Monoclonal Antibody Disrupts Biofilm Structure and Restores Antibiotic Susceptibility in an Orthopedic Implant Infection Model.

Bacterial biofilms on orthopedic implants are resistant to the host immune response and to traditional systemic antibiotics. Novel therapies are needed to improve patient outcomes. TRL1068 is a human monoclonal antibody (mAb) against a biofilm anchoring protein. For assessment of this agent in an orthopedic implant infection model, efficacy was measured by reduction in bacterial burden of Staphylococcus aureus, the most common pathogen for prosthetic joint infections (PJI). Systemic treatment with the biofilm disrupting mAb TRL1068 in conjunction with vancomycin eradicated S. aureus from steel pins implanted in the spine for 26 of 27 mice, significantly more than for vancomycin alone. The mechanism of action was elucidated by two microscopy studies. First, TRL1068 was localized to biofilm using a fluorescent antibody tag. Second, a qualitative effect on biofilm structure was observed using scanning electron microscopy (SEM) to examine steel pins that had been treated in vivo. SEM images of implants retrieved from control mice showed abundant three-dimensional biofilms, whereas those from mice treated with TRL1068 did not. Clinical Significance: TRL1068 binds at high affinity to S. aureus biofilms, thereby disrupting the three-dimensional structure and significantly reducing implant CFUs in a well-characterized orthopedic model for which prior tested agents have shown only partial efficacy. TRL1068 represents a promising systemic treatment for orthopedic implant infection.

Evading the host response: Staphylococcus "hiding" in cortical bone canalicular system causes increased bacterial burden.

Extremity reconstruction surgery is increasingly performed rather than amputation for patients with large-segment pathologic bone loss. Debate persists as to the optimal void filler for this "limb salvage" surgery, whether metal or allograft bone. Clinicians focus on optimizing important functional gains for patients, and the risk of devastating implant infection has been thought to be similar regardless of implant material. Recent insights into infection pathophysiology are challenging this equipoise, however, with both basic science data suggesting a novel mechanism of infection of Staphylococcus aureus (the most common infecting agent) into the host lacunar-canaliculi network, and also clinical data revealing a higher rate of infection of allograft over metal. The current translational study was therefore developed to bridge the gap between these insights in a longitudinal murine model of infection of allograft bone and metal. Real-time Staphylococci infection characteristics were quantified in cortical bone vs metal, and both microarchitecture of host implant and presence of host immune response were assessed. An orders-of-magnitude higher bacterial burden was established in cortical allograft bone over both metal and cancellous bone. The establishment of immune-evading microabscesses was confirmed in both cortical allograft haversian canal and the submicron canaliculi network in an additional model of mouse femur bone infection. These study results reveal a mechanism by which Staphylococci evasion of host immunity is possible, contributing to elevated risks of infection in cortical bone. The presence of this local infection reservoir imparts massive clinical implications that may alter the current paradigm of osteomyelitis and bulk allograft infection treatment.

Outpatient Posterior Lumbar Fusion: A Population-Based Analysis of Trends and Complication Rates.

STUDY DESIGN: A retrospective case-control study. OBJECTIVE: The aim of this study was to determine the nationwide trends and complication rates associated with outpatient posterior lumbar fusion (PLF). SUMMARY OF BACKGROUND DATA: Outpatient lumbar spine fusion is now possible secondary to minimally invasive techniques that allow for reduced hospital stays and analgesic requirements. Limited data are currently available regarding the clinical outcome of outpatient lumbar fusion. METHODS: The Humana administrative claims database was queried for patients who underwent one to two-level PLF (CPT-22612 or CPT-22633 AND ICD-9-816.2) as either outpatients or inpatients from Q1 2007 to Q2 2015. The incidence of perioperative medical and surgical complications was determined by querying for relevant International Classification of Diseases and Current Procedural Terminology codes. Multivariate logistic regression adjusting for age, gender, and Charlson Comorbidity Index was used to calculate odds ratios (ORs) of complications among outpatients relative to inpatients undergoing PLF. RESULTS: Cohorts of 770 patients who underwent outpatient PLF and 26,826 patients who underwent inpatient PLF were identified. The median age was in the 65 to 69 years age group for both cohorts. The annual relative incidence of outpatient PLF remained stable across the study period (R = 0.03, P = 0.646). Adjusting for age, gender, and comorbidities, patients undergoing outpatient PLF had higher likelihood of revision/extension of posterior fusion [(OR 2.33, confidence interval (CI) 2.06-2.63, P < 0.001], anterior fusion (OR 1.64, CI 1.31-2.04, P < 0.001), and decompressive laminectomy (OR 2.01, CI 1.74-2.33, P < 0.001) within 1 year. Risk-adjusted rates of all other postoperative surgical and medical complications were statistically comparable. CONCLUSION: Outpatient lumbar fusion is uncommonly performed in the United States. Data collected from a national private insurance database demonstrate a greater risk of postoperative surgical complications including revision anterior and posterior fusion and decompressive laminectomy. Surgeons should be cautious in performing PLF in the outpatient setting, as the risk of revision surgery may increase in these cases. LEVEL OF EVIDENCE: 3.

