Aims. Treatment outcomes for methicillin-resistant Staphylococcus aureus (MRSA) periprosthetic joint infection (PJI) using systemic vancomycin and antibacterial cement spacers during two-stage revision arthroplasty remain unsatisfactory. This study explored the efficacy and safety of intra-articular vancomycin injections for PJI control after debridement and cement spacer implantation in a rat model. Methods. Total knee arthroplasty (TKA), MRSA inoculation, debridement, and vancomycin-spacer implantation were performed successively in rats to mimic first-stage PJI during the two-stage revision arthroplasty procedure. Vancomycin was administered intraperitoneally or intra-articularly for two weeks to control the infection after debridement and spacer implantation. Results. Rats receiving intra-articular vancomycin showed the best outcomes among the four treatment groups, with negative bacterial cultures, increased weight gain, increased capacity for weightbearing activities, increased residual bone volume preservation, and reduced inflammatory reactions in the joint tissues, indicating MRSA eradication in the knee. The vancomycin-spacer and/or systemic vancomycin failed to eliminate the MRSA infections following a two-week antibiotic course. Serum vancomycin levels did not reach nephrotoxic levels in any group. Mild renal histopathological changes, without changes in serum creatinine levels, were observed in the intraperitoneal vancomycin group compared with the intra-articular vancomycin group, but no changes in hepatic structure or serum alanine aminotransferase or aspartate aminotransferase levels were observed. No local complications were observed, such as sinus tract or non-healing surgical incisions. Conclusion. Intra-articular vancomycin injection was effective and safe for PJI control following debridement and spacer implantation in a rat model during two-stage revision arthroplasties, with better outcomes than systemic vancomycin administration. Cite this article: Bone Joint Res 2022;11(6):371–385

Aims. Prompt and sufficient broad-spectrum empirical antibiotic treatment is key to preventing infection following open tibial fractures. Succeeding co-administration, we dynamically assessed the time for which vancomycin and meropenem concentrations were above relevant epidemiological cut-off (ECOFF) minimal inhibitory concentrations (T > MIC) in tibial compartments for the bacteria most frequently encountered in open fractures. Low and high MIC targets were applied: 1 and 4 µg/ml for vancomycin, and 0.125 and 2 µg/ml for meropenem. Methods. Eight pigs received a single dose of 1,000 mg vancomycin and 1,000 mg meropenem simultaneously over 100 minutes and 10 minutes, respectively. Microdialysis catheters were placed for sampling over eight hours in tibial cancellous bone, cortical bone, and adjacent subcutaneous adipose tissue. Venous blood samples were collected as references. Results. Across the targeted ECOFF values, vancomycin displayed longer T > MIC in all the investigated compartments in comparison to meropenem. For both drugs, cortical bone exhibited the shortest T > MIC. For the low MIC targets and across compartments, mean T > MIC ranged between 208 and 449 minutes (46% to 100%) for vancomycin and between 189 and 406 minutes (42% to 90%) for meropenem. For the high MIC targets, mean T > MIC ranged between 30 and 446 minutes (7% to 99%) for vancomycin and between 45 and 181 minutes (10% to 40%) for meropenem. Conclusion. The differences in the T > MIC between the low and high targets illustrate how the interpretation of these results is highly susceptible to the defined MIC target. To encompass any trauma, contamination, or individual tissue differences, a more aggressive dosing approach may be considered to achieve longer T > MIC in all the exposed tissues, and thereby lower the risk of acquiring an infection after open tibial fractures. Cite this article: Bone Joint Res 2022;11(2):112–120

Aims. The efficacy and safety of intrawound vancomycin for preventing surgical site infection in primary hip and knee arthroplasty is uncertain. Methods. A systematic review of the literature was conducted, indexed from inception to March 2020 in PubMed, Web of Science, Cochrane Library, Embase, and Google Scholar databases. All studies evaluating the efficacy and/or safety of intrawound vancomycin in patients who underwent primary hip and knee arthroplasty were included. Incidence of periprosthetic joint infection (PJI), superficial infection, aseptic wound complications, acute kidney injury, anaphylactic reaction, and ototoxicity were meta-analyzed. Results were reported as odds ratios (ORs) and 95% confidence intervals (CIs). The quality of included studies was assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) assessment tool. Results. Nine studies involving 4,607 patients were included. Intrawound vancomycin was associated with lower incidence of PJI (30 patients (1.20%) vs 58 control patients (2.75%); OR 0.44, 95% CI 0.28 to 0.69) and simultaneous acute kidney injury (four patients (0.28%) vs four control patients (0.35%), OR 0.71, 95% CI 0.19 to 2.55). However, it did not reduce risk of superficial infection (four patients (0.67%) vs six control patients (1.60%), OR 0.60, 95% CI 0.17 to 2.12) and was associated with higher incidence of aseptic wound complications (23 patients (2.15%) vs eight in control patients (0.96%), OR 2.39, 95% CI 1.09 to 5.23). Four studies reported no anaphylactic reactions and three studies reported no ototoxicity in any patient group. Conclusion. The current literature suggests that intrawound vancomycin used in primary hip and knee arthroplasty may reduce incidence of PJI, but it may also increase risk of aseptic wound complications. Cite this article: Bone Joint Res 2020;9(11):778–788

Objectives. The aim of this study was to analyze drain fluid, blood, and urine simultaneously to follow the long-term release of vancomycin from a biphasic ceramic carrier in major hip surgery. Our hypothesis was that there would be high local vancomycin concentrations during the first week with safe low systemic trough levels and a complete antibiotic release during the first month. Methods. Nine patients (six female, three male; mean age 75.3 years (sd 12.3; 44 to 84)) with trochanteric hip fractures had internal fixations. An injectable ceramic bone substitute, with hydroxyapatite in a calcium sulphate matrix, containing 66 mg of vancomycin per millilitre, was inserted to augment the fixation. The vancomycin elution was followed by simultaneously collecting drain fluid, blood, and urine. Results. The antibiotic concentration in the drain reached a peak during the first six hours post-surgery (mean 966.1 mg/l), which decreased linearly to a mean value of 88.3 mg/l at 2.5 days. In the urine, the vancomycin concentration reached 99.8 mg/l during the first two days, followed by a logarithmic decrease over the next two weeks to reach 0 mg/l at 20 days. The systemic concentration of vancomycin measured in blood serum was low and decreased linearly from 2.17 mg/l at one hour post-surgery to 0 mg/l at four days postoperatively. Conclusion. This is the first long-term pharmacokinetic study that reports vancomycin release from a biphasic injectable ceramic bone substitute. The study shows initial high targeted local vancomycin levels, sustained and complete release at three weeks, and systemic concentrations well below toxic levels. The plain ceramic bone substitute has been proven to regenerate bone but should also be useful in preventing bone infection. Cite this article: M. Stravinskas, M. Nilsson, A. Vitkauskiene, S. Tarasevicius, L. Lidgren. Vancomycin elution from a biphasic ceramic bone substitute. Bone Joint Res 2019;8:49–54. DOI: 10.1302/2046-3758.82.BJR-2018-0174.R2

Anterior cruciate ligament injury is the most common and economically costly sport injuries, frequently requiring expensive surgery and rehabilitation. Post-operative knee septic arthritis represents a serious complication with an incidence rate between 0.14% and 1.7%. A common practice to avoid septic arthritis is the “vancomycin wrap”, consisting in the soaking of the graft for 10–15 minutes within a sterile gauze swab previously saturated with 5 mg/mL vancomycin. Even though several studies have been conducted to investigate vancomycin toxicity on different musculoskeletal tissues or cells, little is known about the effect of such antimicrobial on tendon-derived cells. The aim of this study was to determine the in vitro toxicity of different concentrations of vancomycin at different time points on human primary tenocytes (hTCs). hTCs were isolated from hamstring grafts of patients undergoing anterior cruciate ligament reconstruction. After expansion, cells were treated with different concentrations of vancomycin (2.5, 5, 10, 25, 50 and 100 mg/mL) for 10, 15, 30 and 60 minutes. In vitro toxicity was evaluated measuring: metabolic activity through the reduction of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT Assay); cytotoxicity (Live/Dead assay); and cell apoptosis (Annexin V apoptosis kit). The metabolic activity of hTCs was affected by vancomycin treatment starting from 10 mg/mL at all time points (p < 0.05) and dropped down at 100 mg/mL at all time points (0.05 < p < 0.001). Cells viability resulted to be unaffected only by 2.5 mg/mL vancomycin at all time points. Vancomycin resulted to be cytotoxic starting from 10 mg/mL after 15 minutes of treatment and at all higher concentrations under study at all time points. Cells died when treated with vancomycin concentrations higher than 5 mg/mL but not through apoptosis, as confirmed by negative staining for Annexin V. In our experimental conditions, vancomycin resulted to be toxic on hTCs at concentrations higher than 5 mg/mL. The use of this antibiotic on tendons to prevent infections could be useful and safe for resident cells if used at a concentration of 2.5 mg/mL up to 1 hour of treatment

Aims. Periprosthetic joint infections (PJIs) are rare, but represent a great burden for the patient. In addition, the incidence of methicillin-resistant Staphylococcus aureus (MRSA) is increasing. The aim of this rat experiment was therefore to compare the antibiotics commonly used in the treatment of PJIs caused by MRSA. Methods. For this purpose, sterilized steel implants were implanted into the femur of 77 rats. The metal devices were inoculated with suspensions of two different MRSA strains. The animals were divided into groups and treated with vancomycin, linezolid, cotrimoxazole, or rifampin as monotherapy, or with combination of antibiotics over a period of 14 days. After a two-day antibiotic-free interval, the implant was explanted, and bone, muscle, and periarticular tissue were microbiologically analyzed. Results. Vancomycin and linezolid were able to significantly (p < 0.05) reduce the MRSA bacterial count at implants. No significant effect was found at the bone. Rifampin was the only monotherapy that significantly reduced the bacterial count on implant and bone. The combination with vancomycin or linezolid showed significant efficacy. Treatment with cotrimoxazole alone did not achieve a significant bacterial count reduction. The combination of linezolid plus rifampin was significantly more effective on implant and bone than the control group in both trials. Conclusion. Although rifampicin is effective as a monotherapy, it should not be used because of the high rate of resistance development. Our animal experiments showed the great importance of combination antibiotic therapies. In the future, investigations with higher case numbers, varied bacterial concentrations, and changes in individual drug dosages will be necessary to be able to draw an exact comparison, possibly within a clinical trial. Cite this article: Bone Joint Res 2022;11(3):143–151

Objectives. The most concerning infection of allografts and operative procedures is methicillin resistant Staphylococcus aureus (MRSA) and no current iontophoresed antibiotics effectively combat this microbe. It was initially hypothesised that iontophoresis of vancomycin through bone would not be effective due to its large molecular size and lack of charge. The aim of this study was to determine whether this was a viable procedure and to find the optimum conditions for its use. . Methods. An iontophoresis cell was set up with varying concentrations of Vancomycin within the medulla of a section of sheep tibia, sealed from an external saline solution. The cell was run for varying times, Vancomycin concentrations and voltages, to gain information on optimisation of conditions for impregnating the graft. Each graft was then sectioned and dust ground from the exposed surface. The dust was serially washed to extract the Vancomycin and concentrations measured and plotted for all variables tested. Results. Vancomycin was successfully delivered and impregnated to the graft using the iontophoresis technique. The first order fit to the whole data set gave a significant result (p = 0.0233), with a significant concentration (p = 0.02774) component. The time component was the next most significant (p = 0.0597), but did not exceed the 95% confidence level. Conclusions. Iontophoresis is an effective method for delivering Vancomycin to allograft bone. The concentrations of the vancomycin solution affected the bone concentration, but results were highly variable. Further study should be done on the effectiveness of delivering different antibiotics using this method. Cite this article: Bone Joint Res 2014;3:101–7

