The application of ceragenins to orthopedic surgery and medicine

Osteomyelitis and infections associated with orthopedic implants represent a significant burden of disease worldwide. Ceragenins (CSAs) are a relatively new class of small-molecule antimicrobials that target a broad range of Gram-positive and Gram-negative bacteria as well as fungi, viruses, and parasites. This review sets the context of the need for new antimicrobial strategies by cataloging the common pathogens associated with orthopedic infection and highlighting the increasing challenges of managing antibiotic-resistant bacterial strains. It then comparatively describes the antimicrobial properties of CSAs with a focus on the CSA-13 family. More recently developed members of this family such as CSA-90 and CSA-131 may have a particular advantage in an orthopedic setting as they possess secondary pro-osteogenic properties. In this context, we consider several new preclinical studies that demonstrate the utility of CSAs in orthopedic models. Emerging evidence suggests that CSAs are effective against antibiotic-resistant Staphylococcus aureus strains and can prevent the formation of biofilms. There remains considerable scope for developing CSA-based treatments, either as coatings for orthopedic implants or as local or systemic antibiotics to prevent bone infection.     

Direct antimicrobial activity of cationic amphipathic peptide WLBU2 against Staphylococcus aureus biofilms is enhanced in physiologic buffered saline

Periprosthetic joint infection of total knee arthroplasties represents a major challenge to the field of orthopedic surgery. These infections are commonly associated with antibiotic-tolerant Staphylococcus aureus biofilms. Engineered cationic amphipathic peptide WLBU2 has shown the ability to kill antibiotic-resistant pathogens and drug-tolerant bacterial biofilms. The novelty of using WLBU2 during the direct irrigation and debridement of periprosthetic joint infections led our group to investigate the optimal washout conditions for treatment of S. aureus biofilms. S. aureus mature biofilms were grown on metal implant material and treated with WLBU2 dissolved in differing irrigation solvents. Mature biofilms were treated both in vitro as well as in a periprosthetic joint infection murine model. WLBU2 activity against S. aureus biofilms was increased when dissolved in diphosphate-buffered saline (dPBS) with pH of 7.0 compared with normal saline with pH of 5.5. WLBU2 activity was decreased in acidic dPBS and increased in alkaline dPBS. WLBU2 activity could be decreased in hypertonic dPBS and increased in hypotonic dPBS. WLBU2 dissolved in less acidic dPBS displayed increased efficacy in treating periprosthetic joint infection (PJI) implants ex vivo. WLBU2 demonstrated the ability to eliminate PJI associated S. aureus biofilms on arthroplasty material. The efficacy of engineered cationic amphipathic peptide WLBU2 for intraoperative elimination of S. aureus biofilms can be further optimized when kept in a less acidic and more physiologic pH adjusted saline. Understanding optimal physical washout conditions are vital for the success of WLBU2 in treating S. aureus biofilms in PJI clinical trials going forward.     

Staphylococcus aureus Prosthetic Joint Infection Is Prevented by a Fluorine- and Phosphorus-Doped Nanostructured Ti–6Al–4V Alloy Loaded With Gentamicin and Vancomycin

Prosthetic joint infection (PJI) is one of the most devastating complications in orthopedic surgery. One approach used to prevent PJI is local antibiotic therapy. This study evaluates the antibiotic release, in vitro cytocompatibility and in vivo effectiveness in preventing PJI caused by Staphylococcus aureus (S. aureus) of the fluorine- and phosphorus-doped, bottle-shaped, nanostructured (bNT) Ti–6Al–4V alloy loaded with a mixture of gentamicin and vancomycin (GV). We evaluated bNT Ti–6Al–4V loading with a mixture of GV, measuring the release of these antibiotics using high-performance liquid chromatography. Further, we describe bNT Ti–6Al–4V GV cytocompatibility and its efficacy against S. aureus using an in vivo rabbit model. GV was released from bNT Ti–6Al–4V following a Boltzmann non-linear model and maximum release values were obtained at 240 min for both antibiotics. The cell proliferation of MCT3T3-E1 osteoblastic cells significantly increased at 48 (28%) and 168 h (68%), as did the matrix mineralization (52%) of these cells and the gene expression of three of the most important markers related to bone differentiation (more than threefold for VEGF and BGLAP, and 65% for RunX) on bNT Ti–6Al–4V GV compared with control. In vivo study results show that bNT Ti–6Al–4V GV can prevent S. aureus PJI according to histopathological and microbiological results. According to our results, bNT Ti–6Al–4V loaded with a mixture of GV using the soaking method is a promising biomaterial with favorable cytocompatibility and osteointegration, demonstrating local bactericidal properties against S. aureus. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:588–597, 2020     

Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model

Staphyloccocus aureus is one of the major pathogens in orthopedic periprosthetic joint infection (PJI), a devastating complication of total joint arthroplasty that often results in chronic and persistent infections that are refractory to antibiotics and require surgical interventions. Biofilm formation has been extensively investigated as a reason for persistent infection. The cellular composition, activation status, cytokine profile, and role of the immune response during persistent S. aureus PJI are incompletely understood. In this study, we used histology, multiparametric flow cytometry, and gene expression analysis to characterize the immune response in a clinically relevant orthopedic PJI model. We tested the hypothesis that persistent S. aureus infection induces feedback mechanisms that suppress immune cell activation, thereby affecting the course of infection. Surprisingly, persistent infection was characterized by strikingly high cytokine gene expression indicative of robust activation of multiple components of innate and adaptive immunity, along with ongoing severe neutrophil-dominated inflammation, in infected joint and bone tissues. Activation and expansion of draining lymph nodes and a bone marrow stress granulopoiesis reaction were also maintained during late phase infection. In parallel, feedback mechanisms involving T-cell inhibitory receptors and exhaustion markers, suppressive cytokines, and regulatory T cells were activated and associated with decreased T-cell proliferation and tissue infiltration during the persistent phase of infection. These results identify the cellular and molecular components of the mouse immune response to persistent S. aureus PJI and indicate that neutrophil infiltration, inflammatory cytokine responses, and ongoing lymph node and bone marrow reactions are insufficient to clear infection and that immune effector mechanisms are suppressed by feedback inhibitory pathways. These immune-suppressive mechanisms are associated with diminished T-cell proliferation and tissue infiltration and can be targeted as part of adjuvant immunotherapeutic strategies in combination with debridement of biofilm, antibiotics, and other therapeutic modalities to promote eradication of infection. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Tranexamic Acid Administration is Associated With a Decreased Odds of Prosthetic Joint Infection Following Primary Total Hip and Primary Total Knee Arthroplasty: A National Database Analysis

BackgroundTranexamic acid (TXA) for the reduction of blood loss in orthopedic surgery is coming into greater adoption. Because TXA administration lowers the incidence of blood transfusion and of hematoma formation, risk factors for infection, we asked whether TXA use might be associated with a lower incidence of periprosthetic joint infection (PJI) following orthopedic surgery.MethodsWe queried the Premier Healthcare database for ICD-9 codes corresponding to elective inpatient primary total hip replacement (THR) or total knee replacement (TKR) from 2012 to 2016, TXA administration on the day of surgery, and PJI during the hospital stay or within 90 days. We performed a multilevel multivariable logistic regression (SAS version 9.4. SAS Institute, Cary, NC) to determine if TXA administration or other covariates were a significant predictor of infection.ResultsAmong 914,990 total joint arthroplasty patients, 46.0% received TXA on the day of surgery. 0.13% developed PJI within 90 days. After adjusting for patient and hospital-related covariates, TXA use was associated with significantly lower odds of PJI within 90 days of surgery (OR 0.49 [0.69, 0.91]).ConclusionAdministration of TXA on the day of surgery in total knee and total hip arthroplasty was associated with a statistically significant decreased odds of PJI in the first 90 days. We therefore conclude that TXA might play an important role in our attempts to decrease PJI after joint arthroplasty. The exact mechanisms and ideal dosage by which TXA can contribute to such a reduction need further study.     