Intraoperative Hypothermia is Common, but not Associated With Blood Loss or Transfusion in Pediatric Posterior Spinal Fusion.

BACKGROUND: Intraoperative hypothermia may be associated with increased blood loss due to the effects of temperature on clotting but this has not been evaluated in the setting of pediatric posterior spinal fusion (PSF). The purpose of this study was to determine if a correlation exists between intraoperative hypothermia and estimated blood loss (EBL) or transfusion requirements in pediatric patients undergoing PSF. METHODS: A retrospective review of consecutive patients undergoing PSF for scoliosis at a single institution between 6/2004 and 3/2012 was performed. Exclusion criteria were fewer than 10 levels fused, anterior spinal fusion, and patients below 9 years old at time of surgery. Temperature was measured every 15 seconds using esophageal temperature probe. Input variable of hypothermia was analyzed as a binary variable Tmin ≤35°C at any point during anesthesia and as integrated temperature area under the curve (TAUC). RESULTS: A total of 510 with an average age of 14.6 years (range, 9.0 to 24.3 y) met inclusion criteria. Totally, 56% (287/510) had idiopathic scoliosis (IS) and 44% (223/510) were non-IS. Hypothermia (Tmin≤35°C) was experienced by 45% (230/510) of all patients [48% (137/287) of IS; 42% (93/223) of non-IS]. A total of 63% (323/510) of patients were transfused with packed red blood cells (PRBC) [49% (141/287) of IS patients; 82% (182/223) of non-IS patients]. There was no correlation between Tmin≤35°C and transfusion of PRBC in all included patients (P=0.49); (IS patients P=0.45, non-IS patients P=0.61). There was no significant difference in EBL between patients who experienced hypothermia and those who did not (P=0.33; IS patients P=0.21, non-IS patients P=0.87). There was no significant correlation between TAUC and transfusion of PRBC for all patients (P=0.35), IS patients (P=0.26) and non-IS patients (P=0.54) or between TAUC and EBL (P=0.80); (IS patients P=0.57. non-IS patients P=0.62). CONCLUSIONS: There was no significant correlation between intraoperative hypothermia and EBL or transfusion of PRBC in pediatric patients undergoing PSF. LEVEL OF EVIDENCE: Level III.

Ambulatory anterior cervical discectomy and fusion is associated with a higher risk of revision surgery and perioperative complications: an analysis of a large nationwide database.

BACKGROUND CONTEXT: With the changing landscape of health care, outpatient spine surgery is being more commonly performed to reduce cost and to improve efficiency. Anterior cervical discectomy and fusion (ACDF) is one of the most common spine surgeries performed and demand is expected to increase with an aging population. PURPOSE: The objective of this study was to determine the nationwide trends and relative complication rates associated with outpatient ACDF. STUDY DESIGN/SETTING: This is a large-scale retrospective case control study. PATIENT SAMPLE: The patient sample included Humana-insured patients who underwent one- to two-level ACDF as either outpatients or inpatients from 2011 to 2016 OUTCOME MEASURES: The outcome measures included incidence and the adjusted odds ratio (OR) of postoperative medical and surgical complications within 1 year of the index surgery. MATERIALS AND METHODS: A retrospective review was performed of the PearlDiver Humana insurance records database to identify patients undergoing one- to two-level ACDF (Current Procedural Terminology [CPT]-22551 and International Classification of Diseases [ICD]-9-816.2) as either outpatients or inpatients from 2011 to 2016. The incidence of perioperative medical and surgical complications was determined by querying for relevant ICD and CPT codes. Multivariate logistic regression adjusting for age, gender, and Charlson Comorbidity Index was used to calculate ORs of complications among outpatients relative to inpatients undergoing ACDF. RESULTS: Cohorts of 1,215 patients who underwent outpatient ACDF and 10,964 patients who underwent inpatient ACDF were identified. The median age was in the 65-69 age group for both cohorts. The annual relative incidence of outpatient ACDF increased from 0.11 in 2011 to 0.22 in 2016 (R2=0.82, p=.04). Adjusting for age, gender, and comorbidities, patients undergoing outpatient ACDF were more likely to undergo revision surgery for posterior fusion at both 6 months (OR 1.58, confidence interval [CI] 1.27-1.96, p<.001) and 1 year (OR 1.79, CI 1.51-2.13, p<.001) postoperatively. Outpatient ACDF was also associated with a higher likelihood of revision anterior fusion at 1 year postoperatively (OR 1.46, CI 1.26-1.70, p<.001). Among medical complications, postoperative acute renal failure was more frequently associated with outpatient ACDF than inpatient ACDF (OR 1.25, CI 1.06-1.49, p=.010). Adjusted rates of all other queried surgical and medical complications were comparable. CONCLUSIONS: Outpatient ACDF is increasing in frequency nationwide over the past several years. Nationwide data demonstrate a greater risk of perioperative surgical complications, including revision anterior and posterior fusion, as well as a higher risk of postoperative acute renal failure. Candidates for outpatient ACDF should be counseled and carefully selected to reduce these risks.