Objectives. Vancomycin and fosfomycin are antibiotics commonly used to treat methicillin-resistant Staphylococcus aureus (MRSA) infection. This study compares the in vitro inhibitory effects against MRSA of articulating cement spacers impregnated with either vancomycin or fosfomycin. Methods. Vancomycin-impregnated articulating cement spacers and fosfomycin-impregnated articulating cement spacers were immersed in sterile phosphate-buffered saline (PBS) solutions and then incubated. Samples were collected for bioactivity evaluation. The aliquots were tested for MRSA inhibition with the disc diffusion method, and the inhibition zone diameters were measured. The inhibition zone differences were evaluated using the Wilcoxon Rank Sum Test. Results. The vancomycin group had significantly larger inhibition zones than the fosfomycin group from day three through to completion of the fourth week of incubation (p < 0.001). The vancomycin group exhibited a MRSA inhibition zone up to four weeks but the fosfomycin group showed an inhibition zone for only three days and after that did not show the the potential to inhibit MRSA. Conclusion. This in vitro study found that the inhibitory effect of vancomycin-impregnated articulating cement spacers against MRSA outperformed fosfomycin-impregnated articulating cement spacers. Further comparing our results to other published reports suggests there might be a limitation of the disc diffusion bioassay to show a large inhibitory zone in a high concentration of a highly soluble antibiotic. Cite this article: V. Yuenyongviwat, N. Ingviya, P. Pathaburee, B. Tangtrakulwanich. Inhibitory effects of vancomycin and fosfomycin on methicillin-resistant Staphylococcus aureus from antibiotic-impregnated articulating cement spacers. Bone Joint Res 2017;6:132–136. DOI: 10.1302/2046-3758.63.2000639

Aims. Calcium sulphate (CaSO. 4. ) is a resorbable material that can be used simultaneously as filler of a dead space and as a carrier for the local application of antibiotics. Our aim was to describe the systemic exposure and the wound fluid concentrations of vancomycin in patients treated with vancomycin-loaded CaSO. 4. as an adjunct to the routine therapy of bone and joint infections. Patients and Methods. A total of 680 post-operative blood and 233 wound fluid samples were available for analysis from 94 implantations performed in 87 patients for various infective indications. Up to 6 g of vancomycin were used. Non-compartmental pharmacokinetic analysis was performed on the data from 37 patients treated for an infection of the hip. Results. The overall systemic exposure remained within a safe range, even in patients with post-operative renal failure, none requiring removal of the pellets. Local concentrations were approximately ten times higher than with polymethylmethacrylate (PMMA) as a carrier, but remained below reported cell toxicity thresholds. Decreasing concentrations in wound fluid were observed over several weeks, but remained above the common minimum inhibitory concentrations for Staphylococcus up to three months post-operatively. . Conclusion. This study provides the first pharmacokinetic description of the local application of vancomycin with CaSO. 4. as a carrier, documenting slow release, systemic safety and a release profile far more interesting than from PMMA. In particular, considering in vitro data, concentrations of vancomycin active against staphylococcal biofilm were seen for several weeks. Cite this article: Bone Joint J 2017;99-B:1537–44

Aim. The use of bone substitutes such as calcium sulfate (CaSO4) and hydroxyapatite with local antibiotics are crucial in the treatment of osteomyelitis. They allow the treatment of the dead space and locally provide large concentrations of antibiotics. However, it is unknown whether use of local vancomycin may elute and influence on vancomycin plasma levels. The aim of this study is to assess whether the addition of vancomycin to CaSO4 with hydroxyapatite may increase vancomycin plasma concentrations in in patients with osteomyelitis and therefore alter dosage adjustments. Method. The present study investigates the vancomycin plasma concentrations at 72–94 h post-surgery after the application of local vancomycin within CaSO4 (660mg vancomycin/10cc) and hydroxyapatite bone substitute in patients treated with empiric intravenous vancomycin and surgically treated for osteomyelitis. Vancomycin plasma concentrations were analyzed in twelve patients with osteomyelitis surgically treated with local release of vancomycin by CaSO4 and hydroxyapatite and undergoing therapeutic drug monitoring (TDM) of their vancomycin plasma concentrations as it is routinely done in our hospital. From 2019 to 2022, demographic data, microbiology, type of osteomyelitis, amount of local vancomycin applied, alteration of renal function, and vancomycin levels were retrospectively analyzed. Results. Twelve patients were included: 9(75%) were men. Median (range) demographic and clinical data: age: 51(26–67) years; body mass index: 27.7(18–46.4) kg/m2;baseline serum creatinine: 0.85 (0.7–1.24)mg/dl and 5(41.7%) with and glomerular filtration rate < 90ml/min(CPD-EPI, ml/min). Most frequently isolated microorganisms were Staphylococci (58%). Seven (54%) patients were classified as Cierny-Mader Osteomyelitis type III, 3(23%) as type IV and 2(23%) as type I. Treatment data: initial dose of vancomycin: 1g/8h in 9(75.0%) and 1g/12h in 3(25%) patients, total daily dose/body weight: 35.3(15.9–46.2) mg/kg. Pharmacokinetic data:days of iv vancomycin treatment until first TDM measurement: 3(3–4) days; minimum and maximum vancomycin plasma concentrations: 9.4(3–17.3) mg/L and 19.6(11.3–33.4) mg/L, respectively; patients with therapeutic concentrations: 6(50%); infratherapeutic: 4(33.3%) and supratherapeutic/potentially toxic: 2(16.7%). These 2 patients were young, had a baseline conserved renal function and were receiving the higher dose of 1g/8h. Conclusions. Vancomycin incorporated into the bone substitute appears not to increase blood concentrations of the glycopeptide in patients with osteomyelitis treated surgically and with intravenous vancomycin. However, 2 of the 12 patients presented supratherapeutic and potentially nephrotoxic vancomycin concentrations in the first TDM measurement, even though they were young and without renal impairment and needed and unexpected dose reduction. These results suggest the need to confirm the safety of local vancomycin in further larger clinical studies

Topically applied vancomycin powder has been used to decrease surgical site infection rates in spinal surgeries, however, randomized controlled trials in total joint arthroplasty are lacking. Application of vancomycin powder topically in the surgical site has theoretical benefit including high local concentration. In this study, we aimed to determine whether intra-operative topical antibiotics are safe and effective as IV antibiotics in preventing post-surgical site infections. The trial was a randomized controlled, double blind, non-inferiority study. All patients received pre-operative IV antibiotics (cefazolin or vancomycin) within 60 minutes of skin incision. The controlled group received two doses of post-operative IV antibiotics (two grams cefazolin or one gram vancomycin if cefazolin allergy). In the treatment group, the orthopaedic surgeon applied one gram vancomycin powder (500mg applied directly on the prosthesis and 500mg applied above the closed joint capsule). The incidence of acute surgical site infection was defined as positive deep cultures within 42 days of procedure. All patients with evidence of infection underwent joint aspiration for culture. After one year, 80 patients had received the topical vancomycin treatment and 85 patients had received the standard treatment. In the topical vancomycin group versus the controlled group, the average age was 64 vs 66, average BMI was 35.7 vs 33.4, number of males 33 vs 29, number of females 47 vs 56, and diabetic patients 16 vs 13. The number of infections in the topical vancomycin group was three vs zero in the post-operative IV antibiotic treatment group. One Tailed Z-test P Value = 0.03. This study statistically demonstrated inferiority of topical vancomycin in comparison to the use of IV antibiotics post-operatively in preventing deep wound infections in TKA. The authors would caution against the sole use of intra-operative vancomycin in TKA to prevent post-operative infection

Aims. Intra-articular administration of antibiotics during primary total knee arthroplasty (TKA) may represent a safe, cost-effective strategy to reduce the risk of acute periprosthetic joint infection (PJI). Vancomycin with an aminoglycoside provides antimicrobial cover for most organisms isolated from acute PJI after TKA. However, the intra-articular doses required to achieve sustained therapeutic intra-articular levels while remaining below toxic serum levels is unknown. The purpose of this study is to determine the intra-articular and serum levels of vancomycin and tobramycin over the first 24 hours postoperatively after intra-articular administration in primary cementless TKA. Methods. A prospective cohort study was performed. Patients were excluded if they had poor renal function, known allergic reaction to vancomycin or tobramycin, received intravenous vancomycin, or were scheduled for same-day discharge. All patients received 600 mg tobramycin and 1 g of vancomycin powder suspended in 25 cc of normal saline and injected into the joint after closure of the arthrotomy. Serum from peripheral venous blood and drain fluid samples were collected at one, four, and 24 hours postoperatively. All concentrations are reported in µg per ml. Results. A total of 22 patients were included in final analysis. At one, four, and 24 hours postoperatively, mean (95% confidence interval (CI)) serum concentrations were 2.4 (0.7 to 4.1), 5.0 (3.1 to 6.9), and 4.8 (2.8 to 6.9) for vancomycin and 4.9 (3.4 to 6.3), 7.0 (5.8 to 8.2), and 1.3 (0.8 to 1.8) for tobramycin; intra-articular concentrations were 1,900.6 (1,492.5 to 2,308.8), 717.9 (485.5 to 950.3), and 162.2 (20.5 to 304.0) for vancomycin and 2,105.3 (1,389.9 to 2,820.6), 403.2 (266.6 to 539.7), and 98.8 (0 to 206.5) for tobramycin. Conclusion. Intra-articular administration of 1 g of vancomycin and 600 mg of tobramycin as a solution after closure of the arthrotomy in primary cementless TKA achieves therapeutic intra-articular concentrations over the first 24 hours postoperatively and does not reach sustained toxic levels in peripheral blood. Cite this article: Bone Joint J 2021;103-B(11):1702–1708

Periprosthetic joint infection (PJI) occurs in 0.2-2% of primary hip and knee arthroplasty and is a leading cause of revision surgery, impaired function, and increased morbidity and mortality. Topical, intrawound vancomycin administration allows for high local drug concentrations at the surgical site and has demonstrated good results in prevention of surgical site infection after spinal surgery. It is a promising treatment to prevent infection following hip and knee arthroplasty. Prior studies have been limited by small sample sizes and the low incidence of PJI. This systematic review and meta-analysis was performed to determine the effectiveness of topical vancomycin for the primary prevention of PJI in hip and knee arthroplasty. A search of Embase, MEDLINE, and PubMed databases as of June 2020 was performed according to PRISMA guidelines. Studies comparing topical vancomycin to standard perioperative intravenous antibiotics in primary THA and TKA with a minimum of three months follow-up were identified. The results from applicable studies were meta-analysed to determine the impact of topical vancomycin on PJI rates as well as wound-related and overall complications. Results were expressed as odds ratios (ORs) and 95% confidence intervals. Nine comparative observational studies were eligible for inclusion. 3371 patients treated with 0.5-2g of topical vancomycin were compared to 2884 patients treated with standard care. Only one of nine studies found a significantly lower rate of PJI after primary THA or TKA (OR 0.09-1.97, p=0.04 for one study, p>0.05 for eight of nine studies), though meta-analysis showed a significant benefit, with vancomycin lowering PJI rates from 1.6% in controls to 0.7% in the experimental group (OR 0.47, p=0.02, Figure 1). Individually, only one of five studies showed a significant benefit to topical vancomycin in THA, while none of seven studies investigating PJI after TKA showed a benefit to topical vancomycin. In meta-analysis of our subgroups, there was a significant reduction in PJI with vancomycin in THA (OR 0.34, p=0.04), but there was no significant difference in PJI after TKA (OR 0.60, p = 0.13). In six studies which reported complication rates other than PJI, there were no significant differences in overall complication rates with vancomycin administration for any study individually (OR 0.48-0.94, p>0.05 for all studies), but meta-analysis found a significant difference in complications, with a 6.7% overall complication rate in controls compared to 4.8% after topical vancomycin, largely driven by a lower PJI incidence (OR 0.76, p=0.04). Topical vancomycin is protective against PJI after hip and knee arthroplasty. No increase in wound-related or overall complication rates was found with topical vancomycin. This meta-analysis is the largest to date and includes multiple recent comparative studies while excluding other confounding interventions (such as povidone-iodine irrigation). However, included studies were predominantly retrospective and no randomized-controlled trials have been published. The limited evidence summarized here indicates topical vancomycin may be a promising modality to decrease PJI, but there is insufficient evidence to conclusively show a decrease in PJI or to demonstrate safety. A prospective, randomized-controlled trial is ongoing to better answer this question. For any figures or tables, please contact the authors directly