Combined local and systemic antibiotic treatment is effective against experimental Staphylococcus aureus peri‐implant biofilm infection

We hypothesized that systemic ceftriaxone and high concentration local antibiotics might eradicate peri‐implant sepsis. Experiment 1: Eighty‐four implants inoculated with biofilm‐forming Staphylococcus aureus were treated in vitro with gentamicin, vancomycin, gentamicin + rifampin, or vancomycin + rifampin for 2, 4, or 8 days. Experiment 2: Forty‐five implants were wired in vivo to rat femurs and inoculated with 1 × 10⁶ CFU S. aureus. After 48 h, rats were treated once daily for 5 days with systemic ceftriaxone, local tobramycin or ceftriaxone, and tobramycin. Experiment 3: Forty implants with established S. aureus biofilms were wired in vivo to rat femurs. After 48 h, rats were treated with systemic ceftriaxone alone or in combination with local gentamicin, gentamicin and rifampin, or vancomycin. Experiment 1: 100% of implants treated in vitro with gentamicin were sterile after 48 h. The other treatments did not become sterile until 4 days. Experiment 2: No implant was culture negative. The combination of systemic ceftriaxone and local tobramycin was significantly better than others (p < 0.008). Experiment 3: Systemic ceftriaxone alone was ineffective. All implants treated with systemic ceftriaxone and local gentamicin were sterile (p < 0.001), the other groups were less effective. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1320–1326, 2015.     

Large variations in clinical antibiotic activity against Staphylococcus aureus biofilms of periprosthetic joint infection isolates

Staphylococcus aureus biofilms have a high tolerance to antibiotics, making the treatment of periprosthetic joint infection (PJI) challenging. From a clinical perspective, bacteria from surgical specimens are cultured in a planktonic state to determine antibiotic sensitivity. However, S. aureus exists primarily as established biofilms in PJI. To address this dichotomy, we developed a prospective registry of total knee and hip arthroplasty PJI S. aureus isolates to quantify the activity of clinically important antibiotics against isolates grown as biofilms. S. aureus planktonic minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were assessed using clinical laboratory standard index assays for 10 antibiotics (cefazolin, clindamycin, vancomycin, rifampin, linezolid, nafcillin, gentamicin, trimethoprim/sulfamethoxazole, doxycycline, and daptomycin). Mature biofilms of each strain were grown in vitro, after which biofilm MIC (MBIC) and biofilm MBC (MBBC) were determined. Overall, isolates grown as biofilms displayed larger variations in antibiotic MICs as compared to planktonic MIC values. Only rifampin, doxycycline, and daptomycin had measurable biofilm MIC values across all S. aureus isolates tested. Biofilm MBC observations complemented biofilm MIC observations; rifampin, doxycycline, and daptomycin were the only antibiotics with measurable biofilm MBC values. 90% of S. aureus biofilms could be killed by rifampin, 50% by doxycycline, and only 15% by daptomycin. Biofilm formation increased bacterial antibiotic tolerance nonspecifically across all antibiotics, in both MSSA and MRSA samples. Rifampin and doxycycline were the most effective antibiotics at killing established S. aureus biofilms. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1604–1609, 2019.     

Systemic versus local application of gentamicin in prophylaxis of implant-related osteomyelitis in a rat model

Administration of perioperative antibiotic prophylaxis is a routine procedure in orthopedic surgery. Besides systemic prophylaxis, only few techniques are established for local application of antibiotics to reduce infection related to orthopedic implants. The aim of this study was to evaluate the efficacy of locally versus systemically applied gentamicin in a rat model (n = 60). For local application, the antibiotic was delivered from a biodegradable poly(D,L-lactide) (PDLLA) coating of titanium implants. The efficacy of local prophylaxis was compared to a systemic single shot application of gentamicin as well as a combination of both administrations. Half of the animals received a weight-adopted single shot application of gentamicin 30 min prior to surgery. At surgery, the medullary cavities of the tibiae were contaminated with Staphylococcus aureus (10(2) colony forming units /CFU) and titanium Kirschner wires were implanted into the medullary canals. The implants were either uncoated, PDLLA coated, or coated with PDLLA + 10% w/w gentamicin. The animals were followed up for 42 days. X-ray examinations were performed; body weight, temperature, and the clinical condition were determined. After sacrifice, infection was evaluated by histological and microbiological analysis. All animals treated with uncoated or PDLLA-coated Kirschner wires without systemic application of the antibiotic developed osteomyelitis and all cultures of implants were tested positive on S. aureus. Implant-related osteomyelitis could be prevented by prophylaxis of systemically applied gentamicin in 15% of animals. In contrast, local application of gentamicin delivered from a PDLLA coating was more effective. Onset of infection could be prevented in 90% of animals treated with gentamicin coated Kirschner wires, and in 80% of the animals that were treated with a combination of local and systemic application. The local application from PDLLA-coated implants might support systemic antibiotic prophylaxis in preventing implant-associated osteomyelitis.     

