vitro compared to beads made and tested immediately. These results provide preliminary evidence that tobramycin and vancomycin retain their antimicrobial activity in calcium sulfate beads for at least six months stored at room temperature. Additional studies on sterilization techniques are necessary prior to considering use of prefabricated antibiotic-loaded calcium sulfate beads in clinical practice.

Knee Arthrodesis: An Analysis of Surgical Risk Factors and Complications Using a National Database.

Background: Knee arthrodesis is predominantly a salvage procedure. In present time, knee arthrodesis is mostly considered for cases of unreconstructable failed total knee arthroplasty after prosthetic joint infection or trauma. Knee arthrodesis has shown better functional outcomes than amputation for these patients but has a high complication rate. The purpose of this study was to characterize the acute surgical risk profile of patients undergoing a knee arthrodesis for any indication. Methods: The American College of Surgeons National Surgical Quality Improvement Program database was queried to determine 30-day outcomes after knee arthrodesis between 2005 and 2020. Demographics, clinical risk factors, and postoperative events were analyzed, along with reoperation and readmission rates. Results: A total of 203 patients that underwent a knee arthrodesis were identified. Forty-eight percent of patients had at least 1 complication. The most common complication was acute surgical blood loss anemia requiring a blood transfusion (38.4%), followed by organ space surgical site infection (4.9%), superficial surgical site infection (2.5%), and deep vein thrombosis (2.5%). Smoking was associated with higher rates of reoperation and readmission (odds ratio 9, P < .01, and odds ratio 6, P < .05). Conclusions: Overall, knee arthrodesis is a salvage procedure that has a high rate of early postoperative complications and is most often performed in patients at higher risk. Early reoperation is strongly associated with a poor preoperative functional status. Smoking places patients at higher risk of early complications.

Thirty-Day Outcomes After Acute Total Hip Arthroplasty Combined With Internal Fixation of Acetabular Fractures: A Multi-Institutional Database Analysis.

INTRODUCTION: The purposes of this study were to characterize the 30-day surgical risk of patients undergoing open reduction and internal fixation (ORIF) and total hip arthroplasty stratified by an acetabular fracture pattern and to compare postoperative complications with ORIF alone using a large database. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried to determine 30-day outcomes after the combined hip procedure (CHP) compared with ORIF alone between 2005 and 2020. Current Procedural Terminology codes categorized fracture patterns. Univariate analysis was performed using the chi-square, Fisher exact, or Wilcoxon rank sum test. Logistic regression models were fitted to evaluate for any differences in postoperative complications. Total hospital length of stay was compared. RESULTS: A total of 1,187 patients were identified. One hundred eighty-four patients underwent a CHP, consisting of 99 acetabular wall fractures, 45 elementary acetabular fractures, and 40 associated acetabular fractures. There was no notable difference in any surgical site infection, thromboembolic events, transfusion rates, 30-day revision surgery, and readmission, regardless of the fracture pattern when controlling for comorbidities. Total hospital length of stay was shorter for patients who underwent a CHP for acetabular wall fractures or elementary acetabular fractures (P < 0.001). CONCLUSION: This combined surgical approach appears to have a similar 30-day risk profile when compared with ORIF alone regardless of the fracture pattern.

Dalbavancin is thermally stable at clinically relevant temperatures against methicillin-sensitive Staphylococcus Aureus.

