Aims. The aim of this study was to analyze the prevalence of culture-negative periprosthetic joint infections (PJIs) when adequate methods of culture are used, and to evaluate the outcome in patients who were treated with antibiotics for a culture-negative PJI compared with those in whom antibiotics were withheld. Methods. A multicentre observational study was undertaken: 1,553 acute and 1,556 chronic PJIs, diagnosed between 2013 and 2018, were retrospectively analyzed. Culture-negative PJIs were diagnosed according to the Muskuloskeletal Infection Society (MSIS), International Consensus Meeting (ICM), and European Bone and Joint Society (EBJIS) definitions. The primary outcome was recurrent infection, and the secondary outcome was removal of the prosthetic components for any indication, both during a follow-up period of two years. Results. None of the acute PJIs and 70 of the chronic PJIs (4.7%) were culture-negative; a total of 36 culture-negative PJIs (51%) were treated with antibiotics, particularly those with histological signs of infection. After two years of follow-up, no recurrent infections occurred in patients in whom antibiotics were withheld. The requirement for removal of the components for any indication during follow-up was not significantly different in those who received antibiotics compared with those in whom antibiotics were withheld (7.1% vs 2.9%; p = 0.431). Conclusion. When adequate methods of culture are used, the incidence of culture-negative PJIs is low. In patients with culture-negative PJI, antibiotic treatment can probably be withheld if there are no histological signs of infection. In all other patients, diagnostic efforts should be made to identify the causative microorganism by means of serology or molecular techniques. Cite this article: Bone Joint J 2022;104-B(1):183–188

Aims. Bacterial infection activates neutrophils to release neutrophil extracellular traps (NETs) in bacterial biofilms of periprosthetic joint infections (PJIs). The aim of this study was to evaluate the increase in NET activation and release (NETosis) and haemostasis markers in the plasma of patients with PJI, to evaluate whether such plasma induces the activation of neutrophils, to ascertain whether increased NETosis is also mediated by reduced DNaseI activity, to explore novel therapeutic interventions for NETosis in PJI in vitro, and to evaluate the potential diagnostic use of these markers. Methods. We prospectively recruited 107 patients in the preoperative period of prosthetic surgery, 71 with a suspicion of PJI and 36 who underwent arthroplasty for non-septic indications as controls, and obtained citrated plasma. PJI was confirmed in 50 patients. We measured NET markers, inflammation markers, DNaseI activity, haemostatic markers, and the thrombin generation test (TGT). We analyzed the ability of plasma from confirmed PJI and controls to induce NETosis and to degrade in vitro-generated NETs, and explored the therapeutic restoration of the impairment to degrade NETs of PJI plasma with recombinant human DNaseI. Finally, we assessed the contribution of these markers to the diagnosis of PJI. Results. Patients with confirmed PJI had significantly increased levels of NET markers (cfDNA (p < 0.001), calprotectin (p < 0.001), and neutrophil elastase (p = 0.022)) and inflammation markers (IL-6; p < 0.001) in plasma. Moreover, the plasma of patients with PJI induced significantly more neutrophil activation than the plasma of the controls (p < 0.001) independently of tumour necrosis factor alpha. Patients with PJI also had a reduced DNaseI activity in plasma (p < 0.001), leading to a significantly impaired degradation of NETs (p < 0.001). This could be therapeutically restored with recombinant human DNaseI to the level in the controls. We developed a model to improve the diagnosis of PJI with cfDNA, calprotectin, and the start tail of TGT as predictors, though cfDNA alone achieved a good prediction and is simpler to measure. Conclusion. We confirmed that patients with PJI have an increased level of NETosis in plasma. Their plasma both induced NET release and had an impaired ability to degrade NETs mediated by a reduced DNaseI activity. This can be therapeutically restored in vitro with the approved Dornase alfa, Pulmozyme, which may allow novel methods of treatment. A combination of NETs and haemostatic biomarkers could improve the diagnosis of PJI, especially those patients in whom this diagnosis is uncertain. Cite this article: Bone Joint J 2024;106-B(9):1021–1030

Aims

Orthopaedic infection is a potentially serious complication of elective and emergency trauma and orthopaedic procedures, with a high associated burden of morbidity and cost. Optimization of vitamin D levels has been postulated to be beneficial in the prevention of orthopaedic infection. This study explores the role of vitamin D in orthopaedic infection through a systematic review of available evidence.