Cefazolin embedded biodegradable polypeptide nanofilms promising for infection prevention: A preliminary study on cell responses

Implant‐associated infection is a serious complication in orthopedic surgery, and endowing implant surfaces with antibacterial properties could be one of the most promising approaches for preventing such infection. In this study, we developed cefazolin loaded biodegradable polypeptide multilayer nanofilms on orthopedic implants. We found that the amount of cefazolin released could be tuned. A high local concentration of cefazolin was achieved within the first a few hours and therefore may inhibit bacterial colonization in the critical postimplantation period. The developed cefazolin loaded nanofilms showed their in vitro efficacy against Staphylococcus aureus; the more antibiotics loaded, the longer the nanocoated implant had antibacterial properties. More interestingly, antibiotic‐loaded polypeptide multilayer nanofilms also improved osteoblast bioactivity including cell viability and proliferation. These findings suggested that biodegradable polypeptide multilayer nanofilms as antibiotic carriers at the implant/tissue interface are compatible with human cells such as osteoblasts and bactericidal to bacteria such as S. aureus. These characteristics could be promising for preventing implant‐associated infection and potentially improving bone healing. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:992–999, 2010     

The Risk Factor and Outcome of Metachronous Periprosthetic Joint Infections: A Retrospective Analysis With a Minimum Ten-Year Follow-Up

BackgroundPatients with multiple prosthetic joints are at risk of developing periprosthetic joint infections (PJIs). We aimed to determine whether PJI development at one site may lead to infection at another prosthetic joint site and assess the risk factors leading to this subsequent infection.MethodsWe reviewed all cases (294 patients with first-time PJI [159 hips, 135 knees]) with PJI treated at our institute between January 1994 and December 2020. The average follow-up period was 11.2 years (range 10.1-23.2). Patients were included if they had at least one other prosthetic joint at the time of developing a single PJI (96 patients). Patients with synchronous PJI were excluded from the study. The incidence of metachronous PJI was assessed, and the risk factors were determined by comparing different characteristics between patients without metachronous PJI.ResultsOf the 96 patients, 19.79% developed metachronous PJI. The identified causative pathogen was the same in 63.16% of the patients. The time to developing a second PJI was 789.84 days (range 10-3386). The identified risk factors were PJI with systemic inflammatory response syndrome, ≥3 stages of resection arthroplasty, and PJI caused by methicillin-resistant Staphylococcus aureus.ConclusionPJI may predispose patients to subsequent PJI in another prosthesis with identified risks. Most causative organisms of metachronous PJI were the same species as those of the first PJI. We believe that bacteremia may be involved in pathogenesis, but further research is required.     

Mismatch in Capture of Periprosthetic Joint Infections Between the Dutch Arthroplasty Register (LROI) and a Detailed Regional Periprosthetic Joint Infection Registry

BackgroundNational arthroplasty registries are important sources for periprosthetic joint infection (PJI) data and report an average incidence ranging from 0.5% to 2.0%. However, studies have shown that PJI incidence in national arthroplasty registries may be underestimated. Therefore, the incidence of PJI in the Dutch Arthroplasty Register (LROI) was evaluated.MethodsWe matched revisions due to infection within 90 days of index procedure in the LROI database (prospectively registered in 2014-2018) with acute PJI cases registered in a Regional Infection Cohort (RIC) and vice versa. The RIC comprised of 1 university hospital, 3 large orthopedic teaching hospitals and 4 general district hospitals, representing 11.3% of all Dutch arthroplasty procedures with a similar case mix.ResultsFrom the 352 acute PJIs in the RIC, 166 (47%) were registered in the LROI. Of the 186 confirmed PJI cases not registered in the LROI, 51% (n = 95) were a unregistered Debridement, Antibiotics, and Implant Retention procedure without component exchange. The remaining missing PJI cases (n = 91, 49%) were of administrative origin. The acute PJI incidence in the RIC was 1%, compared to a 0.6% incidence of revision <90 days due to infection from LROI data.ConclusionBesides unregistered Debridement, Antibiotics, and Implant Retention procedures without component exchange, administrative errors are an important source of missing PJI data for the LROI, leading to underestimation of PJI incidence in the Netherlands. A national arthroplasty complication registry, linked to the LROI, might decrease the number of missing PJI cases. Although our study concerns Dutch data, it supports the scarce literature on PJI incidence obtained from national arthroplasty registries, which also reports an underestimation.     

