Infection in Arthroplasty: The Basic Science of Bacterial Biofilms in Its Pathogenesis, Diagnosis, Treatment, and Prevention.

In the past, the diagnosis and treatment of periprosthetic joint infection (PJI) in joint arthroplasty has often been frustrating for orthopaedic surgeons. The application of certain diagnostic criteria and different treatment strategies can be better directed if these infections are placed in the context of microbial biofilms. An understanding of this biofilm mode of microbial infection can help to explain the phenomenon of culture-negative infection as well as provide an understanding of why certain treatment modalities often fail. Continued basic research into the role of biofilms in infection will likely provide improved strategies for the clinical diagnosis and treatment of PJI. This is a review of the current preclinical knowledge of biofilm in relation to PJI with an overview of current practices applied in the diagnosis, treatment, and prevention of biofilm formation in this setting.

Treatment Outcomes and Attrition in Gram-Negative Periprosthetic Joint Infection.

BACKGROUND: While the prevailing belief is that periprosthetic joint infection (PJI) caused by Gram-negative (GN) organisms confers a poorer prognosis than Gram-positive (GP) cases, the current literature is sparse and inconsistent. The purpose of this study is to compare the treatment outcomes for GN PJI vs GP PJI and Gram-mixed (GM) PJI. METHODS: A retrospective review of 1189 PJI cases between 2007 and 2017 was performed using our institutional PJI database. Treatment failure defined by international consensus criteria was compared between PJI caused by GN organisms (n = 45), GP organisms (n = 663), and GM (n = 28) cases. Multivariate regression was used to predict time to failure. RESULTS: GM status, but not GN, had significantly higher rates of treatment failure compared to GP PJI (67.9% vs 33.2% failure; hazards ratio [HR] = 2.243, P = .004) in the multivariate analysis. In a subanalysis of only the 2-stage exchange procedures, both GN and GM cases were significantly less likely to reach reimplantation than GP cases (HR = .344, P < .0001; HR = .404, P = .013). CONCLUSION: Although there was no observed difference in the overall international consensus failure rates between GN (31.1% failure) and GP (33.2%) PJI cases, there was significant attrition in the 2-stage exchange GN cohort, and these patients were significantly less likely to reach reimplantation. Our findings corroborate the prevailing notion that GN PJI is associated with poorer overall outcomes vs GP PJI. These data add to the current body of literature, which may currently underestimate the overall failure rates of GN PJI treated via 2-stage exchange and fail to identify pre-reimplantation morbidity.

Are Preoperative Serologic Type and Screen Tests Necessary for Primary Total Joint Arthroplasty Patients in Specialty Surgical Hospitals?

BACKGROUND: Blood loss during total joint arthroplasty (TJA) has been a major concern requiring routine preoperative patient type and screen (T&S); however, with the implementation of blood conserving therapy, a marked decrease for perioperative transfusions has been observed. Many TJAs are now being performed in T&S mandated specialty surgical hospitals (SSHs) that lack on-site blood banks; therefore, the purpose of our study was to determine whether T&S (1) is necessary in SSH for TJA patients and (2) identifies patient risk factors associated with perioperative blood transfusion in SSH. METHODS: A retrospective study was conducted on 1034 consecutive primary TJAs performed between 2013 and 2014 at a 12-bed SSH who all received T&S. Patients were matched (1:1) to 964 inpatient TJA patients performed at a university hospital without routine T&S. Data on surgery type, patient demographics, hemoglobin and hematocrit results, and transfusion rates were collected. Multivariate logistic regression identified perioperative transfusion risk factors. RESULTS: Overall transfusion rates for the matched SSH (1.8% [17/964]) and university hospital populations (2.9% [28/964]) were similar (P = .13), with no emergent transfusions. SSH transfusion rates for simultaneous bilateral THA, simultaneous bilateral TKA, unilateral THA, and unilateral TKA were 21.1% (4/19), 3.1% (4/128), 2.7% (12/439), and 0.0% (0/448), respectively. Multivariate logistic regression identified unilateral THA (P ≤ .001), simultaneous bilateral TJA (P = .001), age (P = .05), and abnormal preoperative hemoglobin (P = .02) as significant transfusion risk factors at SSH. CONCLUSION: Due to low transfusion rates and lack of emergency transfusions, we recommend routinely ordering T&S for bilateral THA but not for unilateral TJA patients, at SSHs.

Timing of Symptomatic Pulmonary Embolism with Warfarin Following Arthroplasty.