Introduction. In recent years, many studies demonstrated the efficacy of an early switch to oral antibiotics after surgical treatment in orthopaedic related infections. However, large analyses on periprosthetic joint infections (PJIs) are lacking. Material and Methods. We conducted a retrospective observational multicenter study in patients diagnosed with an early postoperative PJI (i.e less than 3 months after the index arthroplasty) treated with debridement, antibiotics and implant retention (DAIR). Patients from Europe and the USA were included. These two cohorts served as a quasi-randomised trial since an early oral antibiotic switch is routine practice in Europe versus a long duration of intravenous (IV) antibiotic treatment in the USA. Failure was defined as the clinical need for: i) a second DAIR, ii) implant removal, iii) suppressive antibiotic treatment or iv) infection related death. Results. A total of 668 patients were included. 277 received IV antibiotics for <14 days, 232 were given IV antibiotics between 14 - 27 days and 159 received IV antibiotics for >27 days. The overall 1-year failure rate within the 3 groups was 41.5%, 44.4% and 42.1%, respectively (P 0.80), and mainly comprised the need for a second DAIR. The results did not change when analyzing patients with or without obesity, the causative microorganism or the type of oral antibiotics. Conclusion. In early postoperative PJIs, a longer duration of IV antibiotic treatment is not associated with a lower failure rate of a DAIR procedure

Periprosthetic joint infections (PJIs) and osteosynthesis-associated infections (OSIs) present significant challenges in trauma and orthopaedic surgery, substantially impacting patient morbidity, mortality, and economic burden. This concern is heightened in patients with pre-existing comorbidities, such as diabetes mellitus, which are not always modifiable at presentation. A novel intraoperative strategy to prevent these infections is the use of Defensive Antibacterial Coating (DAC), a bio-absorbable antibiotic-containing hydrogel applied to implant surfaces at implantation, acting as a physical barrier to prevent infection. The purpose of this study is to assess the use of a commercially available hydrogel (DAC), highlighting its characteristics that make it suitable for managing PJIs and OSIs in orthopaedics and traumatology. Twenty-five patients who underwent complex orthopaedic procedures with intraoperative application of DAC between March 2022 and April 2023 at a single hospital site were included. Post-operative assessment encompassed clinical, laboratory, and radiographic examinations. In this study, 25 patients were included, with a mean age of 70 ± 14.77 years and an average ASA grade of 2.46 ± 0.78. The cohort presented an average Charleston Comorbidity score of 5.45 ± 2.24. The procedures included 8 periprosthetic fractures, 8 foot and ankle surgeries, 5 upper limb surgeries, and 4 elective hip and knee surgeries. Follow-up assessments at 6 weeks and 6 months revealed no evidence of PJI or OSI in any patients, nor were any treatments for PJI or OSI required during the interim period. DAC demonstrated efficacy in preventing infections in high-risk patients undergoing complex orthopaedic procedures. Our findings warrant further investigation into the use of DAC in complex hosts with randomized control trials