Introduction: While the rate of orthopaedic infections has remained constant over the years, the burden on healthcare systems continues to rise with an aging population. Local antibiotic delivery via polymethyl methacrylate bone cement is a common adjunct in treating bone and joint infections. Dalbavancin is a novel lipoglycopeptide antibiotic in the same class as vancomycin that has shown efficacy against Gram-positive organisms when used systemically but has not been investigated as a local antibiotic. This study aims to identify whether dalbavancin is thermally stable at the temperatures expected during the polymerization of polymethyl methacrylate cement. Methods: Stock solutions of dalbavancin were prepared and heated using a polymerase chain reaction machine based upon previously defined models of curing temperatures in two clinically relevant models: a 10 mm polymethyl methacrylate bead and a polymethyl methacrylate articulating knee spacer model. Aliquots of heated dalbavancin were then transferred to be incubated at core body temperature (37 ∘C) and analyzed at various time points up to 28 d. The minimum inhibitory concentration at which 90 % of colonies were inhibited (MIC90) for each heated sample was determined against methicillin-sensitive Staphylococcus aureus (American Type Culture Collection, ATCC, 0173K) using a standard microbroth dilution assay. Results: The average MIC90 of dalbavancin was 1.63 µgmL-1 ±0.49 against 0173K S. aureus. There were no significant differences in the relative MIC90 values after heating dalbavancin in either model compared to unheated control dalbavancin. Conclusions: Dalbavancin is thermally stable at the curing temperatures of polymethyl methacrylate cement and at human core body temperature over 28 d. Future in vitro and in vivo studies are warranted to further investigate the role of dalbavancin as a local antibiotic prior to its clinical use.

PRP-1, a toll-like receptor ligand, upregulates the unfolded protein response in human chondrosarcoma cells.

BACKGROUND: Previous studies showed that proline-rich polypeptide (PRP-1) is a ligand for innate immunity toll-like receptors (TLR), and an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) which induces the death of chondrosarcoma cancer stem cells (CSC). The aim of this study was to investigate the effect of PRP-1 on the regulation of unfolded protein response (UPR) in human chondrosarcoma cells. MATERIALS AND METHODS: Lysates were prepared from a monolayer (bulk or ALDHhigh population), or spheroids chondrosarcoma cell cultures and treated with PRP-1 or control, followed by protein levels quantification by western blotting and mRNA expression by RT-qPCR of protein-RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1α), and X-box binding protein (XBP1). RESULTS: The PRP-1 has been shown to increase the expression of PERK, eIF2α, ATF4, CHOP, ATF6, IRE1α, and XBP1, on both protein and mRNA levels. CONCLUSION: PRP-1 activated UPR branches in monolayer, spheroid, and stem cell populations of human chondrosarcoma.

Patients With Opioid Use Disorder Have Increased Readmission Rates, Emergency Room Visits, and Costs Following a Hallux Valgus Procedure.

BACKGROUND: Patients with a history of opioid use disorder (OUD) tend to have more complications, higher readmission rates, and increased costs following orthopaedic procedures. This study evaluated patients undergoing hallux valgus correction for their odds of increased (1) readmission rates, (2) emergency room (ER) visits, and (3) costs. METHODS: Patients undergoing hallux valgus corrections with OUD history were identified using a national Medicare administrative claims database of approximately 24 million orthopaedic surgery patients. OUD patients were matched to non-opioid use disorder (NUD) patients in a 1:4 ratio by age, sex, Elixhauser-Comorbidity Index (ECI), diabetes mellitus, hyperlipidemia, hypertension, and tobacco use. The query yielded 6318 patients (OUD = 1276; NUD = 5042) who underwent a hallux valgus correction. Primary outcomes analyzed included odds of 90-day readmission rates, 30-day ER visits, and 90-day episode-of-care costs. Demographics, odds ratios (ORs), ECI, and cost were assessed as appropriate using a Pearson χ2 test, logistic regression, and a t test. A P value <.05 was considered statistically significant. RESULTS: There were no significant differences in demographics between OUD and NUD patients. OUD patients had higher incidence and odds of 90-day readmission (9.56% vs 6.04%; OR = 1.55; P < .001) and 30-day ER visits (0.86% vs 0.35%; OR = 2.42; P = .021) and incurred greater 90-day episode-of-care costs ($7208.28 vs $6134.75; P < .001) compared with NUD patient controls. CONCLUSION: The study demonstrates the possible influence of OUD on higher odds of readmission, ER visits, and costs following a hallux valgus correction. LEVELS OF EVIDENCE: Level III: Retrospective cohort study.