While pre-soaking grafts in vancomycin has demonstrated to be effective in observational studies for anterior cruciate ligament reconstruction (ACLR) infection prevention, the economic benefit of the technique is uncertain. The primary aim of this study was to determine the cost-effectiveness of vancomycin pre-soaking during primary ACLR to prevent post-operative joint infections. The secondary aims of the study were to establish the breakeven cost-effectiveness threshold of the technique. A Markov model was used to determine cost effectiveness and the incremental cost effectiveness ratio of additional vancomycin pre-soaking compared to intravenous antibiotic prophylaxis alone. A repeated meta-analysis of nine cohort studies (Level III evidence) was completed to determine the odds ratio of infection with vancomycin pre-soaking compared to intravenous antibiotics alone. Estimated costs and transitional probabilities for further surgery were obtained from the literature. Breakeven threshold analysis was performed. The vancomycin soaking technique provides an expected cost saving of $600AUD per patient. There was an improvement in the quality-adjusted life years of 0.007 compared to intravenous antibiotic prophylaxis alone (4.297 versus 4.290). If the infection rate is below 0.023% with intravenous antibiotics alone or the additional intervention cost more than $1000AUD, the vancomycin wrap would no longer be cost-effective. For $30AUD, the vancomycin soaking technique provides a $600AUD cost saving by both reducing the risk of ACLR related infection and economic burden of infection. Treating septic arthritis represents a mean cost per patient of 6 times compared to that of the primary surgery. There has been no previous cost-effectiveness study of the vancomycin wrap technique. The vancomycin pre-soaking technique is a highly cost-effective method to prevent post-operative septic arthritis following primary ACLR

Aim. Vancomycin is frequently used for bone and joint infections (BJI) because of the main role of Gram-positive bacteria as potential causal agents. It is crucial to achieve optimal vancomycin plasma concentrations since the first day to maximize treatment clinical and microbiological efficacy. The aim was to describe the patients’ profile that are more likely to achieve an optimal pharmacokinetic/pharmacodynamics (PK/PD) vancomycin target in the first therapeutic drug monitoring (TDM) sample. Methods. Retrospective study (March 2018-January 2022) in a university hospital including all patients treated with vancomycin for a BJI and undergoing TDM. Initial dose (1g/8-12h) was selected by the responsible clinician. Vancomycin plasma concentrations were obtained pre-dose (Cmin,ss) and 60-minutes after the infusion on day 2 of treatment. Global exposure measured by the area under the curve of plasma concentrations during 24h (AUC024h) was estimated using a bicompartmental PK model. An AUC024h/CMI=400–600mg*h/L was considered optimal, <400 infratherapeutic and >600 supratherapeutic, based on recent guidelines, and patients were classified into these 3 groups. A value of CMI=1 mg/L was considered, following guidelines recommendations. Categorial data: percentages and quantitative data as mean (standard deviation). Results. Ninety-five patients were included: 22(23.2%), 43(45.3%) and 30(31.6%) presented an infratherapeutic, optimal and supratherapeutic PKPD target, respectively. Medium age was 75,8(13,5) in the supratherapeutic group versus 57,2(16,3) in the infratherapeutic group. Weight (kg) was higher in the infratherapeutic group 80,8(18,4) versus 66,8(15,5) in the supratherapeutic group. Vancomycin dose (mg/kg/d) was 43,5(12,4) in the supratherapeutic group versus 34,5(10,8) in the infratherapeutic group. There were 17(56,7) patients who received 1g/8h of vancomycin in the supratherapeutic group and 6 (27,3) in the infratherapeutic group. Baseline glomerular filtration rate (BGF (CKD-EPI) (mL/min/1.73m2) was 71,5(20,1) in the supratherapeutic group and 100,0 (19,9) in the infratherapeutic group. The AUC24h/CMI was 788,0(186,1) in the supratherapeutic group and 323,7(55,4) in the infratherapeutic group. Significant differences observed in age, body weight (BW), baseline renal function and dose/frequency of vancomycin. Dosage adjustments recommendations were made in 62(65.3%) patients: 31(32.6%) dose-increase, 29(30.5%) reduction and 2 cases (2.1%) a temporary suspension. Conclusions. Less than 50% of patients achieved an optimal exposure of vancomycin on day 2 of treatment. Patients with infratherapeutic levels had a younger age and a higher body weight and glomerular filtration rate. In addition, they had received a lower vancomycin initial dose. On the contrary, a potentially toxic exposure was observed within older patients with impaired baseline renal function. These data suggest the relevance of an early vancomycin TDM for optimizing the treatment of BJI

The routine use of intraoperative vancomycin powder to prevent postoperative wound infections has not been borne out in the literature in the pediatric spine population. The goal of this study is to determine the impact of vancomycin powder on postoperative wound infection rates and determine its potential impact on microbiology. A retrospective analysis of the Harms Study Group database of 1269 adolescent idiopathic scoliosis patients was performed. Patients that underwent a posterior fusion from 2004-2018 were analyzed. A comparative analysis of postoperative infection rates was done between patients that received vancomycin powder to those who did not. Statistical significance was determined using Chi-squared test. Additionally, the microbiology of infected patients was examined. In total, 765 patients in the vancomycin group (VG) were compared to 504 patients in the non-vancomycin group (NVG). NVG had a significantly higher rate of deep wound infection (p<0.0001) and associated reoperation rate compared to VG (p<0.0001). Both groups were compared for age, gender, race, weight, surgical time, blood loss, number of levels instrumented, and preop curve magnitude. There were significant differences between the groups for race (p<0.0001); surgical time (p=0.0033), and blood loss (p=0.0021). In terms of microbiology, VG grew p.acnes (n=2), and serratia (n=1), whereas NVG grew p.acnes (n=1) and gram positive bacilli (n=1). The remaining cultures were negative. The use of intraoperative vancomycin powder in adolescent idiopathic scoliosis appears to contribute significantly to deep wound infection prevention and reduction of associated reoperations. Based on this study's limited culture data, Vancomycin does not seem to alter the microbiology of deep wound infections

Aims. Poly(methyl methacrylate) (PMMA)-based bone cements are the industry standard in orthopaedics. PMMA cement has inherent disadvantages, which has led to the development and evaluation of a novel silorane-based biomaterial (SBB) for use as an orthopaedic cement. In this study we test both elution and mechanical properties of both PMMA and SBB, with and without antibiotic loading. Methods. For each cement (PMMA or SBB), three formulations were prepared (rifampin-added, vancomycin-added, and control) and made into pellets (6 mm × 12 mm) for testing. Antibiotic elution into phosphate-buffered saline was measured over 14 days. Compressive strength and modulus of all cement pellets were tested over 14 days. Results. The SBB cement was able to deliver rifampin over 14 days, while PMMA was unable to do so. SBB released more vancomycin overall than did PMMA. The mechanical properties of PMMA were significantly reduced upon rifampin incorporation, while there was no effect to the SBB cement. Vancomycin incorporation had no effect on the strength of either cement. Conclusion. SBB was found to be superior in terms of rifampin and vancomycin elution. Additionally, the incorporation of these antibiotics into SBB did not reduce the strength of the resultant SBB cement composite whereas rifampin substantially attenuates the strength of PMMA. Thus, SBB emerges as a potential weight-bearing alternative to PMMA for the local delivery of antibiotics. Cite this article: Bone Joint Res 2021;10(4):277–284

Aims. Infection complicating primary total knee arthroplasty (TKA) is a common reason for revision surgery, hospital readmission, patient morbidity, and mortality. Increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA) is a particular concern. The use of vancomycin as prophylactic agent alone or in combination with cephalosporin has not demonstrated lower periprosthetic joint infection (PJI) rates, partly due to timing and dosing of intravenous (IV) vancomycin administration, which have proven important factors in effectiveness. This is a retrospective review of a consecutive series of primary TKAs examining incidence of PJI, adverse reactions, and complications using IV versus intraosseous (IO) vancomycin at 30-day, 90-day, and one-year follow-up. Methods. A retrospective review of 1,060 patients who underwent TKA between May 2016 to July 2020 was performed. There were 572 patients in the IV group and 488 in the IO group, with minimal 30 days of follow-up. Patients were followed up at regularly scheduled intervals (two, six, and 12 weeks). No differences between groups for age, sex, BMI, or baseline comorbidities existed. The IV group received an IV dose of 15 mg/kg vancomycin given over an hour preceding skin incision. The IO group received a 500 mg dose of vancomycin mixed in 150 ml of normal saline, injected into proximal tibia after tourniquet inflation, before skin incision. All patients received an additional dose of first generation cephalosporin. Evaluation included preoperative and postoperative serum creatinine values, tourniquet time, and adverse reactions attributable to vancomycin. Results. Incidence of PJI with minimum 90-day follow-up was 1.4% (eight knees) in the IV group and 0.22% (one knee) in IO group (p = 0.047). This preliminary report demonstrated an reduction in the incidence of infection in TKA using IO vancomycin combined with a first-generation cephalosporin. While the study suffers from limitations of a retrospective, multi-surgeon investigation, early findings are encouraging. Conclusion. IO delivery of vancomycin after tourniquet inflation is a safe and effective alternative to IV administration, eliminating the logistical challenges of timely dosing. Cite this article: Bone Joint J 2021;103-B(6 Supple A):13–17

Aim. The rise of multidrug-resistant bacteria and the decreasing efficacy of antibiotic therapy in successfully treating biofilm-associated infections are prompting the exploration of alternative treatment options. This study investigates the efficacy of different bioactive glass (BAG) formulations - alone or combined with vancomycin - to eradicate biofilm. Further, we study the influence of BAG on pH and osmotic pressure as important factors limiting bacterial growth. Method. Different BAG-S53P4 formulations were used for this study, including (a) BAG-powder (<45 μm), (b) BAG-granules (500–800 μm), (c) a cone-shaped BAG-scaffold and (d) two kinds of BAG-putty containing granules, with no powder (putty-A) or with additional powder (putty-B), and a synthetic binder. Inert glass beads were included as control. All formulations were tested in a concentration of 1750 g/ml in Müller-Hinton-Broth. Targeted bacteria included methicillin-resistant Staphylococcus aureus (MRSA) and epidermidis (MRSE). Vancomycin was tested at the minimum-inhibitory-concentration for each strain (1 µg/ml for MRSA; 2 μg/ml for MRSE). To investigate the antibiofilm effect of BAG alone or combined with vancomycin, 3 hour-old MRSA or MRSE biofilms were formed on porous glass beads and exposed to BAG ± vancomycin for 24h, 72h and 168h. After co-incubation, biofilm-beads were deep-washed in phosphate-buffered saline and placed in glass vials containing fresh medium. Recovering biofilm bacteria were detected by measuring growth-related heat production at 37°C for 24h by isothermal microcalorimetry. Changes in pH and osmotic pressure over time were assessed after co-incubation of each BAG formulation in Müller-Hinton-Broth for 0h, 24h, 72h and 168h. Results. All BAG formulations showed antibiofilm activity against MRSA and MRSE in a time-dependent manner, where longer incubation times revealed higher antibiofilm activity. BAG-powder and BAG-putty-B were the most effective formulations suppressing biofilm, followed by BAG-granules, BAG-scaffold and finally BAG-putty-A. The addition of vancomycin had no substantial impact on biofilm suppression. An increase in pH and osmotic pressure over time could be observed for all BAG formulations. BAG-powder reached the highest pH value of 12.5, whereas BAG-putty-A resulted in the lowest pH of 9. Both BAG-putty formulations displayed the greatest increase on osmotic pressure. Conclusions. BAG-S53P4 has demonstrated efficient biofilm suppression against MRSA and MRSE, especially in powder-containing formulations. Our data indicates no additional antibiofilm improvement with addition of vancomycin. Moreover, high pH appears to have a larger antimicrobial impact than high osmolarity. Acknowledgements. This work was supported by PRO-IMPLANT Foundation (Berlin, Germany). The tested materials were provided by Bonalive Biomaterials Ltd (Turku, Finland)