The purpose is to determine the incidence and timing of pulmonary embolism for patients receiving warfarin for thrombo-prophylaxis following total joint arthroplasty (TJA). Current guidelines for duration of prophylaxis are nonspecific. Chemical prophylaxis carries the risk of bleeding and associated periprosthetic joint infection. We retrospectively studied 26,415 primary and revision TJA cases performed at our institution between 2000 and 2010. The overall 90-day rate of symptomatic PE was 1.07%. Fatal PE rate was 0.02%. Out of 283 documented symptomatic PE cases, 81% occurred within three postoperative days, 89% within one postoperative week, and 94% within two postoperative weeks. The risk of symptomatic PE appears to be highest during the first week after TJA. Efforts must be made to minimize risk during this period.

Testing the anti-fibrotic potential of the single-chain Fv antibody against the α2 C-terminal telopeptide of collagen I.

Abstract This study focuses on the single-chain fragment variable (scFv) variant of the original IgA-type antibody, recognizing the α2 C-terminal telopeptide (α2Ct) of human collagen I, designed to inhibit post-traumatic localized fibrosis via blocking the formation of collagen-rich deposits. We have demonstrated that the scFv construct expressed in yeast cells was able to fold into an immunoglobulin-like conformation, but it was prone to forming soluble aggregates. Functional assays, however, indicate that the scFv construct specifically binds to the α2Ct epitope and inhibits collagen fibril formation both in vitro and in a cell culture model representing tissues that undergo post-traumatic fibrosis. Thus, the presented study demonstrates the potential of the scFv variant to serve as an inhibitor of the excessive formation of collagen-rich fibrotic deposits, and it reveals certain limitations associated with the current stage of development of this antibody construct.

Symptomatic pulmonary embolus after joint arthroplasty: stratification of risk factors.

BACKGROUND: Prophylaxis for pulmonary embolism (PE) after total joint arthroplasty (TJA) presents the clinical dilemma of balancing the risk of postoperative thrombotic risk and anticoagulation-related complications such as bleeding, hematoma formation, and infection. Risk stratification of patients undergoing TJA is needed to tailor prophylaxis based on thrombotic and bleeding risk. QUESTIONS/PURPOSES: The purpose of this study was to identify the preoperative comorbidities that were associated with an increased risk of symptomatic PE after joint arthroplasty in a large group of patients who had TJAs and who were treated with either aspirin or warfarin. METHODS: We conducted a retrospective study of 26,391 primary and revision TJAs performed at our institution between January 2000 and April 2011. A total of 24,567 patients received warfarin prophylaxis for 6 weeks (targeted international normalized ratio of 1.5-2.0) and 1824 patients received 325 mg aspirin twice daily. Symptomatic patients with decreased oxygen saturation were evaluated for PE using either a ventilation/perfusion scan or multidetector CT scan. Symptomatic PEs occurring in patients within 90 days postoperatively identified with CT or ventilation/perfusion scans were considered complications related to surgery, and fatal PEs were those that occurred in patients who died during the hospital admission owing to cardiopulmonary failure after PE. Using a logistic regression analysis, a nomogram was created to predict postoperative symptomatic PE risk. RESULTS: Risk of postoperative symptomatic PE after primary and revision TJAs was 1.1%. Risk of postoperative fatal PE was 0.02%. Elevated BMI (p < 0.035), procedures on the knee (p < 0.006), higher Charlson Comorbidity Index (p < 0.015), chronic obstructive pulmonary disorder (p = 0.006), atrial fibrillation (p < 0.001), anemia (p < 0.001), presence of deep vein thrombosis (p < 0.001), and depression (p = 0.012) were independent risk factors for symptomatic PE. Based on these risk factors and derived scoring criteria, patients can be classified into low- (0.35%), medium- (1.4%), and high- (9.3%) risk categories. CONCLUSIONS: Patients who are obese, undergo knee procedures, have an elevated Charlson Comorbidity Index, chronic obstructive pulmonary disease, atrial fibrillation, anemia, depression, or postoperative deep vein thrombosis are at greater risk of having a postoperative PE develop. These risk factors should be considered when deciding on postoperative anticoagulation prophylaxis. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

Bacterial biofilms and periprosthetic infections.

In the past, diagnosing and treating periprosthetic infections in joint arthroplasty have often been challenging for orthopaedic surgeons. Certain diagnostic criteria and different treatment strategies can be better directed if these infections are placed in the context of microbial biofilms. An understanding of the biofilm mode of microbial infection can help explain the phenomenon of culture-negative infection and provide an understanding of why certain treatment modalities often fail. Continued basic research into the role of biofilms in infection will likely provide improved strategies for the clinical diagnosis and treatment of periprosthetic joint infections.