Development of Distal Femoral Metastasis is Rare in Cases of Isolated Proximal Femoral Metastases.

INTRODUCTION: In the setting of pathologic fractures or impending fractures of the femur, intramedullary nailing or hemiarthroplasty are the common surgical procedures indicated. Traditional teaching has stressed the importance of protecting the entire femur, and thus, it is common for these fractures to be treated with long nails or stems. Recent literature has begun to investigate whether this school of thought is valid and may challenge the perceived need for protection of the entire femur. The purpose of our study was to determine the incidence of ipsilateral distal femoral metastases after the treatment of proximal femoral metastases. METHODS: A retrospective chart review was performed that identified 66 patients who presented with completed or impending pathologic fractures of the proximal femur who then underwent either intramedullary nailing or hemiarthroplasty for surgical stabilization. Plain radiographs, in conjunction with CT, MRI, or positron emission tomography-CT when available, were used to determine whether there was disease progression and/or distal metastasis in the femur. RESULTS: There was one patient (1.5%) in this series who developed distal femoral metastasis after hemiarthroplasty from metastatic breast carcinoma. There were three patients (4.54%) with local progression of the disease. No patient required further intervention, and there were no cases of hardware failure or periprosthetic fracture after prophylactic fixation. DISCUSSION: Our findings show that there is an extremely low likelihood of developing distal femoral metastases when isolated proximal femoral metastases are present and thus protecting the entire femur may not be necessary in this clinical scenario. LEVEL OF EVIDENCE: IV, therapeutic study.

Cancer stem cells as a therapeutic target in 3D tumor models of human chondrosarcoma: An encouraging future for proline rich polypeptide­1.

Chondrosarcoma is a malignant bone neoplasm that is refractory to chemotherapy and radiation. With no current biological treatments, mutilating surgical resection is the only effective treatment. Proline rich polypeptide 1 (PRP­1), which is a 15­amino acid inhibitor of mammalian target of rapamycin complex­1 (mTORC1), has been indicated to exert cytostatic and immunomodulatory properties in human chondrosarcoma cells in a monolayer. The aim of the present study was to evaluate the effects of PRP­1 on an in vitro 3D chondrosarcoma tumor model, known as spheroids, and on the cancer stem cells (CSCs) which form spheroids. JJ012 cells were cultured and treated with PRP­1. An ALDEFLUOR™ assay was conducted (with N,N­diethylaminobenzaldehyde as the negative control) to assess aldehyde dehydrogenase (ALDH) activity (a recognized CSC marker), and bulk JJ012, ALDHhigh and PRP­1 treated ALDHlow cells were sorted using flow cytometry. Colony formation and spheroid formation assays of cell fractions, including CSCs, were used to compare the PRP­1­treated groups with the control. CSCs were assessed for early apoptosis and cell death with a modified Annexin V/propidium iodide assay. Western blotting was used to identify mesenchymal stem cell markers (STRO1, CD44 and STAT3), and spheroid self­renewal assays were also conducted. A clonogenic dose­response assay demonstrated that 20 µg/ml PRP­1 was the most effective dose for reducing colony formation capacity. Furthermore, CSC spheroid growth was significantly reduced with increasing doses of PRP­1. Annexin V analysis demonstrated that PRP­1 induced CSC cell death, and that this was not attributed to apoptosis or necrosis. Western blot analysis confirmed the expression of mesenchymal markers, and the spheroid self­renewal assay confirmed the presence of self­renewing CSCs. The results of the present study demonstrate that PRP­1 eliminates anchorage independent CSC growth and spheroid formation, indicating that PRP­1 likely inhibits tumor formation in a murine model. Additionally, a decrease in non­CSC bulk tumor cells indicates an advantageous decline in tumor stromal cells. These findings confirm that PRP­1 inhibits CSC proliferation in a 3D tumor model which mimics the behavior of chondrosarcoma in vivo.

