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Introduction: Implant infections caused by Staphylococcus aureus are responsible for high mortality and morbidity worldwide. Treatment of these infections can be difficult especially when bacterial biofilms are involved. In this study we investigate the potential of infrared photoimmunotherapy to eradicate staphylococcal infection in a mouse model. Methods: A monoclonal antibody that targets Wall Teichoic Acid surface components of both S. aureus and its biofilm (4497-IgG1) was conjugated to a photosensitizer (IRDye700DX) and used as photoimmunotherapy in vitro and in vivo in mice with a subcutaneous implant pre-colonized with biofilm of Staphylococcus aureus. A dose of 400 μg and 200 μg of antibody-photosensitizer conjugate 4497-IgG–IRDye700DXwas administered intravenously to two groups of 5 mice. In addition, multiple control groups (vancomycin treated, unconjugated IRDye700DX and IRDye700DX conjugated to a non-specific antibody) were used to verify anti-microbial effects. Results: In vitro results of 4497-IgG-IRDye700DX on pre-colonized (biofilm) implants showed significant (p<0.01) colony-forming units (CFU) reduction at a concentration of 5 μg of the antibody-photosensitizer conjugate. In vivo, treatment with 4497-IgG-IRDye700DX showed no significant CFU reduction at the implant infection. However, tissue around the implant did show a significant CFU reduction with 400 μg 4497-IgG-IRDye700DX compared to control groups (p = 0.037). Conclusion: This study demonstrated the antimicrobial potential of photoimmunotherapy for selectively eliminating S. aureus in vivo. However, using a solid implant instead of a catheter could result in an increased bactericidal effect of 4497-IgG-IRDye700DX and administration locally around an implant (per operative) could become valuable applications in patients that are difficult to treat with conventional methods. We conclude that photoimmunotherapy could be a potential additional therapy in the treatment of implant related infections, but requires further improvement. [ABSTRACT FROM AUTHOR]

Aim: Haemophilia is characterized by recurrent joint bleeding caused by a lack of clotting factor VIII or IX. Due to repeated joint bleeding, end‐stage arthropathy occurs in relatively young patients. A total knee replacement (TKR) can be a solution. However, TKR may be complicated by perioperative and postoperative bleeds despite clotting factor therapy. The aim of this study was to evaluate the prevalence of pre‐operative synovial hyperaemia and the effects of Genicular Artery Embolization on synovial hyperaemia and 3‐month postoperative joint bleeding. Methods: In this retrospective cohort study, all patients with haemophilia who underwent periarticular catheter angiography between 2009 and 2020 were evaluated after written informed consent. Synovial hyperaemia on angiography was scored by an interventional radiologist. Results: Thirty‐three angiography procedures in 24 patients were evaluated. Median age was 54.4 years (IQR 48.4–65.9). Preoperative synovial hyperaemia was observed in 21/33 joints (64%). Moderate and severe synovial hyperaemia was observed in 10/33 joints (30%). Synovial hyperaemia decreased in 13/15 (87%) joints after embolization. Three‐month postoperative joint bleeding occurred in 5/32 joints: in 2/18 joints (11%) without synovial hyperaemia and in 3/14 joints (21%) with mild synovial hypertrophy. Non‐embolized and embolized joints did not differ regarding 3‐month postoperative bleeding (P =.425). No complications were observed after embolization. Conclusion: One‐third of patients with haemophilia requiring a TKR had moderate or severe synovial hyperaemia which can be reduced safely by Genicular Artery Embolization prior to TKR. Three‐month postoperative bleeding appears to occur independently of the presence of residual mild synovial hyperaemia. [ABSTRACT FROM AUTHOR]

Background: Despite the extensive use of silver ions or nanoparticles in research related to preventing implant-associated infections (IAI), their use in clinical practice has been debated. This is because the strong antibacterial properties of silver are counterbalanced by adverse effects on host cells. One of the reasons for this may be the lack of comprehensive in vitro models that are capable of analyzing host-bacteria and host-host interactions. Methods and results: In this study, we tested silver efficacy through multicellular in vitro models involving macrophages (immune system), mesenchymal stem cells (MSCs, bone cells), and S. aureus (pathogen). Our model showed to be capable of identifying each element of culture as well as tracking the intracellular survival of bacteria. Furthermore, the model enabled to find a therapeuticwindow for silver ions (AgNO3) and silver nanoparticles (AgNPs) where the viability of host cells was not compromised, and the antibacterial properties of silver were maintained. While AgNO3 between 0.00017 and 0.017 µg/mL retained antibacterial properties, host cell viability was not affected. The multicellular model, however, demonstrated that those concentrations had no effect on the survival of S. aureus, inside or outside host cells. Similarly, treatment with 20 nm AgNPs did not influence the phagocytic and killing capacity of macrophages or prevent S. aureus from invading MSCs. Moreover, exposure to 100 nm AgNPs elicited an inflammatory response by host cells as detected by the increased production of TNF-a and IL-6. This was visible only when macrophages and MSCs were cultured together. Conclusions: Multicellular in vitro models such as the one used here that simulate complex in vivo scenarios can be used to screen other therapeutic compounds or antibacterial biomaterials without the need to use animals. [ABSTRACT FROM AUTHOR]