Total joint arthroplasty: should patients have preoperative dental clearance?

Obtaining dental clearance prior to elective total joint arthroplasty is a common practice; however, little published data exist to justify this requirement. Dental clearance data for 365 elective total knee and total hip arthroplasty patients were gathered prospectively. Of these patients, 358 (average age of 62.4 years; 157 men and 201 women; 152 primary total knee arthroplasties (TKAs), 16 revision TKA arthroplasties, one conversion TKA, 168 primary total hip (THAs) arthroplasties and 21 revision THA arthroplasties) proceeded to surgery and follow-up data were available for 355. A comparison group of 218 hip fracture patients (average age of 78.7 years; 52 men and 109 women; 137 THA and 81 hemiarthroplasties) with no preoperative dental clearance who were treated with hip arthroplasty was extracted retrospectively from an institutional database. Follow-up data were available for 161 of these patients. The incidence of dental pathology in the elective arthroplasty group was 8.8%. Early postoperative infection requiring surgical treatment occurred in six patients (1.7%) in the dental clearance elective arthroplasty group and in four patients (2.5%) in the hip fracture arthroplasty group. No statistical difference was found between the two groups. This suggests that the perceived need for routine preoperative dental screening for all hip and knee arthroplasty patients should be reassessed.

Extracellular Targets to Reduce Excessive Scarring in Response to Tissue Injury.

Excessive scar formation is a hallmark of localized and systemic fibrotic disorders. Despite extensive studies to define valid anti-fibrotic targets and develop effective therapeutics, progressive fibrosis remains a significant medical problem. Regardless of the injury type or location of wounded tissue, excessive production and accumulation of collagen-rich extracellular matrix is the common denominator of all fibrotic disorders. A long-standing dogma was that anti-fibrotic approaches should focus on overall intracellular processes that drive fibrotic scarring. Because of the poor outcomes of these approaches, scientific efforts now focus on regulating the extracellular components of fibrotic tissues. Crucial extracellular players include cellular receptors of matrix components, macromolecules that form the matrix architecture, auxiliary proteins that facilitate the formation of stiff scar tissue, matricellular proteins, and extracellular vesicles that modulate matrix homeostasis. This review summarizes studies targeting the extracellular aspects of fibrotic tissue synthesis, presents the rationale for these studies, and discusses the progress and limitations of current extracellular approaches to limit fibrotic healing.

N-acetylcysteine use as an adjuvant to bone cement to fight periprosthetic joint infections: A preliminary in vitro efficacy and biocompatibility study.

When antibiotic laden bone cement is used to manage periprosthetic joint infection (PJI), failure still occurs with its use in up to 30% of cases. Therefore, we designed an in vitro study to assess the bactericidal effect of N-acetylcysteine (NAC), an antibacterial adjuvant, in cement against planktonic and biofilm forms of common PJI pathogens. NAC (10%, 20%, 30%, 40%, and 50% w/v) added to polymethyl methacrylate (PMMA) and incubated in broth at 36°C. PMMA-alone and/or culture bacteria alone were used as a negative control. Aliquots of cement elution from each group were taken at 1 day and 1 week and then were investigated for antimicrobial efficacy against the planktonic-form and the biofilm-form of Staphylococcus aureus and Escherichia coli. The primary outcome was the residual colony-forming unit count. The cytotoxicity and mechanical properties of the NAC-PMMA cement-blocks were also assessed. NAC-PMMA efficacy against the planktonic bacteria was demonstrated at a minimum of 30% at Day 1 and a minimum of 20% at 1 week after (p < .001). NAC-PMMA cement was effective against biofilm at a minimum of 30% of NAC at 1 day and 1 week of cement immersion (p < .001). The PMMA alone group was identified as having the highest cytotoxicity (p < .001). NAC decreased the stiffness (p = .004) and maximum load breaking point of the cement (p = .029). NAC is an effective and biocompatible adjuvant to PMMA in terms of antibacterial activity against Staphylococcus aureus and Escherichia coli. The broad antibacterial spectrum of NAC, its low expense, and minimal cytotoxicity makes it an ideal agent for addition to PMMA cement.

Orthopedic Specialty Hospitals Are Associated With Lower Rates of Deep Surgical Site Infection Compared With Tertiary Medical Centers.