Proline­rich polypeptide­1 decreases cancer stem cell population by targeting BAFF chromatin­remodeling complexes in human chondrosarcoma JJ012 cells.

Chondrosarcoma is the second most common primary malignant bone tumor and is resistant to chemotherapy and radiation. Inadequate treatment response and poor prognosis requires novel therapeutic approaches. Proline­rich polypeptide­1 (PRP­1), synthesized by brain neurosecretory cells, has demonstrated antitumor properties in JJ012­cells; however, its underlying molecular mechanism remains unclear. The present study aimed to investigate the epigenetic regulation by which PRP­1 inhibits chondrosarcoma cancer stem cell (CSC) proliferation and to elucidate additional CSC biomarkers in human chondrosarcoma other than ALDH1A1. Human chondrosarcoma JJ012­cells were treated with PRP­1 prior to performing an Aldefluor™ assay and fluorescence­activated cell sorting in order to determine aldehyde dehydrogenase (ALDH) expression levels and isolate ALDHhigh and ALDHlow cell populations. ALDH is an established marker of CSCs in several neoplasms, including chondrosarcoma. The cells were collected and lysed for gel electrophoresis, followed by western blot analysis. The Aldefluor™ assay was used to assess the expression levels of well­established CSC biomarkers, including CD133, CD4, CD10, CD144, CD177, CD221, CD271, leucine­rich repeat­containing G protein­coupled receptor 5, SOX2 and B lymphoma Mo­MLV insertion region 1 homolog (BMI­1), within the ALDHhigh population of JJ012 cells. The results confirmed that ALDHA1 was the biomarker for chondrosarcoma CSCs. PRP­1 was demonstrated to inhibit the ALDHhigh population colony and sarcosphere formation; 5 µg/ml PRP­1 was indicated to be the optimum concentration in eliminating colonies formed by JJ012 cells (92%, P<0.001) and by the ALDHhigh CSC­population (80.5%, P<0.001) in the clonogenic dose­response assay. Spheroid growth unequivocally decreased with an increase in PRP­1 dose. In order to determine the molecular mechanism by which PRP­1 decreased the CSC population, the regulation of the mammalian Switch/sucrose non­fermenting (SWI/SNF) complex, also referred to as BRG1­associated factor (BAF) complex, which either activates or represses transcription, thus acting as an oncogene or tumor suppressor in human cells, was analyzed. PRP­1 was demonstrated to decrease the expression levels of BRG, BAF170 and BRM; therefore, in JJ012 cells, these key players of the SWI/SNF (BAF) complex served an oncogenic role. The results of the present study demonstrated that PRP­1 targets chromatin­remodeling complexes; therefore, future efforts will be directed towards determining the interconnection between CSC maintenance, self­renewal capacity and BAF complexes.

Neuropathology in respiratory-related motoneurons in young Pompe (Gaa(-/-)) mice.

Respiratory and/or lingual dysfunction are among the first motor symptoms in Pompe disease, a disorder resulting from absence or dysfunction of the lysosomal enzyme acid α-glucosidase (GAA). Here, we histologically evaluated the medulla, cervical and thoracic spinal cords in 6 weeks old asymptomatic Pompe (Gaa(-/-)) mice to determine if neuropathology in respiratory motor regions has an early onset. Periodic acid-Schiff (PAS) staining indicated glycogen accumulation was exclusively occurring in Gaa(-/-) hypoglossal, mid-cervical and upper thoracic motoneurons. Markers of DNA damage (Tunel) and ongoing apoptosis (Cleaved Caspase 3) did not co-localize with PAS staining, but were prominent in a medullary region which included the nucleus tractus solitarius, and also in the thoracic spinal dorsal horn. We conclude that respiratory-related motoneurons are particularly susceptible to GAA deficiency and that neuronal glycogen accumulation and neurodegeneration may occur independently in early stage disease. The data support early therapeutic intervention in Pompe disease.