Aim. Bacteriophages are remerging as alternative and adjunctive therapy for fracture-related infection (FRI). However, current administration protocols involve prolonged retention of a percutaneous draining tube with potential risk of developing superinfection. In this study, we applied a cocktail of in vitro evolved biofilm-targeting phages for Methicillin-resistant Staphylococcus aureus (MRSA) in a hydrogel platform co-delivering vancomycin. In vitro synergy and antibiofilm activity was assessed and a subsequent in vivo study was performed in a mouse FRI model with MRSA. Method. Two evolved bacteriophages (MRSA-R14 and COL-R23) with improved antibiofilm activity against a clinical isolate (MRSA3) were tested in combination with vancomycin and a carboxymethylcellulose (CMC) hydrogel in vitro and in vivo. MRSA3 bacterial biofilms were formed on sterile 4 mm sintered porous glass beads at 37 °C for 24 h. Biofilms were exposed to i-phage cocktail (10. 7. PFU/ml), ii-vancomycin at concentrations of 0.5, 1, 10 and 100 times the MIC, or iii-combination of phage cocktail and vancomycin. Recovered biofilm cells, were quantified by colony counting. The stability and release profiles of phage cocktail and vancomycin in co-delivery hydrogel were assessed in vitro for 8 days and 72 hrs, respectively, and subsequently tested in the treatment of 5-day-old MRSA3 infection of a femoral plate osteotomy in mice. Results. In vitro: The cocktail of evolved phages (10. 7. PFU/ml, 1:1) combined with 0.5 MIC vancomycin achieved 99.72% reduction in MRSA3 biofilm in vitro compared to the growth control. This combination was stable in the co-delivery hydrogel over 8 days. The release profile showed that 57% of phages and 80% of vancomycin were released after 72hrs, which was identical to the performance for gels loaded with phage or antibiotic alone. In the in vivo study, the bacterial load from animals that received co-delivery hydrogel and systemic vancomycin was significantly reduced compared to controls, animals that received systemic vancomycin and animals that received co-delivery hydrogel alone (p<0.05). Conclusions. Our study demonstrates the potential of using evolved phages in combination with vancomycin and hydrogel delivery systems for the treatment of MRSA-related infections. Further research in this area may lead to the development of specific therapies for biofilm-related infection

There is an increasing incidence of revision for periprosthetic joint infection. The addition of vancomycin to beta-lactam antimicrobial prophylaxis in joint arthroplasty may reduce surgical site infections, however, the efficacy and safety have not been established. This was a multicenter, double-blind, superiority, placebo-controlled trial. We randomized 4239 adult patients undergoing joint arthroplasty surgery to receive 1.5g vancomycin or normal saline placebo, in addition to standard cefazolin antimicrobial prophylaxis. The primary outcome was surgical site infection at 90-days from index surgery. Perioperative carriage of Staphylococcus species was also assessed. In the 4113 patients included in the modified intention-to-treat population, surgical site infections occurred in 72/2069 (3.5%) in the placebo group and 91/2044 (4. 5%) in the vancomycin group (risk ratio 1.28; 95% confidence interval 0.94 to 1.73; p value 0.11). No difference was observed between the two groups for primary hip arthroplasty procedures. A higher proportion of infections occurred in knee arthroplasty patients in the vancomycin group (63/1109 [4.7%]) compared with the placebo group (42/1124 [3.7%]; risk ratio 1.52; 95% confidence interval 1.04 to 2.23; p value 0.031). Hypersensitivity reactions occurred in 11 (0.5%) patients in the placebo group and 24 (1.2%) in the vancomycin group (risk ratio 2.20; 95% confidence interval 1.08, 4.49) and acute kidney injury in 74 (3.7%) patients in the placebo group and 42 (2.1%) in the vancomycin group (risk ratio 0.57; 95% confidence interval 0.39, 0.83). Perioperative Staphylococcus aureus carriage was detected in 1089/3748 (29.1%) of patients. This is the first randomized controlled trial examining the addition of a glycopeptide antimicrobial to standard beta-lactam surgical antimicrobial prophylaxis in joint arthroplasty. The addition of vancomycin to standard cefazolin prophylaxis was not superior to placebo for the prevention of surgical site infections in hip and knee arthroplasty surgery

Aims. The aim of this study was to determine if the local delivery of vancomycin and tobramycin in primary total knee arthroplasty (TKA) can achieve intra-articular concentrations exceeding the minimum inhibitory concentration thresholds for bacteria causing acute prosthetic joint infection (PJI). Methods. Using a retrospective single-institution database of all primary TKAs performed between January 1 2014 and May 7 2019, we identified patients with acute PJI that were managed surgically within 90 days of the initial procedure. The organisms from positive cultures obtained at the time of revision were tested for susceptibility to gentamicin, tobramycin, and vancomycin. A prospective study was then performed to determine the intra-articular antibiotic concentration on postoperative day one after primary TKA using one of five local antibiotic delivery strategies with tobramycin and/or vancomycin mixed into the polymethylmethacrylate (PMMA) or vancomycin powder. Results. A total of 19 patients with acute PJI after TKA were identified and 29 unique bacterial isolates were recovered. The mean time to revision was 37 days (6 to 84). Nine isolates (31%) were resistant to gentamicin, ten (34%) were resistant to tobramycin, and seven (24%) were resistant to vancomycin. Excluding one Fusobacterium nucleatum, which was resistant to all three antibiotics, all isolates resistant to tobramycin or gentamicin were susceptible to vancomycin and vice versa. Overall, 2.4 g of tobramycin hand-mixed into 80 g of PMMA and 1 g of intra-articular vancomycin powder consistently achieved concentrations above the minimum inhibitory concentrations of susceptible organisms. Conclusion. One-third of bacteria causing acute PJI after primary TKA were resistant to the aminoglycosides commonly mixed into PMMA, and one-quarter were resistant to vancomycin. With one exception, all bacteria resistant to tobramycin were susceptible to vancomycin and vice versa. Based on these results, the optimal cover for organisms causing most cases of acute PJI after TKA can be achieved with a combination of tobramycin mixed in antibiotic cement, and vancomycin powder. Cite this article: Bone Joint J 2020;102-B(6 Supple A):163–169

Background. Systemically administered vancomycin may provide insufficient target-site concentrations. Intraosseous vancomycin administration has the potential to overcome this concern by providing high target-site concentrations. Aim. To evaluate the local bone and tissue concentrations following tibial intraosseous vancomycin administration in a porcine model. Method. Eight female pigs were assigned to receive 500 mg diluted vancomycin (50 mg/mL) through an intraosseous cannula into the proximal tibial cancellous bone. Microdialysis was applied for sampling of vancomycin concentrations in tibial cancellous bone adjacent to the intraosseous cannula, in cortical bone, in the intramedullary canal of the diaphysis, in the synovial fluid of the knee joint, and in the subcutaneous tissue. Plasma samples were obtained. Samples were collected for 12 hours. Results. High vancomycin concentrations were found in the tibial cancellous bone with a mean peak drug concentration of 1,236 (range 28–5,295) µg/mL, which remained high throughout the sampling period with a mean end concentration of 278 (range 2.7–1,362.7) µg/mL after 690 min. The mean (standard derivation (SD)) peak drug concentration in plasma was 19 (2) µg/mL, which was obtained immediately after administration. For the intramedullary canal, in the synovial fluid of the knee joint, and subcutaneous tissue, comparable mean peak drug concentration and mean time to peak drug concentration were found in the range of 7.5–8.2 µg/mL and 45–70 min, respectively. Conclusions. Tibial intraosseous administration of vancomycin provided high mean concentrations in tibial cancellous bone throughout a 12-hour period, but with an immediate and high systemic absorption. The concentrations in cancellous bone had an unpredictable and wide range of peak concentration. Low mean concentrations were found in all the remaining compartments. Our findings suggest that intraosseous vancomycin administration in proximal tibial cancellous bone only is relevant as treatment in cases requiring high local concentrations nearby the intraosseous cannula

Introduction. Vancomycin is a commonly used antibiotic for prophylaxis in total joint replacement surgery. Several studies have reported superior local tissue concentration of vancomycin using intraosseous (IO) infusion compared with standard intravenous (IV) administration in total knee arthroplasty (TKA). We reviewed patients undergoing primary TKA who received IO vancomycin to a group receiving IV vancomycin. Methods. A retrospective review of 1038 patient who underwent primary TKA at our institution was performed from May 1, 2016 to May 1, 2019. This was a consecutive series of patients before and after we adopted this technique. IO vancomycin administration technique has been previously reported from our institution (500mg vancomycin in 200mL solution). Comparisons included preoperative and postoperative creatinine values, adverse reaction to vancomycin, tourniquet time, re-operation rates, periprosthetic joint infection rate at 1 year. Results. There were 482 patients in IO vancomycin group and 572 patients in IV vancomycin group. No differences between groups were present for patient age, sex, or BMI. No differences in creatinine values or tourniquet time were present and there were no adverse reactions to vancomycin in either group. Eight periprosthetic joint infections (1.4%) were reported in the IV group, and 1 (0.2%) periprosthetic joint infection was reported in the IO group at 1 year follow up, and this was statistically significant (p = 0.04, Fishers exact test). The overall reoperation rate was 1.7% (10 patients) in the IV group and 1.1% (5 patients), however, this was not statistically significant (p = 0.4371). The additional reoperations were for retained suture or small areas of poor superficial wound healing and were considered minor. Conclusion. Our study demonstrated that IO vancomycin in primary TKA reduced periprosthetic joint infection and is a safe and effective alternative to IV administration. Furthermore, IO infusion also eliminates the logistical challenges of timely prophylactic antibiotic administration before TKA

Introduction. Vancomycin is a prophylactic antibiotic used to protect against methicillin resistant staph aureus. Recent literature has suggested that using intraosseus (IO) infusions are capable of providing improved local tissue concentrations compared to intravenous (IV) access. The purpose of this study is to evaluate clinical outcomes of patients who received pre-operative IO vancomycin for total knee arthroplasty (TKA). Methods. Patients who received IO vancomycin (500mg vancomycin in 200ml NS) as standard of care from September 1, 2018 to March 1, 2019 were retrospectively evaluated. This data was compared to primary and revision TKAs performed immediately prior to the initiation of IO administration. Evaluation included pre and post-op creatinine values, tourniquet time (TT), and knee-related 30 and 90-day complications. Data for primary and revision TKA cases were analyzed independently. Results. Final analysis had 100 primaries and 29 revisions in the control (IV) and 100 primaries and 19 revisions in the intervention (IO) arm. 30 and 90-day complications were not significantly different in primaries, while decreased 30–day complications for revisions approached significance (control=17.2%, intervention=10.5%). 90-day complications were decreased in the revision group receiving IO (Control=27.6%, Intervention = 0%; p=0.015). No cases of Redman Syndrome were identified. No increase in post-operative creatinine values occurred. TT was increased by 1.87min in the PI, which was not statistically significant (p=0.10). Discussion / Conclusion. We've demonstrated IO vancomycin is a safe and effective alternative to using pre-operative IV vancomycin. This is one of the largest series to date evaluating the clinical outcomes while using IO antibiotics pre-operatively in TKA. Patients who receive IO vancomycin have equivalent or improved 30 and 90-day complication rates, significantly so in revision TKAs. In addition, this study evaluated longer-term outcomes of revision TKAs that are provided IO vancomycin, proving it may be appropriate to extend indications. For figures, tables, or references, please contact authors directly