Orthopedic specialty hospitals may allow for more streamlined and efficient care, resulting in shorter lengths of stay, lower costs, and fewer complications. Surgical site infection can be a devastating complication of orthopedic procedures and is difficult to treat successfully, requiring substantial cost and resources. The goal of this study was to determine whether specialty hospitals had lower rates of infection than tertiary care institutions. Records were reviewed for patients undergoing primary total hip, knee, or shoulder arthroplasty and single-level lumbar fusion from 2010 to 2017 at 2 academic tertiary hospitals and 2 specialty hospitals. Patient demographic information, comorbidities, and the development of deep surgical site infection within 1 year of the index procedure were recorded and compared between the groups. Multivariate analysis identified variables that significantly correlated with infection rates. A total of 20,264 patients (73.9%) underwent surgery at a tertiary hospital, and 7169 (26.1%) underwent a procedure at a specialty hospital. Patients treated at orthopedic specialty hospitals had lower rates of infection at 1 year (0.6% vs 0.2%, P<.0001). Of the infections, 42 (32.3%) occurred in the knee, 50 (38.5%) in the hip, 24 (18.5%) in the spine, and 12 (10.8%) in the shoulder. When controlling for a healthier patient population, procedures performed at specialty hospitals were an independent predictor of infection within 1 year (odds ratio, 0.3693; P=.0012). Although tertiary hospitals care for older patients with more medical comorbidities, patients undergoing orthopedic procedures at a specialty hospital may be at lower risk for infection. Further study is needed to identify the processes associated with reduced infection rates and to determine whether they can be adopted at tertiary centers. [Orthopedics. 2021;44(4):e521-e526.].

Preoperative Sedative Use and Other Risk Factors for Continued Narcotic Use After Total Knee Arthroplasty: A Comprehensive Analysis of a Mandatory Database.

Opioids are used for pain control after total knee arthroplasty (TKA) and carry risk for abuse. Mandatory statewide databases have been created to monitor their use. The goal of this study was to identify patient risk factors for prolonged opioid use after TKA. The authors retrospectively reviewed a consecutive series of 676 primary TKA procedures performed between January 2017 and July 2017. Information on fulfillment of narcotic, sedative, benzodiazepine, and stimulant prescriptions was obtained from the Pennsylvania State Controlled Substance Monitoring website 6 months before and 1 year after the procedure. Bivariate and multivariate analyses were used to identify risk factors for the need for a second prescription and opioid use for longer than 6 months. Of this cohort, 30.3% used preoperative opioids, 60.5% filled a second opioid prescription, and 11.8% continued opioid use for longer than 6 months. Patients who had opioid use before the index procedure had more than 3-fold (odds ratio [OR], 3.29; P<.001) increased odds of filling a second opioid prescription and 8-fold (OR, 8.05; P<.001) increased odds of postoperative opioid use for longer than 6 months. Multivariate analysis was used to identify independent risk factors for requiring a second prescription, including discharge to a rehabilitation facility (OR, 2.77), bilateral procedures (OR, 1.88), preoperative narcotic use (OR, 1.70), and younger age (OR, 0.95). Independent risk factors for narcotic use for longer than 6 months included preoperative sedative (OR, 3.30) or narcotic use (OR, 1.49). This study identified several risk factors associated with prolonged narcotic use after TKA, including preoperative sedative use, and determined their relative weight. [Orthopedics. 2021;44(1):e50-e54.].

Mechanisms of reducing joint stiffness by blocking collagen fibrillogenesis in a rabbit model of posttraumatic arthrofibrosis.

Posttraumatic fibrotic scarring is a significant medical problem that alters the proper functioning of injured tissues. Current methods to reduce posttraumatic fibrosis rely on anti-inflammatory and anti-proliferative agents with broad intracellular targets. As a result, their use is not fully effective and may cause unwanted side effects. Our group previously demonstrated that extracellular collagen fibrillogenesis is a valid and specific target to reduce collagen-rich scar buildup. Our previous studies showed that a rationally designed antibody that binds the C-terminal telopeptide of the α2(I) chain involved in the aggregation of collagen molecules limits fibril assembly in vitro and reduces scar formation in vivo. Here, we have utilized a clinically relevant arthrofibrosis model to study the broad mechanisms of the anti-scarring activity of this antibody. Moreover, we analyzed the effects of targeting collagen fibril formation on the quality of healed joint tissues, including the posterior capsule, patellar tendon, and subchondral bone. Our results show that blocking collagen fibrillogenesis not only reduces collagen content in the scar, but also accelerates the remodeling of healing tissues and changes the collagen fibrils' cross-linking. In total, this study demonstrated that targeting collagen fibrillogenesis to limit arthrofibrosis affects neither the quality of healing of the joint tissues nor disturbs vital tissues and organs.