Background. Data regarding the diagnostic value of ultrasound (US)-determined fluid film and joint aspiration prior to revision total hip arthroplasty (THA) for suspected periprosthetic joint infections (PJIs) is limited. This study aimed to analyse (1) the value of US-determined fluid film, (2) characterisation of the pre- and intraoperative microbiological spectrum and resistance patterns and (3) the concordance between preoperative synovial fluid and intraoperative culture results. Methods. We analysed 366 US-examinations from 340 patients prior to revision THA. Selected cases were categorized into clearly infected, non-infected and inconclusive, according to the International Consensus Meeting (ICM) 2018 Criteria. If US-determined fluid film was <1mm, no aspiration was performed based on our institutional standard protocol. Patients were grouped into no-aspiration (144/366;[39.3%]), dry-tap (21/366;[5.7%]) and a successful-tap (201/366;[54.9%]). The microbiological spectrum and antibiotic resistance patterns were determined and differences were compared between pre- and intraoperative results. Results. The absence of US-determined fluid film showed no correlation with the presence of hip PJI. Overall, 29.9% cases of the no-aspiration-group had a confirmed PJI. Discrepancies were found in 43.2% between successful taps and intraoperative cultures. The most prevalent microorganisms in preoperative synovial fluid were Staphylococcus epidermidis (20.9%), Staphylococcus aureus (20.9%) and Enterococcus faecalis (9.3%). The most prevalent microorganisms in intraoperative cultures were Staphylococcus epidermidis, Cutibacterium acnes and other coagulase-negative Staphylococci (14.2%). Additional microorganisms were identified in 43.8% intraoperatively. Staphylococcus aureus was more often detected preoperatively (20.9% vs. 5.8%;P=0.003), and Cutibacterium acnes intraoperatively (2.3% vs. 14.4%;P=0.01). There were no differences between the antibiotic resistance patterns of pre- and intraoperative concordant microorganisms. Conclusion. Absence of US-determined fluid film cannot rule out the presence of hip PJI. US-guided joint aspirations is a well-established technique. However, the preoperative analysis of synovial fluid shows high discrepancies especially in Cutibacterium acnes and other rare gram-positive microorganisms compared to intraoperative cultures

Aim. The management of PJIs is slowed down by the presence of bacteria forming biofilms where they may withstand antibiotic therapy. The use of adjuvant strategies, such as hydrolytic enzymes cocktail targeting biofilm matrices and facilitating their dispersion, is a promising option to limit impact of biofilms. Our aim was to evaluate the effect of enzymes cocktail combined with antibiotic dual therapy of rifampicin and vancomycin in a relevant in-vitro model. Method. Mature methicillin-resistant Staphylococcus aureus biofilms were grown on Ti-6Al-4V coupons by adding 1mL of a 8Log10 ATCC 33591 suspension in TGN (TSB + 1% glucose + 2% NaCl) to 24-wells plates containing the coupons and incubating the plates for 24h at 37°C with a continuous 50rpm agitation. The samples were rinsed and placed in 6 wells plates containing 1ml of the enzymatic cocktail (C.D.D.) solution (tris-buffered (pH 7.0) solution of 400 U/ml of aspecific DNA/RNA endonuclease, 50 U/ml of endo-1,4-b-D-glucanase, and 0.06 U/ml of β-N-acetylhexosaminidase). 9ml of TGN or TGN containing antibiotics RIF/VAN (rifampicin 5µg/mL + vancomycin 8µg/mL) at clinically relevant concentrations found locally in bone or joints, was then added and the samples were incubated in identical conditions for 24h. The samples were then recovered and rinsed. CFU counts were obtained by recovering the bacteria with sonication, serial dilutions, and TSA plating. Biomass was determined via crystal violet staining, followed by dye solubilization in acetic acid, and absorbance measurement using a spectrophotometer. Results. Significant reductions in bacterial counts were observed in biofilms exposed to either RIF/VAN or RIF/VAN+CDD, by respectively 2,6 and 3,7Log10 when compared to samples reincubated with TGN alone (p <0.05). Additionally, CFU counts in samples exposed to RIF/VAN+CDD were reduced by 1,1Log10 when compared to those exposed to RIF/VAN (p<0,05). Significant reduction in biomass (-29,8%, p<0.05) was observed for coupons exposed to RIF/VAN+CDD when compared to C.D.D alone (figure 1). Conclusions. The concurrent utilization of enzymes with rifampicin and vancomycin, holds promise as a feasible method to address periprosthetic joint infections (PJIs). For any tables or figures, please contact the authors directly