Aims. There is increasing evidence to support the use of topical antibiotics to prevent surgical site infections. Although previous research suggests a minimal nephrotoxic risk with a single dose of vancomycin powder, fracture patients often require multiple procedures and receive additional doses of topical antibiotics. We aimed to determine if cumulative doses of intrawound vancomycin or tobramycin powder for infection prophylaxis increased the risk of drug-induced acute kidney injury (AKI) among fracture patients. Methods. This cohort study was a secondary analysis of single-centre Program of Randomized Trials to Evaluate Pre-operative Antiseptic Skin Solutions in Orthopaedic Trauma (PREP-IT) trial data. We included patients with a surgically treated appendicular fracture. The primary outcome was drug-induced AKI. The odds of AKI per gram of vancomycin or tobramycin powder were calculated using Bayesian regression models, which adjusted for measured confounders and accounted for the interactive effects of vancomycin and tobramycin. Results. Of the 782 included patients (mean age 48 years (SD 20); 59% male), 83% (n = 648) received at least one vancomycin dose (cumulative range 1 to 12 g). Overall, 45% of the sample received at least one tobramycin dose (cumulative range 1.2 to 9.6 g). Drug-induced AKI occurred in ten patients (1.2%). No association was found between the cumulative dose of vancomycin and drug-induced AKI (odds ratio (OR) 1.08 (95% credible interval (CrI) 0.52 to 2.14)). Additional doses of tobramycin were associated with a three-fold increase in the adjusted odds of drug-induced AKI (OR 3.66 (95% CrI 1.71 to 8.49)). Specifically, the risk of drug-induced AKI rose substantially after 4.8 g of tobramycin powder (7.5% (95% CrI 1.0 to 35.3)). Conclusion. Cumulative doses of vancomycin were not associated with an increased risk of drug-induced AKI among fracture patients. While the risk of drug-induced AKI remains less than 4% with three or fewer 1.2 g tobramycin doses, the estimated risk increases substantially to 8% after four cumulative doses. Level of evidence: Therapeutic Level III. Cite this article: Bone Jt Open 2022;3(4):284–290

Aim. Prompt and sufficient broad spectrum empirical antibiotic treatment is key to prevent infection following open tibial fractures. Succeeding co-administration, we dynamically assessed the time for which vancomycin and meropenem concentrations were above relevant epidemiological cut-off minimal inhibitory concentrations (T>MIC) in tibial compartments for the bacteria most frequently encountered in open fractures. Low and high MIC-targets were applied: 1 and 4 µg/mL for vancomycin and 0.125 and 2 µg/mL for meropenem. Materials and methods. 8 pigs received a single dose of 1000 mg vancomycin and 1000 mg meropenem simultaneously over 100 min and 10 min, respectively. Microdialysis catheters were placed for sampling over 8 h in tibial cancellous bone, cortical bone, and adjacent subcutaneous adipose tissue. Venous blood samples were collected as references. Results. Across the targeted epidemiological cut-off values, vancomycin displayed longer T>MIC in all the investigated compartments in comparison to meropenem. For both drugs, cortical bone exhibited the shortest T>MIC. For the low MIC targets and across compartments, T>MIC ranged between 208–499 min (46–100%) for vancomycin and 189–406 min (42–90%) for meropenem. For the high MIC targets, T>MIC ranged between 30–446 min (7–99%) for vancomycin and 45–181 min (10–40%) for meropenem. Conclusion. The differences in the T>MIC between the low and high targets illustrates how the interpretation of these results is highly susceptible to the defined MIC target. To encompass any trauma, contaminating or individual tissue differences, a more aggressive dosing approach may be considered to achieve longer T>MIC in all the exposed tissues and thereby lowering the risk of acquiring an infection after open tibial fractures

Introduction. Infections in total joint arthroplasty (TJA) are a burden to the healthcare system. An infection in total joint arthroplasty costs nearly $60,000–80,000 to the system. 3 major tenets to decrease surgical site infections, focus on patient preoperative optimization, intraoperative techniques, and postoperative care. Intraoperative vancomycin powder been successful in lowering infection rates in other areas of orthopaedics. The purpose of our study was to investigate whether topical intraoperative vancomycin powder had any effect on surgical site infection, complication rate, or reoperation rate. Our hypothesis was vancomycin powder may decrease the rate of surgical site infections without any effect on wound complications. Materials & Methods. 208 consecutive patients undergoing either total hip or total knee arthroplasty (THA or TKA) were given intraoperative vancomycin powder or none. 64 patients received vancomycin poweder compared to 164 patients who did not. All preoperative, intraoperative and postoperative management was similar. Preoperative data including age, sex, BMI, diabetes status and comorbidities were recorded. Surgical techniques included medial parapatellar or subvastus for TKA, posterolateral for THA. 90-day culture positive infection and reoperation rates were recorded. Results. Preoperative variables between the two groups were similar. Average age, ASA, BMI, diabetes status and other preoperative patient variables were not significantly different (p=0.31, 0.19, 0.65, 0.31). 5/64 patients (7.8%) in the vancomycin group underwent reoperation, compared with 13/164 (9.0%) in the no vancomycin group. There was no difference in the rate of reoperations (p=0.777). Of these patients, 3/64 (4.69%) patients in the vancomycin group had a positive infection compared with 8/164 (5.55%) in the no vancomycin group. There was no significant differences between the two infection rates (p=0.807). Discussion. Surprisingly, vancomycin powder did not have any effect on reoperation nor infection rates in our study group. Although other studies may have shown a decrease in infection, ours failed to do so. Due to low study numbers, we could not differentiate deep versus superficial surgical site infections. Based on our study, we are unable to recommend the use of intraoperative vancomycin powder for total joint arthroplasty

Aims. Biofilm infections are among the most challenging complications in orthopaedics, as bacteria within the biofilms are protected from the host immune system and many antibiotics. Halicin exhibits broad-spectrum activity against many planktonic bacteria, and previous studies have demonstrated that halicin is also effective against Staphylococcus aureus biofilms grown on polystyrene or polypropylene substrates. However, the effectiveness of many antibiotics can be substantially altered depending on which orthopaedically relevant substrates the biofilms grow. This study, therefore, evaluated the activity of halicin against less mature and more mature S. aureus biofilms grown on titanium alloy, cobalt-chrome, ultra-high molecular weight polyethylene (UHMWPE), devitalized muscle, or devitalized bone. Methods. S. aureus-Xen36 biofilms were grown on the various substrates for 24 hours or seven days. Biofilms were incubated with various concentrations of halicin or vancomycin and then allowed to recover without antibiotics. Minimal biofilm eradication concentrations (MBECs) were defined by CFU counting and resazurin reduction assays, and were compared with the planktonic minimal inhibitory concentrations (MICs). Results. Halicin continued to exert significantly (p < 0.01) more antibacterial activity against biofilms grown on all tested orthopaedically relevant substrates than vancomycin, an antibiotic known to be affected by biofilm maturity. For example, halicin MBECs against both less mature and more mature biofilms were ten-fold to 40-fold higher than its MIC. In contrast, vancomycin MBECs against the less mature biofilms were 50-fold to 200-fold higher than its MIC, and 100-fold to 400-fold higher against the more mature biofilms. Conclusion. Halicin is a promising antibiotic that should be tested in animal models of orthopaedic infection. Cite this article: Bone Joint Res 2024;13(3):101–109

Aim. The increasing incidence of orthopaedic methicillin-resistant Staphylococcus aureus (MRSA) infections represents a significant therapeutic challenge. Being effective against MRSA, the role of vancomycin may become more important in the orthopaedic setting in the years to come. Nonetheless, vancomycin bone and soft tissue penetration during infection remains unclear. We assessed the effect of a traumatically induced, implant-associated acute osteomyelitis on vancomycin bone penetration in a porcine model. Method. In eight pigs, implant-associated osteomyelitis was induced on day 0, using a Staphylococcus aureus strain. Following administration of 1,000 mg of vancomycin on day 5, vancomycin concentrations were obtained with microdialysis for eight hours in the implant bone cavity, in cancellous bone adjacent to the implant cavity, in subcutaneous adipose tissue (SCT) adjacent to the implant cavity, and in healthy cancellous bone and healthy SCT in the contralateral leg. Venous blood samples were also obtained. The extent of infection and inflammation was evaluated by post-mortem computed tomography scans, C-reactive protein serum levels and cultures of blood and swabs. Results. In relation to all the implant cavities, bone destruction was found. Ranging from 0.20 to 0.74, tissue penetration, expressed as the ratio of tissue to plasma area under the concentration-time curve from 0 to the last measured value, was incomplete for all compartments except for healthy SCT. The lowest penetration was found in the implant cavity. Conclusions. Staphylococcus aureus implant-associated osteomyelitis was found to reduce vancomycin bone penetration, especially in the implant cavity. These findings suggest that it may be unsafe to rely solely on vancomycin therapy when treating acute osteomyelitis. Particularly when metaphyseal cavities are present, surgical debridement seems necessary

Aim. The incidence of orthopaedic methicillin-resistant staphylococcus aureus infections is increasing. Vancomycin may therefore play an increasingly important role in orthopaedic perioperative antimicrobial prophylaxis. Adequate antimicrobial concentrations at target site is essential for prevention of orthopaedic infections. Current studies investigating perioperative bone and soft tissue concentrations of vancomycin are sparse and challenged by a lack of appropriate methods. The aim of this study was therefore to assess the concentration of vancomycin in plasma, subcutaneous tissue and bone after single dose administration using microdialysis (MD) in patients undergoing total knee replacement. Method. 1,000 mg of vancomycin was postoperatively administered intravenously over 100 minutes to 10 male patients undergoing primary total knee replacement. Vancomycin concentrations in plasma, subcutaneous tissue (SCT), cancellous and cortical bone were measured the following 8 hours. MD was applied for sampling in solid tissues. The vancomycin concentration in MD-samples was determined using ultra-high performance liquid chromatography, whilst the free plasma concentration was determined using a chemistry analyzer*. Results. For all extravascular tissue, an impaired penetration was demonstrated, with lower area under the concentration-time curve (AUC) compared to free plasma. The lowest AUC was found in cortical bone. For all tissues, tissue penetration expressed as the ratio of the area under the concentration–time curve from 0 to the last measured value (AUC0-last tissue/AUC0-last plasma) were below 0.5. The time to a mean clinically relevant minimal inhibitory concentration (MIC) of 2 mg/L were 3, 36, 27 and 110 min for plasma, SCT, cancellous and cortical bone, respectively. As opposed to the other compartments, a mean MIC of 4 mg/L was not reached in cortical bone. The AUC0-last and peak drug concentrations (Cmax) for SCT, cancellous and cortical bone were lower than those of free plasma. The time to Cmax was higher for all tissues compared with free plasma. Conclusions. Penetration of vancomycin to bone and SCT was found to be impaired and delayed in male patients undergoing total knee replacement surgery. Adequate perioperative vancomycin concentrations may not be reached at target site using standard prophylactic dosage. *Cobas c501