Prophylaxis of infection and effects on osseointegration using a tobramycin-periapatite coating on titanium implants—An experimental study in the rabbit

No options are available for local antibiotic delivery from uncemented implants. By loading a porous titanium implant with a biomimetic HA-coating (PeriApatite, PA) with antibiotics, we could obtain adequate local antibiotic concentrations and reduce infection susceptibility. This study investigated the efficacy of a tobramycin-loaded PA-coated titanium foam implant in preventing infection, as well as the effects on osseointegration. In 72 New Zealand White rabbits, an uncoated (Ti), PA-coated (PA), or Tobramycin-PA-coated (PA-tobra) titanium foam rod was implanted intramedullary in the left tibiae after contamination of the implant bed with none (control), 10³, 10⁴ or 10⁵ CFU Staphylococcus aureus. PA-tobra implants were loaded with 2.4 mg tobramycin. After 28 days analysis was done by bacteriology, histopathology and histomorphometry. Six percent of the contaminated PA-tobra rabbits were infected, whereas this was 53 and 67% for PA and Ti, respectively (p < 0.001). Quantitative cultures were also significantly lower in the PA-tobra group (p = 0.003). None of the control rabbits were infected. Histopathological and histomorphometrical scores were both better for the PA-tobra group, although only significant compared to Ti. No significant differences were observed between PA and Ti rabbits. We conclude that the application of tobramycin to PA-coated titanium foam implants appears to be an effective local antibiotic strategy for uncemented implants for infection prophylaxis and has a beneficial effect on implant fixation, which will result in improved long-term implant survival. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 710–716, 2009     

Longer Operative Time Results in a Higher Rate of Subsequent Periprosthetic Joint Infection in Patients Undergoing Primary Joint Arthroplasty

Background

Whether prolonged operative time is an independent risk factor for subsequent surgical site infection (SSI) and periprosthetic joint infection (PJI) following total joint arthroplasty (TJA) remains a clinically significant and underexplored issue. The aim of this study is to investigate the association between operative time and the risk of subsequent SSI and PJI in patients undergoing primary TJA.

Longitudinal Model of Periprosthetic Joint Infection in the Rat

The majority of periprosthetic joint infections occur shortly after primary joint replacement (<3 months) and require the removal of all implant components for the treatment period (~4 months). A clinically relevant animal model of periprosthetic infection should, therefore, establish an infection with implant components in place. Here, we describe a joint replacement model in the rat with ultrahigh molecular weight polyethylene (UHMWPE) and titanium components inoculated at the time of surgery by methicillin-sensitive Staphylococcus aureus (S. aureus), which is one of the main causative microorganisms of periprosthetic joint infections. We monitored the animals for 4 weeks by measuring gait, weight-bearing symmetry, von Frey testing, and micro-CT as our primary endpoint analyses. We also assessed the infection ex vivo using colony counts on the implant surfaces and histology of the surrounding tissues. The results confirmed the presence of a local infection for 4 weeks with osteolysis, loosening of the implants, and clinical infection indicators such as redness, swelling, and increased temperature. The utility of specific gait analysis parameters, especially temporal symmetry, hindlimb duty factor imbalance, and phase dispersion was identified in this model for assessing the longitudinal progression of the infection, and these metrics correlated with weight-bearing asymmetry. We propose to use this model to study the efficacy of using different local delivery regimens of antimicrobials on addressing periprosthetic joint infections. Statement of clinical significance: We have established a preclinical joint surgery model, in which postoperative recovery can be monitored over a multi-week course by assessing gait, weight-bearing, and allodynia. This model can be used to study the efficacy of different combinations of implant materials and medication regimens. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:1101-1112, 2020     

The Economics of Antibiotic Cement in Total Knee Arthroplasty: Added Cost with No Reduction in Infection Rates