Implant infections caused by Staphylococcus aureus are difficult to treat due to biofilm formation, which complicates surgical and antibiotic treatment. We introduce an alternative approach using monoclonal antibodies (mAbs) targeting S. aureus and provide evidence of the specificity and biodistribution of S.-aureus-targeting antibodies in a mouse implant infection model. The monoclonal antibody 4497-IgG1 targeting wall teichoic acid in S. aureus was labeled with indium-111 using CHX-A"-DTPA as a chelator. Single Photon Emission Computed Tomography/computed tomographyscans were performed at 24, 72 and 120 h after administration of the 111In-4497 mAb in Balb/cAnNCrl mice with a subcutaneous implant that was pre-colonized with S. aureus biofilm. The biodistribution of this labelled antibody over various organs was visualized and quantified using SPECT/CT imaging, and was compared to the uptake at the target tissue with the implanted infection. Uptake of the 111In-4497 mAbs at the infected implant gradually increased from 8.34 %ID/cm3 at 24 h to 9.22 %ID/cm3 at 120 h. Uptake at the heart/blood pool decreased over time from 11.60 to 7.58 %ID/cm3, whereas the uptake in the other organs decreased from 7.26 to less than 4.66 %ID/cm3 at 120 h. The effective half-life of 111In-4497 mAbs was determined to be 59 h. In conclusion, 111In-4497 mAbs were found to specifically detect S. aureus and its biofilm with excellent and prolonged accumulation at the site of the colonized implant. Therefore, it has the potential to serve as a drug delivery system for the diagnostic and bactericidal treatment of biofilm. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilic ankle arthropathy (HAA) causes major morbidity. When conservative treatment fails, major surgical interventions are indicated. An alternative treatment to maintain joint mobility and postpone these interventions is desired. Aim: To gather prospective data on clinical/structural changes after ankle joint distraction (AJD) in HAA. Methods: This study includes patients with severe HAA insufficiently responding to conservative treatment. AJD was performed during 8–10 weeks by use of an external frame. Questionnaires, physical examination and radiology were used to evaluate pain, function and structural changes before and 6, 12, 24 and 36 months after distraction. Mixed effect models were used for analysis. Results: This study includes eight cases (21–53 years). The fixed effects estimates of the visual analogue score (0–10) improved from 7.5 at baseline to 3.4 (p =.023) 3 years after distraction. The Haemophilia Activities List (HAL, 0–100) for basic/complex lower extremities functions improved from respectively 29.6 and 31.5 to 54.3 (p =.015) and 50.7 (p =.031). Joint mobility was maintained. Magnetic resonance imaging (MRI) showed thickened cartilage and reduced bone marrow oedema and subchondral cysts. Pin tract infections (n = 6) were effectively treated and no adverse bleeding events occurred. At 3‐year follow‐up, in none of the patients the originally indicated arthrodesis was performed. Conclusion: This first prospective study showed that AJD in HAA results in decreased pain, improved function and decreased arthropathy‐related MRI findings in the majority of patients for prolonged time. Although the study population is small and follow‐up is relatively short, AJD may be promising to postpone invalidating interventions and might be a breakthrough treatment. [ABSTRACT FROM AUTHOR]

Background and purpose -- The long-term results of the 1- or 2-stage revision procedure and infection-free prosthesis survival in a tertiary referral center are unknown. In this retrospective observational study, the long-term results of infection control and infection-free prosthesis survival of the periprosthetic joint infection-related 1- and 2-stage revision procedure are evaluated. Furthermore, the merits of performing an antibiotic-free window in the 2-stage revision is evaluated. Patients and methods -- All patients who received a 1- or 2-stage revision procedure of the hip or knee between 2010 and 2017 were included. Data was collected on patient and infection characteristics. The primary treatment aim was successful infection control without the use of antibiotic therapy afterwards. Infection-free survival analysis was performed using the Kaplan--Meier method with type of periprosthetic joint infection-related revision as covariate. Within the group of 2-stage revisions, use of an antibioticfree window was selected as covariate. Results -- 128 patients were treated for a periprosthetic joint infection-related revision procedure (81 hips and 47 knees). Successful infection control was achieved in 18 of 21 cases for the 1-stage and 89 out of 107 cases for the 2-stage revision procedure (83%) respectively after follow-up of more than 4 years. In addition, 2-stage revision procedure infection control was achieved in 52 of 60 cases with an antibiotic- free interval and 37 of 45 cases without such interval (p = 0.6). The mean infection-free survival of the 1-stage revision was 90 months (95% CI 75--105) and 98 months (CI 90--106) for the 2-stage revision procedure. Interpretation -- There seems to be no difference in infection control and infection-free survival between the 1- and 2-stage revision procedure. Second, an antibiotic-free window in the case of a 2-stage revision did not seem to influence treatment outcome. However, one must be cautious when interpreting these results due to confounding by indication and the small study population. Therefore, no definite conclusion can be drawn. [ABSTRACT FROM AUTHOR]