Reconstructive Science in Orthopedic Oncology.

Limb salvage is widely practiced as standard of care in most cases of extremity bone sarcoma. Allograft and endoprosthesis reconstructions are the most widely utilized modalities for the reconstruction of large segment defects, however complication rates remain high. Aseptic loosening and infection remain the most common modes of failure. Implant integration, soft-tissue function, and infection prevention are crucial for implant longevity and function. Macro and micro alterations in implant design are reviewed in this manuscript. Tissue engineering principles using nanoparticles, cell-based, and biological augments have been utilized to develop implant coatings that improve osseointegration and decrease infection. Similar techniques have been used to improve the interaction between soft tissues and implants. Tissue engineered constructs (TEC) used in combination with, or in place of, traditional reconstructive techniques may represent the next major advancement in orthopaedic oncology reconstructive science, although preclinical results have yet to achieve durable translation to the bedside.

Fever is common postoperatively following posterior spinal fusion: infection is an uncommon cause.

OBJECTIVE: To determine the frequency and clinical significance of postoperative fever in pediatric patients undergoing posterior spinal fusion (PSF). STUDY DESIGN: A retrospective chart review was performed for consecutive patients undergoing PSF at a single institution between June 2005 and April 2011, with a minimum of 2-year follow up. Exclusion criteria were previous spine surgery, a combined anterior-posterior approach, and delayed wound closure at the time of surgery. RESULTS: Two hundred and seventy-eight patients with an average age of 13 years (1-22 years) met inclusion criteria, with the following diagnoses: adolescent idiopathic scoliosis 43%, neuromuscular/syndromic scoliosis 39%, congenital scoliosis 11%, spondylolisthesis 4%, and Scheuermann kyphosis 3%. Seventy-two percent (201/278) of patients had a maximum temperature (Tmax) >38(°) postoperatively, and 9% (27/278) Tmax >39(°). The percentage of febrile patients trended down following the first postoperative day. Infection rate was 4% (12/278). There was no correlation between Tmax >38(°) or Tmax >39(°), and timing of fever, positive blood or urine cultures, pneumonia, or surgical site infection. CONCLUSION: Seventy-two percent of pediatric patients undergoing PSF experienced postoperative fever, and 9% of patients had Tmax>39(°). There was no significant correlation between fever and positive blood culture, urine culture, pneumonia, or surgical site infection. This information may help relieve stress for families and healthcare providers, and obviate routine laboratory evaluation for fever alone.

Effect of Delta-9-tetrahydrocannabinol on mouse resistance to systemic Candida albicans infection.

Delta-9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, is known to suppress the immune responses to bacterial, viral and protozoan infections, but its effects on fungal infections have not been studied. Therefore, we investigated the effects of chronic Δ9-THC treatment on mouse resistance to systemic Candida albicans (C. albicans) infection. To determine the outcome of chronic Δ9-THC treatment on primary, acute systemic candidiasis, c57BL/6 mice were given vehicle or Δ9-THC (16 mg/kg) in vehicle on days 1-4, 8-11 and 15-18. On day 19, mice were infected with 5×10(5) C. albicans. We also determined the effect of chronic Δ9-THC (4-64 mg/kg) treatment on mice infected with a non-lethal dose of 7.5×10(4) C. albicans on day 2, followed by a higher challenge with 5×10(5) C. albicans on day 19. Mouse resistance to the infection was assessed by survival and tissue fungal load. Serum cytokine levels were determine to evaluate the immune responses. In the acute infection, chronic Δ9-THC treatment had no effect on mouse survival or tissue fungal load when compared to vehicle treated mice. However, Δ9-THC significantly suppressed IL-12p70 and IL-12p40 as well as marginally suppressed IL-17 versus vehicle treated mice. In comparison, when mice were given a secondary yeast infection, Δ9-THC significantly decreased survival, increased tissue fungal burden and suppressed serum IFN-γ and IL-12p40 levels compared to vehicle treated mice. The data showed that chronic Δ9-THC treatment decreased the efficacy of the memory immune response to candida infection, which correlated with a decrease in IFN-γ that was only observed after the secondary candida challenge.