BackgroundTo reduce the substantial clinical and financial burden of periprosthetic joint infection (PJI), some surgeons advocate for the use of antibiotic-loaded bone cement (ALBC) in primary total knee arthroplasty (TKA), although its effectiveness continues to be debated in the literature. The purpose of this study was to determine whether the routine use of ALBC is cost-effective in reducing PJI after primary TKA.MethodsWe retrospectively reviewed a consecutive series of patients undergoing cemented primary TKA at two hospitals within our institution from 2015 to 2017. We compared demographics, comorbidities, costs, and PJI rates between patients receiving ALBC and plain cement. We performed a multivariate regression analysis to determine the independent effect of ALBC on PJI rate. We calculated readmission costs for PJI and reduction in PJI needed to justify the added cost of ALBC.ResultsOf 2511 patients, 1077 underwent TKA with ALBC (43%), with no difference in PJI rates (0.56% vs 0.14%, P = .0662) or complications (1.2% vs 1.6%, P = .3968) but higher cement costs ($416 vs $117, P < .0001) and overall procedure costs ($6445 vs $5.968, P < .0001). ALBC had no effect on infection rate (P = .0894). Patients readmitted with PJI had higher overall 90-day episode-of-care claims costs ($49,341 vs $19,032, P < .001). To justify additional costs, ALBC would need to prevent infection in one of every 101 patients.ConclusionRoutine use of ALBC in primary TKA is not cost-effective, adding $299 to the cost of episode of care without a reduction in PJI rate. Further study is needed to determine whether select use of ALBC would be justified in high-risk patients.     

Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review

Implant-related infection is a feared complication in orthopedic and trauma surgery with tremendous consequences for the patient. To reduce this risk, administration of perioperative antibiotic prophylaxis is a routine procedure in orthopedic surgery. A local delivery system for antibiotics based on a polymer implant coating has been developed to optimize the prophylaxis. In an animal experiment, the efficacy of local prophylaxis of gentamicin was compared to a systemic single shot of gentamicin and to a combination of both administrations. The medullary cavities of rat tibiae were contaminated with Staphylococcus aureus and titanium K-wires were implanted into the medullary canals. For local antibiotic therapy, the implants were coated with poly(D,L-Lactide) (PDLLA) loaded with gentamicin. All the animals not treated with local and systemic application of the antibiotic developed osteomyelitis and all cultures of the implants tested positive for S. aureus. Onset of infection was prevented in 80-90% of animals treated with gentamicin-coated K-wires, with and without systemic prophylaxis. Gentamicin-coated intramedullary tibial nails are CE-certified for Europe and Canada and several patients have already been treated for implant-related infection. Up to now, eight patients with open tibia fractures have been treated with an unreamed tibial nail (UTN) coated with PDLLA and gentamicin. In the 1-year follow up, none of the patients developed an infection. A prospective randomized clinical documentation is currently in progress. So far, the results suggest that a local application of gentamicin from PDLLA-coated implants might support systemic antibiotic prophylaxis in preventing implant-associated osteomyelitis.     

Vancomycin Powder and Dilute Povidone-Iodine Lavage for Infection Prophylaxis in High-Risk Total Joint Arthroplasty

BackgroundDilute povidone-iodine lavage has been shown to be safe and effective in decreasing acute periprosthetic joint infection (PJI) following total joint arthroplasty (TJA). Vancomycin powder is reported to be effective in preventing infection in spine surgery. We hypothesize that a “vanco-povidone protocol” (VIP) for TJA patients at high risk for infection is safe and will decrease the rate of PJI.MethodsHigh-risk TJA patients (body mass index >40, active smokers, American Society of Anesthesiologists ≥3, immunosuppression/diabetes, methicillin-resistant Staphylococcus aureus colonization, revision surgery) utilizing VIP were compared to a high-risk historical cohort not treated with VIP, at a single institution. VIP consisted of dilute povidone-iodine lavage followed by application of vancomycin powder prior to wound closure. Primary endpoint was PJI within 3 months postoperatively.ResultsThe historical, high-risk control cohort consisted of 3251 patients with a PJI incidence of 1.8%. A total of 1413 subjects received the VIP protocol with a PJI incidence of 1.3%. There was a 27.8% risk reduction when compared to the control group of high-risk subjects not treated with the VIP. There were no medical complications secondary to the use of VIP, no increase in vancomycin-resistant enterococcus or vancomycin-resistant Staph aureus, and no cases of acute renal impairment secondary to application of the local vancomycin.ConclusionsPJI remains a common complication of TJA, especially in high-risk populations. This study indicates that a protocol of dilute povidone-iodine lavage combined with topical vancomycin powder is safe and may reduce PJI incidence in high-risk TJA patients. Due to low, current PJI rates, a multi-institutional randomized controlled trial is necessary to assess interventions that minimize the risk of PJI.Level of EvidenceRetrospective Observational Cohort.     