The clinical impact of bacterial infections on bone regeneration has been incompletely quantified and documented. As a result, controversy exists about the optimal treatment strategy to maximize healing of a contaminated defect. Animal models are extremely useful in this respect, as they can elucidate how a bacterial burden influences quantitative healing of various types of defects relative to non‐infected controls. Moreover, they may demonstrate how antibacterial treatment and/or bone grafting techniques facilitate the osteogenic response in the harsh environment of a bacterial infection. Finally, it a well‐known contradiction that osteomyelitis is characterized by uncontrolled bone remodeling and bone loss, but at the same time, it can be associated with excessive new bone apposition. Animal studies can provide a better understanding of how osteolytic and osteogenic responses are related to each other during infection. This review discusses the in vivo impact of bacterial infection on osteogenesis by addressing the following questions (i) How does osteomyelitis affect the radiographic bone appearance? (ii) What is the influence of bacterial infection on histological bone healing? (iii) How do bacterial infections affect quantitative bone healing? (iv) What is the effect of antibacterial treatment on the healing outcome during infection? (v) What is the efficacy of osteoinductive proteins in infected bones? (vi) What is the balance between the osteoclastic and osteoblastic response during bacterial infections? (vii) What is the mechanism of the observed pro‐osteogenic response as observed in osteomyelitis? © 2019 The Authors. Journal of Orthopaedic Research© published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2067–2076, 2019 [ABSTRACT FROM AUTHOR]

Purpose We investigated the hypothesis that many total hip arthroplasty revisions that are classified as aseptic are in fact low-grade infections missed with routine diagnostics. Methods In 7 Dutch hospitals, 176 consecutive patients with the preoperative diagnosis of aseptic loosening of their total hip arthroplasty were enrolled. During surgery, between 14 and 20 tissue samples were obtained for culture, pathology, and broad-range 16S rRNA PCR with reverse line blot hybridization. Patients were classified as either not being infected, suspected of having infection, or infected according to strict, predefined criteria. Each patient had a follow-up visit after 1 year. Results 7 patients were classified as infected, 4 of whom were not identified by routine culture. 15 additional patients were suspected of having infection. 20 of these 22 patients received a cemented prosthesis, fixated with antibiotic-loaded bone cement. All 22 patients received prophylactic systemic antibiotics. 7 of them reported complaints one year after surgery, but only one showed signs of early loosening. However, additional surgery was not performed in any of the patients. Interpretation Although the proportions were not as high as previously reported in the literature, between 4% and 13% of patients with the preoperative diagnosis of aseptic loosening were infected. However, as thorough debridement was performed during surgery and prophylactic antibiotics were used, the diagnosis of infection did not have any obvious clinical consequences, as most patients performed well at the 1-year follow-up. Whether this observation has implications for long-term implant survival remains to be seen. [ABSTRACT FROM AUTHOR]

Data from literature showed that a new type of metallic silver PMMA cement had good results in infection prophylaxis. This study investigated the in vivo efficacy of silver cement in the prevention of methicillin-sensitive Staphylococcal infections, compared to plain and tobramycin-containing cement. In 48 rabbits, 0.6% silver, 1% silver, plain, or tobramycin PMMA cement was injected into the femoral medullary canal after contamination with 105, 106, or 107 colony forming units (CFU) Staphylococcus aureus. After 14 days, bone was collected for bacteriology and histopathology. All plain and silver cement rabbits were infected, whereas only two tobra rabbits were infected ( p < 0.001). The number of bacteria cultured (10logCFU) from bone adjacent to the cement, was 6.4 ± 0.3 and 6.1 ± 0.3 for the 0.6% and 1% silver rabbits. For the rabbits with plain and tobra cement, this was 6.2 ± 0.2 ( p > 0.95) and 0.0 ± 0.0 ( p < 0.001), respectively. Two tobra rabbits had a positive culture of a distal bone sample. Histological sections of plain, 0.6%, and 1% silver rabbits all showed signs of infection; these signs were absent in the tobra rabbits. Silver and plain cement were not effective in preventing infection, whereas tobra cement was effective. As silver cement predominantly exhibits an antimicrobial effect at the direct cement surface, this cement seems less useful in situations where there are bacteria present in surrounding tissues, like revision surgery. Whether silver cement has relevance in the prevention of bacterial colonization of cement remains to be determined. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 1002-1007, 2009 [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]