Primary hip and knee joint replacements in Canada have been estimated to cost over $1.4 billion dollars annually, with revision surgery costing $177 million. The most common cause of revision arthroplasty surgery in Canada is infection. Periprosthetic joint infections (PJIs) are a devastating though preventable complication following arthroplasty. Though variably used, antibiotic laden bone cement (ALBC) has been demonstrated to decrease PJIs following primary total knee arthroplasty (TKA). Unfortunately, ALBC is costlier than regular bone cement (RBC). Therefore, the aim of this study was to determine if the routine use of ALBC in primary TKA surgery is a cost-effective practice from the perspective of the Canadian healthcare system. A decision tree was constructed using a decision analysis software (TreeAge Software, Williamstown, Massachusetts) to a two-year time horizon comparing primary TKA with either ALBC or RBC from the perspective of a single-payer healthcare system. All costs were in 2020 Canadian dollars. Health utilities were in the form of quality adjusted life years (QALYs). Model inputs for cost were derived from regional and national databases. Health utilities and probability parameters were derived from the latest literature. One-way deterministic sensitivity analysis was performed on all model parameters. The primary outcome of this analysis was an incremental cost-effectiveness ratio (ICER) with a willingness-to-pay (WTP) threshold of $50,000 per QALY. Primary TKA with ALBC (TKA-ALBC) was found to be more cost-effective compared to primary TKA with RBC (TKA-RBC). More specifically, TKA-ALBC dominated TKA-RBC as it was less costly on the long term ($11,160 vs. $11,118), while providing the same QALY (1.66). The ICER of this cost-utility analysis (CUA) was $-11,049.72 per QALY, much less than the WTP threshold of $50,000 per QALY. The model was sensitive to costs of ALBC-TKA as well as the probability of PJI following ALBC-TKA and RBC-TKA. ALBC ceased to be cost effective once the cost of ALBC was greater than $223.08 CAD per bag of cement. The routine use of ALBC in primary TKA is a cost-effective practice in the context of the Canadian healthcare system as long as the cost of ALBC is maintained at a reasonable price and the published studies to-date keep supporting the efficacy of ALBC in decreasing PJI following primary TKA. Further, this analysis is very conservative, and ALBC is likely much more cost-effective than presented. This is due to this model's revision surgery cost parameter being based on the average cost of all revision TKA surgery in Canada, regardless of etiology. Considering many PJIs require two-stage revisions, the cost parameter used in this analysis for revision surgery is an underestimate of true cost. Ultimately, this is the first cost-effectiveness study evaluating this topic from the perspective of the Canadian healthcare system and can inform future national guidelines on the subject matter

Aim. Synovial calprotectin point-of-care test (POC) has shown promising clinical value in diagnosing periprosthetic joint infections (PJIs). However, limited data are available in unclear cases. Moreover, cut-off values for calprotectin lateral flow assay (LFA) and enzyme-linked immunosorbent assay (ELISA) need to be adapted. The aim of this study was to evaluate the performance of an upgraded and more sensitive version of a synovial calprotectin LFA along with ELISA immunoassay in patients with septic, aseptic, and unclear cases. Methods. Overall, 206 prospectively collected periprosthetic synovial fluid samples from 169 patients (106f/63m; 38 hip/131 knee) who underwent revision surgeries were retrospectively evaluated for calprotectin concentration. The following groups were analyzed: unexpected negative cultures (UNC; 32/206), unexpected positive cultures (UPC; 28/206), and unclear cases (65/206) with conflicting clinical results. In addition, we added a true aseptic (40/206), and true septic (41/206) control groups according to the international consensus meeting (ICM) 2018 PJI classification. Calprotectin concentration was determined by a rapid quantitative LFA (n=206) (Lyfstone®, Norway), and compared to calprotectin ELISA immunoassay (171/206). For the determination of a new calprotectin cut-off value, analysis of the area under the curve (AUC) followed by Youden's J statistic were performed using the calproctectin values from clear septic and aseptic cases. Sensitivity and specificity for calprotectin were calculated. All statistical analyses were performed using IBM-SPSS® version 25 (Armonk, NY, USA). Results. An absolute calprotectin value of 43 mg/ml, and 40.15 mg/ml was determined to be the optimal cut-off for PJI diagnosis using the new version of the LFA and ELISA, respectively. With this cut-off, the sensitivity and specificity of synovial calprotectin concentration for PJI were 88.1% (95% CI 77.8 to 94.7) and 76.6% (95% CI 61.9 to 87.7) for LFA, and 97.06% (95% CI 89.8 to 99.64) and 93.6% (95% CI 82.5 to 98.66) for ELISA, respectively. Of the evaluated groups, UNC 30/32 (93.8%) vs 26/27 (96.3%), UPC 6/28 (21.4%) vs 4/21 (19%), and unclear samples 45/65 (69.2%) vs 30/56 (53.6%) displayed a high likelihood of infection by using LFA, and ELISA, respectively. Conclusion. The upgraded version of the calprotectin quantitative LFA with a new suggested cut-off for infected samples showed additional clinical value in identifying cases at high risk of infection in unclear PJI revisions. Additionally, calprotectin ELISA immunoassay had a better performance than LFA. Further large sample-size validation studies are warranted