Aims. There is a lack of biomaterial-based carriers for the local delivery of rifampicin (RIF), one of the cornerstone second defence antibiotics for bone infections. RIF is also known for causing rapid development of antibiotic resistance when given as monotherapy. This in vitro study evaluated a clinically used biphasic calcium sulphate/hydroxyapatite (CaS/HA) biomaterial as a carrier for dual delivery of RIF with vancomycin (VAN) or gentamicin (GEN). Methods. The CaS/HA composites containing RIF/GEN/VAN, either alone or in combination, were first prepared and their injectability, setting time, and antibiotic elution profiles were assessed. Using a continuous disk diffusion assay, the antibacterial behaviour of the material was tested on both planktonic and biofilm-embedded forms of standard and clinical strains of Staphylococcus aureus for 28 days. Development of bacterial resistance to RIF was determined by exposing the biofilm-embedded bacteria continuously to released fractions of antibiotics from CaS/HA-antibiotic composites. Results. Following the addition of RIF to CaS/HA-VAN/GEN, adequate injectability and setting of the CaS/HA composites were noted. Sustained release of RIF above the minimum inhibitory concentrations of S. aureus was observed until study endpoint (day 35). Only combinations of CaS/HA-VAN/GEN + RIF exhibited antibacterial and antibiofilm effects yielding no viable bacteria at study endpoint. The S. aureus strains developed resistance to RIF when biofilms were subjected to CaS/HA-RIF alone but not with CaS/HA-VAN/GEN + RIF. Conclusion. Our in vitro results indicate that biphasic CaS/HA loaded with VAN or GEN could be used as a carrier for RIF for local delivery in clinically demanding bone infections. Cite this article: Bone Joint Res 2022;11(11):787–802

Aims. Vancomycin may be an important drug for intravenous perioperative antimicrobial prophylaxis in spine surgery. We assessed single-dose vancomycin intervertebral disc, vertebral cancellous bone, and subcutaneous adipose tissue concentrations using microdialysis in a pig model. Methods. 8 female pigs received 1,000 mg of vancomycin intravenously as a single dose over 100 minutes. Microdialysis probes were placed in the C3-C4 intervertebral disc, C3 vertebral cancellous bone, and subcutaneous adipose tissue, and vancomycin concentrations were obtained over 8 hours. Venous blood samples were obtained as reference. Results. Ranging from 0.24 to 0.60, vancomycin tissue penetration, expressed as the ratio of tissue to plasma area under the concentration-time curve from 0 to the last measured value, was incomplete for all compartments. The lowest penetration was found in the intervertebral disc. The time to a mean clinically relevant minimal inhibitory concentration (MIC) of 4 μg/mL were 3, 17, 25, and 156 min for plasma, subcutaneous adipose tissue, vertebral cancellous bone and the intervertebral disc, respectively. In contrast to the other compartments, a mean MIC of 8 μg/mL was not reached in the intervertebral disc. An approximately 3-time longer elimination rate was observed in the intervertebral disc in comparison to all the other compartments (p < 0.001), and the time to peak drug concentration was higher for all tissues compared with plasma. Conclusions. Preoperative administration of 1,000 mg of vancomycin may provide adequate vancomycin tissue concentrations with a considerable delay, though tissue penetration was incomplete. However, in order also to achieve adequate intervertebral disc concentrations in all individuals and accommodating a potentially higher MIC target, supplemental application of vancomycin may be necessary

The use of antibiotic-loaded cement has become a well-accepted method to develop high local antibiotic concentrations in orthopedic surgery. A new surgical technique has been established in our department in order to further increase the local antibiotic concentration, when implanting a prosthesis during revision surgery. By additional superficial vancomycin coating of the bone cement, high local antibiotic concentrations are generated. They should reach inhibiting and bactericidal concentrations of the respective pathogen during the first days after surgery. The aim of this study was to state the safety of this method by analyzing postoperative serum and drain vancomycin concentrations. Attention was focused on possible systemic side effects. To determine nephrotoxicity, creatinine levels were also measured. In total 32 revision operations (hip n=10, knee n=22) with additional superficial vancomycin coating were performed between 05/2013 and 04/2015. Procedures with removal of the prosthesis following temporary spacer implantation were excluded. In nine cases a one-stage procedure was performed, while in the others an arthroplasty or arthrodesis was performed after temporary spacer explantation. Vancomycin powder (2 grams) was added superficially to the surface of the bone cement and pressed onto manually before curing. Postoperative Vancomycin levels were measured in serum and the drain on day 1 to 5 or until the drain has been removed. In total 90 blood serum samples and 100 drain fluid samples were obtained. The highest median vancomycin level from the drain was documented on postoperative day 1 with a value of 555.3 μg/mL (range 66.1 – 1081.8), continually decreasing until postoperative day 4. The highest value was documented on the second postoperative day with 2170.0 μg/mL. On the first postoperative day, a median serum vancomycin level of 3.35 μg/mL was present (range <2.0 – 8.5), while from postoperative day 2 to 5 a median level less than 2.0 μg/mL (range <2.0 – 7.2) was documented. Anaphylactic reaction, red man syndrome or fever and chills were not observed after the surgical procedure. Furthermore, no subjective hearing loss was reported. Only in one case, a creatinine increase of 0.5 mg/dL from baseline value was detected. In this case the patient suffered preoperatively from a chronic kidney insufficiency. In total two reinfections occurred, one after explanting a spacer with subsequent hip total endoprosthesis, the other one after a one-stage hip revision. Superficial Vancomycin Coating of bone cement in orthopedic revision surgery represents a safe method to increase local inhibiting vancomycin concentrations

Abstract. 3D printing of synthetic scaffolds mimicking natural bone chemical composition, structure, and mechanical properties is a promising approach for repairing bone injuries. Direct ink writing (DIW), a type of 3D printing, confers compatibility with a wide range of materials without exposing these materials to extreme heat. Optimizing ink properties such as filament formation capabilities, shear-thinning, and high storage modulus recovery would improve DIW fabrication characteristics. In this study, composite inks based on biodegradable polycaprolactone (PCL), reinforced with nano-hydroxyapatite (HAp), and loaded with vancomycin were designed and evaluated for their rheological properties, wettability, mechanical properties, and antimicrobial properties. The formulated composite inks displayed a shear-thinning behaviour exhibited storage modulus recovery percentages above 80% for all formulations, which is essential for extrusion deposition by DIW at room temperature. Ink formulations were able to form fully interconnected lattice scaffolds with porosities ranging from 42% to 65%. Increasing the HAp concentrations from 55% to 85% w/w increased the shear thinning behaviour and reduced the printed filament width to more closely match the nozzle diameter; this indicates higher HAp proportion reduces ink shrinkage. The scaffold had high wettability at HAp proportions above 65% w/w and the compressive elastic modulus of DIW printed scaffolds exhibited within the range of trabecular bone. Antimicrobial activity was apparent from the agar diffusion assay; zones of inhibition ranging from 15.82 ± 0.25 mm and 20.06 ± 0.25 mm were observed after 24 hr for composite scaffolds loaded with 3% and 9% w/w vancomycin respectively. Vancomycin-loaded PCL/HAp composite inks were developed, displaying good printability, wettability, mechanical properties, and antimicrobial properties, making them an attractive choice for bone repair and regeneration. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Aim. Determine the time concentration profile required to achieve vancomycin-mediated eradication of Staphylococcus aureus biofilm. This is critical for the identification of performance targets for local antibiotic delivery, yet has not been described. Method. Mature S. aureus UAMS-1 biofilms were grown on titanium-aluminum-niobium discs in Mueller Hinton broth (MHB). After 7 days, the discs were incubated in MHB containing vancomycin at 100, 200, 500, 1′000 and 2′000 mg/L. Both static and shaking conditions were tested. Samples were retrieved at intervals for up to 28 days for quantification of residual biofilm by sonication and serial dilution plating. One additional disc was processed per time point for scanning electron microscopy. Results. Progressive and significant reduction of viable bacteria was observed over time at all vancomycin concentrations in both static and shaking conditions. After 28 days under static conditions, the S. aureus biofilm was completely eradicated at 200 mg/L vancomycin and higher concentrations. Biofilm could could however not be eradicated under shaking conditions at any concentration. Logistic regression documents time of exposure at ≥200 mg/L as being the essential determinant of eradication. Conclusions. The clinical relevance of the present study is that it is not impossible to eradicate mature S. aureus biofilm from metal implants by vancomycin alone, fostering efforts to optimize local delivery. The required time concentration profile cannot be achieved yet by systemic administration or any of the local delivery vehicles available. Even longer exposure as 28 days might be required as wound fluid flow might influence unfavourably biofilm resistance to vancomycin

Introduction. PJI is a devastating complication following total joint arthroplasty. In this study, we explore the efficacy of a bacteriophage-derived lysin, PlySs2, against in-vitro biofilm on titanium implant surfaces and in an acute in-vivo murine debridement antibiotic implant retention (DAIR) model of PJI. Methods. In-vitro: Xen 36 S. aureus biofilm was grown on Ti-6Al-4V mouse tibial implants for 1 day or 5 days and subsequently exposed to growth media, 1000× minimal inhibitory concentration (MIC) Vancomycin, or 5× MIC PlySs2. Implants were sonicated and analyzed for Colony Forming Units (CFU). In-vivo: A Ti-6Al-4V implant was inserted into the proximal tibia of C57BL/6J mice (n=21). All mice received 10. 4. CFU inoculation of Xen 36 S. aureus to the knee joint capsule and the infection was permitted 5 days to progress. On day 5 the mice were separated into three groups (n=7/group): (1) no further surgical intervention (control group), (2) irrigation and debridement (I&D) with saline, (3) I&D with 2mg/mL PlySs2. No implant-exchange was performed to mimic a debridement, antibiotic, and implant retention (DAIR) therapeutic strategy. All mice were sacrificed at day 10. Results. CFU counts for 1-day and 5-day in-vitro grown biofilm on implants demonstrate a >3log-fold reduction with PlySs2 compared to Vancomycin (p=0.01) with no significant difference between Vancomycin and control. In-vivo the addition of PlySs2 to Vancomycin treated mice reduces bacterial load in the periposthetic tissue and implant (p<0.05) with 5 days of treatment. Conclusion. PlySs2 5× MIC exhibits superior anti-microbial effect compared to Vancomycin on implants with 1-day and 5–5day biofilm maturities. The addition of PlySs2 to Vancomycin treatment of an acute established PJI further reduces tissue CFU and implants CFU. For any tables or figures, please contact the authors directly

The use of polymethylmethacrylate (PMMA) bone cement loaded with antibiotics has become increasingly common in orthopaedic surgery. However, bacterial resistance in antibiotics is an increasing and emerging problem. PMMA bone cements containing different antibiotics, such as gentamicin plus vancomycin may be effective in prevention and treatment of infections (particularly from MRSA and MRSE). The purpose of this study was to determine the in vitro elution characteristics of gentamicin and vancomycin when combined in acrylic cement. Three groups of ten cement disks were prepared. Group I (control group) contained 0.5g of gentamicin per 40-g packet of Palacos-R+G powder. Group II contained 0.5g of gentamicin and 1g of powdered vancomycin and group III contained 0.5g of gentamicin and aqueous solution of vancomycin. Each cement disc (25mm x 20mm) was immersed in a 50-mL bath of normal saline at 37oC. Samples were taken at specific sampling intervals (1, 3, 7, 15, 30, 60, 90, 120, 150, 180 days). Antibiotic concentrations were measured using fluorescence polarisation immunoassay. With regards to gentamicin release, high but rapidly decreasing antibiotic levels were detected within the first week and low concentration after the first month. Samples from Group II eluted significantly more gentamicin (120%–20% during the first month). The influence on the gentamicin release was significant but minor when aqueous solution of vancomycin (Group III) was added. With regards to vancomycin release, high antibiotic levels were detected within the first 3 days and low concentrations after the first week. Cement samples from Group II eluted significantly more antibiotic in comparison with samples from Group III. Bone cements loaded with combinations of gentamicin and vancomycin are more effective in releasing gentamicin than bone cements with gentamicin as a single drug. Powdered vancomycin in cement samples has better elution characteristics in comparison with aqueous solution of vancomycin