Bacterial toxins in musculoskeletal infections.

Musculoskeletal infections (MSKIs) remain a major health burden in orthopaedics. Bacterial toxins are foundational to pathogenesis in MSKI, but poorly understood by the community of providers that care for patients with MSKI, inducing an international group of microbiologists, infectious diseases specialists, orthopaedic surgeons and biofilm scientists to review the literature in this field to identify key topics and compile the current knowledge on the role of toxins in MSKI, with the goal of illuminating potential impact on biofilm formation and dispersal as well as therapeutic strategies. The group concluded that further research is needed to maximize our understanding of the effect of toxins on MSKIs, including: (i) further research to identify the roles of bacterial toxins in MSKIs, (ii) establish the understanding of the importance of environmental and host factors and in vivo expression of toxins throughout the course of an infection, (iii) establish the principles of drug-ability of antitoxins as antimicrobial agents in MSKIs, (iv) have well-defined metrics of success for antitoxins as antiinfective drugs, (v) design a cocktail of antitoxins against specific pathogens to (a) inhibit biofilm formation and (b) inhibit toxin release. The applicability of antitoxins as potential antimicrobials in the era of rising antibiotic resistance could meet the needs of day-to-day clinicians.

Adjuvant antibiotic-loaded bone cement: Concerns with current use and research to make it work.

Antibiotic-loaded bone cement (ALBC) is broadly used to treat orthopaedic infections based on the rationale that high-dose local delivery is essential to eradicate biofilm-associated bacteria. However, ALBC formulations are empirically based on drug susceptibility from routine laboratory testing, which is known to have limited clinical relevance for biofilms. There are also dosing concerns with nonstandardized, surgeon-directed, hand-mixed formulations, which have unknown release kinetics. On the basis of our knowledge of in vivo biofilms, pathogen virulence, safety issues with nonstandardized ALBC formulations, and questions about the cost-effectiveness of ALBC, there is a need to evaluate the evidence for this clinical practice. To this end, thought leaders in the field of musculoskeletal infection (MSKI) met on 1 August 2019 to review and debate published and anecdotal information, which highlighted four major concerns about current ALBC use: (a) substantial lack of level 1 evidence to demonstrate efficacy; (b) ALBC formulations become subtherapeutic following early release, which risks induction of antibiotic resistance, and exacerbated infection from microbial colonization of the carrier; (c) the absence of standardized formulation protocols, and Food and Drug Administration-approved high-dose ALBC products to use following resection in MSKI treatment; and (d) absence of a validated assay to determine the minimum biofilm eradication concentration to predict ALBC efficacy against patient specific micro-organisms. Here, we describe these concerns in detail, and propose areas in need of research.

Understanding Opioid Use After Total Hip Arthroplasty: A Comprehensive Analysis of a Mandatory Prescription Drug Monitoring Program.

INTRODUCTION: Opioids remain the most prescribed medication after total hip arthroplasty (THA) despite the potential for abuse and adverse effects. Given the high rates of opioid abuse and potential adverse effects, the reporting of controlled substances is now mandatory in many statewide databases. This study aimed to use a mandatory statewide database to analyze opioid prescription patterns in postoperative THA patients and identify independent risk factors for those patients who need a second prescription and/or require prolonged use (>6 months). METHODS: We retrospectively reviewed a consecutive series of 619 primary THAs. Demographic and comorbidity information were collected for all patients. Narcotic prescription data (converted to morphine milligram equivalents) as well as prescription data for sedatives, benzodiazepines, and stimulants were collected from the State's Controlled Substance Monitoring websites 6 months before and 9 months after the index procedure. Bivariate and multivariate analyses were done for second prescription and continued use. RESULTS: Of the 619 patients who underwent THA, 34.9% (216/619) used preoperative opioids, 36.2% (224/619) filled a second opioid prescription, and 10.5% (65/619) had continued use past 6 months. Patients with preoperative opioids were at an approximately 4-fold increased odds of requiring a second script and 12 times odds of continued opioid use. In the multivariate analysis, independent risk factors for requiring a second prescription, in descending order of magnitude, included the use of any sedative or sleep aid prescription and preoperative narcotic use. Independent risk factors for continued narcotic use longer than 6 months after THA included preoperative narcotic use and increased length of stay. DISCUSSION: Several risk factors and their relative weight have been identified for continued narcotic consumption after THA. It is important for surgeons to consider these predisposing factors preoperatively during the informed consent process and for managing postoperative pain expectations.