Aim. The primary aim of this study was to examine whether the use of iodine impregnated incision drape (IIID) decreased the risk of periprosthetic joint infections (PJIs). The secondary aim was to investigate whether intraoperative contamination could predict postoperative infection. PJI is a devastating incident for the patients and in a population that is getting older and the incidence of arthroplasty surgery is rising it is vital to keep the infection rate as low as possible. Despite prophylactic measures as pre-operative decontamination, antisepsis and prophylactic antibiotics the infection rate has been constant at 1–2%. Method. We performed a transregional, prospective, randomized two arm study (IIID vs control group) of 1187 patients undergoing primary knee arthroplasty surgery. A database with patient demographics and surgical observations was established with the purpose of following the patients for ten years. Patients, who developed an infection within the first year of surgery were analyzed for correlation with the intraoperative bacterial findings and the use of IIID. Results. 31/1187 (3.6%) patients were re-operated during the follow-up period. 18/1187 (1.5%) patients were deemed infected and received antibiotic treatment. 9/18 patients deemed infected were male. Of the 18 infected patients 2 were contaminated at the primary surgery. Chi square test showed no correlation between contamination and infection (OR 0.97, 95% CI 0.38–2.46, p=0.95). 9 of the 18 infected patients were operated with IIID at the primary surgery. No correlation was found between the use of IIID at primary surgery and subsequent infection (OR 0.86, 95% CI 0.20–3.79, p=1). Conclusions. We found no effect of the use of IIID and subsequent development of PJI. Nor did we find a correlation between the intraoperative contamination and development of PJI within the first year of follow-up. Acknowledgements. University of Copenhagen and 3M Health Care (St. Paul, Minnesota) funded the study. 3M did not participate in the design of the study, data collection, data analysis or data interpretation

High-dose antibiotic-loaded acrylic cement (ALAC) is used for managing periprosthetic joint infections (PJIs). The marked increase in resistant high-virulence bacteria is drawing the attention of physicians towards alternative antimicrobial formulations to the routinely used antibiotics. To date, few studies simultaneously investigated the elution properties of a broad range of antibiotics. The aim of thepresent in-vitrostudy was to determine the elution kinetics of 14 different high-dose ALACs. All the ALAC samples showed a burst release of antibiotics in the first hour, progressively decreasing overtime, and elution curves strictly adhered to a non-linear regression analysis formula. Among aminoglycosides, commonly addressed as the most appropriate antibiotics to be loaded into the bone cement, the highest elution rate was that of tobramycin. Among the glycopeptides, commonly used to treat PJIs because of the prevalence of aminoglycoside resistance, vancomycin showed better elution in comparison with teicoplanin. Clindamycin, that can be associated with aminoglycosides to prepare ALACsshowed the highest absolute and relative elutions among all the tested formulations. A noticeable elution was also detected for colistin, an antibiotic of last resort for treating multi-drug resistant bacteria. The current study demonstrates theoretical advantages in the preparation of ALAC for some antibiotics notroutinely used in the clinical setting for PJIs. The use of these antibiotics based on the infecting bacteria sensitivity may represent an useful option for physicians to eradicate PJIs. In vivo testing should be considered in the future to confirm the results of this study

Aims

It is well described that patients with bone and joint infections (BJIs) commonly experience significant functional impairment and disability. Published literature is lacking on the impact of BJIs on mental health. Therefore, the aim of this study was to assess health-related quality of life (HRQoL) and the impact on mental health in patients with BJIs.