Introduction. Intraosseous administration of low dose vancomycin has been proven to produce 6 to 20 times higher tissue concentrations compared to intravenous administration in both primary and revision knee replacement. However, these superior levels are achieved when the antibiotic given intraosseously is administered distal to a tourniquet that is inflated for the majority of the case. With increasing interest in limited, or no, tourniquet use during TKA we sought to study the tissue concentrations achieved with limited tourniquet use and intraosseously administered vancomycin compared to weight-based, time optimized intravenous administration. Methods. Twenty-four patients undergoing primary TKA were randomized to two groups. The Intravenous (IV) Group received weight based (15mg/kg) vancomycin timed to finish before incision. The Intraosseous (IO) Group received 500 mg of vancomycin injected as a bolus through a needle into the proximal tibia distal to an inflated tourniquet prior to skin incision. In the IO group, the tourniquet was deflated 10 minutes following the injection and re-inflated only for cementation. In the IV group, the tourniquet was only inflated for cementation. During the procedure, fat and bone samples were taken at regular intervals. Tissue antibiotic concentrations were measured using a validated technique involving high performance liquid chromatography. Results. Mean tissue concentrations of vancomycin in fat and bone samples from all time points were 3–10 times greater in the IO group (all results, p<0.01). At closure, mean vancomycin levels in fat were 6.0ug/g in the IV group vs 40.5ug/g in the IO group (p<0.001). Final bone levels were 8.3ug/g in the IV group vs 26.9ug/g in the IO group (p=0.009). Conclusion. In total knee replacement, IO administration of prophylactic vancomycin achieves significantly higher tissue concentrations versus IV administration given under ideal conditions despite limited tourniquet use. For figures, tables, or references, please contact authors directly

We wanted to study the risk of systemic toxic effect of gentamycin/vancomycin loaded spacers, and to investigate whether there is any difference in the elution of gentamycin and vancomycin to the joint fluid between theatre- made and in factory ready-made spacers. The study consists of 28 patients. In group one, 14 patients were given a in factory ready-made spacer containing gentamycin 1,1g – 3,2g and vancomycin 1,1g – 3,2g depending of the size of the spacer. In group two, 14 patients were given spacers made in the operating theatre. from PMMA containing 0,5 g gentamycin in each 40 g batch. 4 g vancomycin were added to each batch of 40 g PMMA. The concentration of gentamycin and vancomycin was measured from drainfluid and in serum day 1 and 2 after the operation. Group one Group two Significance. Vancomycin drain day 1 10,3 (2,0–23.3) 88,5 (11,7–242,9) p<0,001. Vancomycin drain day 2 6,3 (2,0–17,5) 55,2 (7,5–161,0) p<0,001. Vancomycin serum day 1 2,0 (2,0–2,0) 1,8 (0,7–2.0) ns. Vancomycin serum day 2 2,0 (1,6–2,2) 1,9 (1,0–2,0) ns. Gentamycin drain day 1 23,4 (0,5–68,0) 44,3 (11,0–117,5) p=0,05. Gentamycin drain day 2 8,7 (0,8–16,1) 18,0 (6,8–45,3) p<0,005. Gentamycin serum day 1 0,2 (0,2–0,2) 0,3 (0,2–1,3) ns. Gentamycin serum day 2 0,2 (0,0–0,2) 0,3 (0,2–1,1) ns. In theatre-made spacers had a significant higher concentration of both gentamycin and vancomycin in the joint fluid. Even with very high consentrations of gentamycin and vancomycin in the joint fluid the concentrations in serum were far below the toxic limit and no toxic reactions were observed. Gentamycin and vancomycin added to the hip spacers only to a very small degree passes to the circulation system. In theatre-made spacers have a significantly higher elution of gentamycin and vancomycin than in factory ready-made spacers. If a high initial concentration of gentamycin and vancomycin in joint fluid is desired. in theatre-made spacers should be considered

In two-stage revision surgery of infected joint prosthesis, temporary bone cement spacers have been used for several years. By adding antibiotics to the cement, high local antibiotic concentrations that exceed the minimum inhibiting and bactericidal concentration of the respective pathogen during the first days after surgery, are achieved. Currently, aminoglycosides (e.g. gentamicin and tobramycin), as well as glycopetides (e.g vancomycin) are used as antibiotic agents and mixed into the acrylic cement. In order to increase the quantity of active antibiotic substances, we established a novel surgical technique of additional superficial vancomycin coating (SVC) of temporary bone cement spacer. The aim of this study was to analyze the safety of this method by measuring postoperative joint and serum vancomycin concentrations, as well as the creatinine levels. We reviewed prospectively collected data on all patients, which were treated by explanting the prosthetic components, following temporary spacer implantation and SVC between 05/2013 and 04/2015 at the Department of Orthopedic Surgery, Medical University of Graz. In total 13 patients were treated by addition SVC during the study period. Before hardening, vancomycin powder (2 grams) was pressed manually onto the surface of the bone cement. Vancomycin levels were obtained from drains and blood samples on postoperative days 1 to 5. Forty-six blood serum samples and 52 drain fluid samples were available for further. On postoperative day one to five, a median serum vancomycin level of < 2.0 μg/mL was present (range <2.0 – 3.9). The highest median vancomycin level from the drain was documented on postoperative day 1 with a value of 388.0 μg/mL (range 44.4–1650.0), continually decreasing until postoperative day 4. After SVC, neither an anaphylactic reaction nor side effects such as a red man syndrome, fever and chills were observed. Furthermore, no patient complained about subjective hearing loss. No serum creatinine increase of 0.5 mg/dL from creatinine baseline value or a ≥50% increase from baseline was detected. After a median of 64 days (range 18–82), the temporary cement spacer was explanted followed by prosthesis implantation. During this time no reinfection occurred. One patient suffered from a dislocation of the spacer with a distal femur fracture and was therefore re-operated after 18 days. Powdered vancomycin as an additional superficial coating of bone cement spacer results in much higher local antibiotic concentrations than in conventional spacers. The newly introduced method is feasible, safe and promising to enhance local inhibiting concentrations of vancomycin

Introduction: There is extensive literature on the effect of vancomycin on the compression strength of plain cements, none however on antibiotic-loaded cements. The addition of vancomycin to antibiotic-loaded bone cement is common practice in revision joint replacement surgery for infection. The scope of this study was to record the effect of vancomycin addition on the compression strength of antibiotic-loaded bone cement and to compare the results with the international standard (ISO 5833–2) in order to evaluate safety in clinical use. Materials & Methods: The formulations used were Palamed G, containing 0.55g of gentamicin; and Copal, containing 1g of gentamicin and 1g of clindamicin. Vancomycin concentrations of 2.5%, 5% and 10% per powder weight were added. The ISO requirements for the testing procedures were followed. Samples of Palamed G with 5% vancomycin and non-standardised mixing procedures were also tested, as well as samples of both bone cements without vancomycin, as controls. Results: The mean compression strength of plain Palamed G was 91.08 MPa. With the addition of 2.5%, 5% and 10% vancomycin, the mean compression strengths were 79.82, 82.3 and 74.56 MPa respectively, a reduction of 12.36%, 9.64% and 18.13%. The mean strength of the Palamed G specimens with 5% vancomycin and non-standardised mixing was 72.88 MPa, a 19.9% reduction. The mean compression strength of the plain Copal was 86.27 MPa. With the addition of 2.5%, 5% and 10% vancomycin, the mean compression strengths were 76.59, 78.92 and 71.19 MPa respectively, a reduction of 11.22%, 8.52% and 17.48%. Copal with 10% and Palamed G with 5% vancomycin and non-standardised mixing, were the only cements with compression strengths not significantly exceeding the ISO standard of 70 MPa. Conclusion: The addition of up to 5% vancomycin per powder weight to the antibiotic-loaded Copal and 10% to Palamed G bone cements can be considered safe. Care should be given to the mixing procedure of the cement, as it significantly affects its compression strength

Periprosthetic joint infection (PJI) remains one of the most devastating complications that can occur following total joint arthroplasty. Failure rate of standard treatment for PJI is estimated to be around 40% at two years post revision surgery. A major clinical challenge contributing to treatment failure and antibiotics tolerance is the biofilm formation on implant surfaces. Lytic bacteriophages (phages) can target biofilm associated bacteria at localized sites of infection by penetrating and disrupting biofilm matrices; furthermore, phage replication within the biofilm leads to high local concentrations resulting in a powerful therapeutic effect. The aim of this study is to test if phage cocktail has better antimicrobial effect than vancomycin or a single agent phage against biofilm forming MRSA clinical strain Staphylococcus aureus (S. aureus). S. aureus BP043 was utilized in this study. This strain is a PJI clinical isolate, methicillin resistant (MRSA) and biofilm-former. Three lytic phages, namely, 44AHJD, Team1 and P68, known to infect S. aureus, were tested for their efficiency against S. aureus BP043. The ability of the phages to eliminate S. aureus BP043 planktonic or biofilm cultures was tested either as singular phages or as a cocktail of the three phages. Planktonic cells were adjusted to ∼ 1×109 CFU/mL in tryptic soy broth (TSB) and each phage was added alone or as a cocktail at ∼ 1×109 PFU/mL with moi of 1 (a multiplicity of infection). Bacterial growth was assessed by measuring optical densities at 24hr and was compared to the control of S. aureus BP043 with no phage. BP043 biofilms was grown for 24hr on plasma sprayed titanium (Ti-6Al-4V) alloy disc surfaces. Mature biofilms were then treated with one of the three phages or a cocktail of the 3 phages for 24hr at ∼ 1×109 PFU/mL in TSB. Then, biofilms were dislodged, and bacterial survival was assessed by plating on tryptic soy agar plates. Survival in treated biofilms was compared to control biofilm that was exposed only to TSB. Planktonic cells growth in the presence of phage 44AHJD was reduced significantly (p <0.0001) after 24hr compared to the control. The other two phages did not show a similar pattern when used alone. The reduction in growth was more pronounced when the three phages were combined together (p <0.0001, compared to the control, p=0.011 3, 44AHJD alone versus 3 phages). Exposing BP043 biofilm to the phage cocktail resulted in more than three logs (CFU/mL) reduction in bacterial load residing in the biofilm while no effect was detected when either vancomycin or each phage was used solely. We have demonstrated that the usage of lytic phage cocktail contributes to better clearance of planktonic cultures of the S. aureus MRSA isolate. More importantly, viable bacteria in the biofilms that were grown on plasma sprayed titanium discs were reduced by more than 37% when a phage cocktail was used compared to using a single phage or vancomycin. This work is aimed at gathering preclinical evidence for using phage as a new therapeutic avenue to treat PJI