Normal CRP and WBC values in total hip arthroplasty (THA) with signs of loosening. Do we need a joint aspiration?

PurposeOverall Total hip arthroplasty (THA) is a very successful procedure. However, in case of complication dedicated management is required. Two major complications of THA failures are aseptic loosening (AL) and periprosthetic joint infection (PJI). The primary hypothesis of this study was that joint aspirations in patients with signs of loosening after THA are capable to detect PJI in suspected AL with negative serologic testing.MethodsIn this study a total of 108 symptomatic patients with radiographic signs of prosthetic loosening and hip pain in THA were included. Based on a standardized algorithm all patients underwent serological testing followed by joint aspiration preoperatively. Intraoperatively harvested samples were subjected to microbiological testing and served as the gold standard in differential diagnosis. Demographics, as well as the results of serologic and microbiological testing were collected from the medical records.ResultsOf the included patients 85 were finally diagnosed with an AL and 23 with PJI. Within the patients with PJI 13 (56%) patients demonstrated elevated CRP and WBC counts, as well as positive synovial cultures after joint aspiration. In ten patients (44%) diagnosed with PJI neither CRP nor WBC were abnormal.ConclusionThe diagnosis of PJI can be difficult in THA with radiographic signs of loosening. Clinical features including pain, fever, and local sings of infection are uncommon especially a long period after index operation. First-line screening testing relies on serological evaluation of CRP and WBC. However, normal CRP and WBC values cannot rule out a PJI. These cases can be detected by joint aspiration and synovial cultures reliably.     

Evidence of Staphylococcus Aureus Deformation,Proliferation, and Migration in Canaliculi of Live Cortical Bone in Murine Models of Osteomyelitis

Although Staphylococcus aureus osteomyelitis is considered to be incurable, the major bacterial reservoir in live cortical bone has remained unknown. In addition to biofilm bacteria on necrotic tissue and implants, studies have implicated intracellular infection of osteoblasts and osteocytes as a mechanism of chronic osteomyelitis. Thus, we performed the first systematic transmission electron microscopy (TEM) studies to formally define major reservoirs of S. aureus in chronically infected mouse (Balb/c J) long bone tissue. Although rare, evidence of colonized osteoblasts was found. In contrast, we readily observed S. aureus within canaliculi of live cortical bone, which existed as chains of individual cocci and submicron rod‐shaped bacteria leading to biofilm formation in osteocyte lacunae. As these observations do not conform to the expectations of S. aureus as non‐motile cocci 1.0 to 1.5 μm in diameter, we also performed immunoelectron microscopy (IEM) following in vivo BrdU labeling to assess the role of bacterial proliferation in canalicular invasion. The results suggest that the deformed bacteria: (1) enter canaliculi via asymmetric binary fission; and (2) migrate toward osteocyte lacunae via proliferation at the leading edge. Additional in vitro studies confirmed S. aureus migration through a 0.5‐μm porous membrane. Collectively, these findings define a novel mechanism of bone infection, and provide possible new insight as to why S. aureus implant‐related infections of bone tissue are so challenging to treat. © 2016 American Society for Bone and Mineral Research.     

Fungal periprosthetic joint infection: Rare but challenging problem

Periprosthetic joint infection (PJI) is the most difficult complication following total joint arthroplasty. Most of the etiological strains, accounting for over 98% of PJI, are bacterial species, with Staphylococcus aureus and Coagulase-negative staphylococci present in between 50% and 60% of all PJIs. Fungi, though rare, can also cause PJI in 1%–2% of cases and can be challenging to manage. The management of this uncommon but complex condition is challenging due to the absence of a consistent algorithm. Diagnosis of fungal PJI is difficult as isolation of the organisms by traditional culture may take a long time, and some of the culture-negative PJI can be caused by fungal organisms. In recent years, the introduction of next-generation sequencing has provided opportunity for isolation of the infective organisms in culture-negative PJI cases. The suggested treatment is based on consensus and includes operative and non-operative measures. Two-stage revision surgery is the most reliable surgical option for chronic PJI caused by fungi. Pharmacological therapy with antifungal agents is required for a long period of time with antibiotics and included to cover superinfections with bacterial species. The aim of this review article is to report the most up-to-date information on the diagnosis and treatment of fungal PJI with the intention of providing clear guidance to clinicians, researchers and surgeons.