Introduction: The use of polymethylmethacrylate (PMMA) bone cement loaded with antibiotics has become increasingly common in the treatment of infected knee and hip arthroplasties and also as prophylaxis in primary joint replacement. However bacterial resistance in antibiotics is an increasing and emerging problem. PMMA bone cements containing different antibiotics, such as gentamicin plus vancomycin may be effective in prevention and treatment of infections (particularly from MRSA and MRSE). The purpose of this study was to determine the in vitro elution characteristics of gentamicin and van-comycin when combined in acrylic cement. Material and methods: Three groups of six cement disks were prepared. Group I (control group) contained 0.5g of gentamicin sulphate per 40-g packet of Palacos-R+G powder. Group II contained 0.5g of gentamicin sulphate and 1g of finely powdered vancomycin and Group III contained 0.5g of gentamicin sulphate and aqueous solution of vancomycin (containing 2mL water for injection and 1g vancomycin). All discs were prepared using vacuum mixing technique. Each cement disc (25mm diameter × 20mm thick) was fully immersed in a 50-mL bath of normal saline at 37o C temperature in a covered beaker. At specific sampling intervals (1, 3, 7, 15, 30, 60, 90, 120, 150, 180 days) the discs were removed and placed in fresh 50 ml bath for 24 hours. Then a 2 mL sample of each solution was taken. Samples were frozen at −60° C until they were analyzed. Gentamicin and vancomycin concentrations were measured using fluorescence polarization immunoassay. Results: With regards to gentamicin release, high but rapidly decreasing antibiotic levels were detected within the first week, resulting in an almost steadily low concentration by the end of the first month. Cement samples eluted significantly more gentamicin (120%-20% during the first month) when powdered vancomycin (Group II) was added. The influence on the gentamicin release was significant but minor when aqueous solution of vancomycin (Group III) was added (40%-20% during the same period). With regards to vancomycin release, high antibiotic levels were detected within the first 3 days and low concentrations after the first week. Cement samples from Group II eluted significantly more antibiotic (80%–100%) in comparison with samples from Group III during the first days. Gentamicin and vancomycin are detectable in measurements at 150 and 180 days samples. Conclusions: Bone cements loaded with combinations of gentamicin and vancomycin are more effective in releasing gentamicin than bone cements with gentamicin as a single drug. The presence of powdered vancomycin in cement samples has major influence on the total gen-tamicin release in comparison with cements containing aqueous solution of vancomycin

Aim. In vivo studies have shown a preventive and curative effect of using an injectable vancomycin containing biphasic ceramic in an osteomyelitis model. No clinical long term pharmacokinetic release study has been reported. Inadequate concentration in target tissues results in treatment failure and selection pressure for antibiotic-resistant organisms. Our hypothesis was that vancomycin in the first week would reach high local concentrations but with low systemic levels. Method. 9 patients (6 women, 3 men) with trochanteric hip fractures classified as A1 and A2 according to the AO-classification all had internal fixations. The mean age was 75.3 years (± S.D. 12.3 years, range 44–84y). An injectable ceramic with hydroxyapatite embedded in a calcium sulphate matrix containing 66mg vancomycin per mL augmented the fixation. A mean of 9.7 mL (± S.D. 0.7 mL, range 8–10mL) was used. The elution of vancomycin was followed by collecting drain fluid, blood (4 days) and urine (4 weeks). Results. The concentration of antibiotics in the drain showed an important burst during the first 12h after surgery, with a mean value of 709.9 µmol/L (± S.D. 383.9), which decreased linearly to a mean value of 60.9 µmol/L at 2.5 days. In the urine, the vancomycin concentration reached 68.9 µmol/L (± S.D. 34.4) during the first day, which was decreased logarithmic over the first two weeks to reach zero at 20 days (see Figure). The systemic concentration of vancomycin was constantly low, not exceeding 2.6 µmol/L. Conclusions. This is the first long term pharmacokinetic study reporting vancomycin release from a biphasic injectable ceramic bone substitute. The study shows initial high targeted local vancomycin levels (wound drainage), sustained and complete release at three weeks (verified by the urine concentrations), and systemic concentrations well below toxic levels. This system should be useful in preventing and treating bone infection

Introduction. Vancomycin is commonly added to acrylic bone cement during revision arthroplasty surgery. Proprietary cement preparations containing vancomycin are available but significantly more expensive. We investigated whether the antibiotic elution and mechanical strength of ‘home-made’ vancomycin containing bone cement was comparable to commercial vancomycin-impregnated cement. Methods. A total of 18 cement discs of constant size, containing either proprietary CopalG+V. ®. ; or ‘home-made’ CopalR+G. ®. with vancomycin added by hand, were made. Each disc contained the same antibiotic quantities (0.5g gentamycin, 2g vancomycin) and was immersed in ammonium acetate buffer in a sealed container. Fluid from each container was sampled at eight time points over a two week period. The concentration of gentamicin and vancomycin in the fluid was analysed using high performance liquid chromatography mass spectrometry. The impact strength of each PMMA cement preparation was measured using a Charpy-type impact tester. Results. Highest peak antibiotic concentrations were observed from the ‘home-made’ vancomycin containing cement, added as in the operating theatre. Overall antibiotic elution was, five-fold (vancomycin) and two-fold (gentamicin), greater from the ‘home-made’ mix compared to commercially mixed cement. However the ‘home-made’ cements showed greater variation in elution kinetics compared to the commercial mix. Use of a vacuum during mixing had no significant effect on antibiotic elution in any of the samples. Impact strength testing showed no significant differences between the groups. Discussion. Our findings suggest the addition of 2g vancomycin powder to gentamicin-impregnated bone cement in theatre, significantly increases elution of both antibiotics, with no significant loss of strength, compared to commercially prepared cement. Conclusion. We have found no significant advantages of expensive off-the-shelf vancomycin-impregnated bone cement and recommend the addition of vancomycin powder by hand when making cement beads and spacers

Aims. The management of periprosthetic joint infection (PJI) after total knee arthroplasty (TKA) is challenging. The correct antibiotic management remains elusive due to differences in epidemiology and resistance between countries, and reports in the literature. Before the efficacy of surgical treatment is investigated, it is crucial to analyze the bacterial strains causing PJI, especially for patients in whom no organisms are grown. Methods. A review of all revision TKAs which were undertaken between 2006 and 2018 in a tertiary referral centre was performed, including all those meeting the consensus criteria for PJI, in which organisms were identified. Using a cluster analysis, three chronological time periods were created. We then evaluated the antibiotic resistance of the identified bacteria between these three clusters and the effectiveness of our antibiotic regime. Results. We identified 129 PJIs with 161 culture identified bacteria in 97 patients. Coagulase-negative staphylococci (CNS) were identified in 46.6% cultures, followed by Staphylococcus aureus in 19.8%. The overall resistance to antibiotics did not increase significantly during the study period (p = 0.454). However, CNS resistance to teicoplanin (p < 0.001), fosfomycin (p = 0.016), and tetracycline (p = 0.014) increased significantly. Vancomycin had an 84.4% overall sensitivity and 100% CNS sensitivity and was the most effective agent. Conclusion. Although we were unable to show an overall increase in antibiotic resistance in organisms that cause PJI after TKA during the study period, this was not true for CNS. It is concerning that resistance of CNS to new antibiotics, but not vancomycin, has increased in a little more than a decade. Our findings suggest that referral centres should continuously monitor their bacteriological analyses, as these have significant implications for prophylactic treatment in both primary arthroplasty and revision arthroplasty for PJI. Cite this article: Bone Joint J 2021;103-B(6 Supple A):171–176

Perioperative antibiotic prophylaxis remains one of the most important strategies for prevention of periprosthetic joint infection (PJI) with current guideline recommending a first or second generation cephalosporin. Penicillin (PCN) allergy is often reported by patients, which often results in avoidance of administration of cephalosporins due to fear of cross-reactivity. Alternative medications, such as vancomyin, are often used despite reduced antimicrobial coverage. The purpose of this study was to determine if PCN allergic patients who received vancomycin alone prior to elective primary total joint arthroplasty were at increased risk of developing a subsequent PJI. A retrospective review of 7,602 primary total joint arthroplasties (TJAs) performed between 2005 and 2013 in two institutions were identified using a prospective institutional database. Patient reported PCN or cephalosporin allergy was electronically queried from the anesthesia note. Patients who recieved multiple prophylactic antibiotics, or had unavailable perioperative antibiotic information, or those who received medication other than cefazolin and vancomycin were excluded. PJI was determined using a cross-match with an institutional PJI database constructed from International Classification of Diseases (ICD)-9 codes. Logistic regression analysis was then performed to evaluate the risk of subsequent PJI. The rate of PJI was 1.4% (32/2296) in patients with a reported PCN allergy that received vancomycin alone versus 1.1% (59/5306) in non-PCN allergic patients that received cefazolin alone. The multivariate analysis, with the given sample size, did not detect a statistically significant increased risk of PJI when vancomycin was administered alone (adjusted odds ratio: 1.23, 95% CI 0.6–3.1, p=0.35). While there was no significant differences in the organism profile between PJIs in both groups, the rate of PJI caused by resistant organisms was higher in patients who received vancomycin alone (11.9%, 7/59) compared to those who received cefazolin (3.1%, 1/32). While administration of perioperative prophylactic vancomycin alone during elective primary arthroplasty does not seem to result in a higher rate of subsequent PJI, patients who received vancomycin alone and developed a PJI were more likely to develop an infection with an antibiotic resistant organism. Future studies are needed to determine the most appropriate prophylactic antibiotic for patients who undergo elective arthroplasty and report PCN allergy

Aims. Vancomycin is commonly added to acrylic bone cement during revision arthroplasty surgery. Proprietary cement preparations containing vancomycin are available, but are significantly more expensive. We investigated whether the elution of antibiotic from ‘home-made’ cement containing vancomycin was comparable with more expensive commercially available vancomycin impregnated cement. Materials and Methods. A total of 18 cement discs containing either proprietary CopalG+V; or ‘home-made’ CopalR+G with vancomycin added by hand, were made. Each disc contained the same amount of antibiotic (0.5 g gentamycin, 2 g vancomycin) and was immersed in ammonium acetate buffer in a sealed container. Fluid from each container was sampled at eight time points over a two-week period. The concentrations of gentamicin and vancomycin in the fluid were analysed using high performance liquid chromatography mass spectrometry. Results. The highest peak concentrations of antibiotic were observed from the ‘home-made’ cements containing vancomycin, added as in the operating theatre. The overall elution of antibiotic was, fivefold (vancomycin) and twofold (gentamicin) greater from the ‘home-made’ mix compared with the commercially mixed cement. The use of a vacuum during mixing had no significant effect on antibiotic elution in any of the samples. Conclusion. These findings suggest that the addition of 2 g vancomycin powder to gentamicin-impregnated bone cement by hand significantly increases the elution of both antibiotics compared with commercially prepared cements containing vancomycin. We found no significant advantages of using expensive commercially produced vancomycin-impregnated cement and recommend the addition of vancomycin powder by hand in the operating theatre. Cite this article: Bone Joint J 2017;99-B:73–7

There is a lack of carriers for the local delivery of rifampicin (RIF), one of the cornerstone second defence antibiotic for Staphylococcus aureus deep bone infections (DBIs). RIF is also associated with systemic side effects, and known for causing rapid development of antibiotic resistance when given as monotherapy. We evaluated a clinically usedbi-phasic calcium sulphate/hydroxyapatite (CaS/HA) biomaterial as a carrier for dual delivery of RIF with vancomycin (VAN) or gentamicin (GEN). It was hypothesized that this combined approach could provide improved biofilm eradication and prevent the development of RIF resistance. Methods: 1) Biofilm eradication: Using a modified crystal violet staining biofilm quantification method, the antibiotics released at different time points (Day 1, 3, 7, 14, 21, 28 and 35) from the hemispherical pellets of CaS/HA(500 mg)-VAN (24.57 mg) / GEN (10.35 mg) composites with or without RIF (8.11 mg) were tested for their ability to disrupt the preformed 48-h old biofilms of S. aureus ATCC 25923, and S. aureus clinical strain P-3 in 96-well microtitre plate. For each tested group of antibiotic fractions, five separate wells were used (n=5). 2) Testing for resistance development: Similar to the method mentioned above the 48-h biofilm embeded bacteria exposed to antibiotic fractions from different time points continuously for 7 days. The biofilms remained were then tested for RIF resistant strains of bacteria. Overall, there was clear antibiofilm biofilm activity observed with CaS/HA-VAN/GEN+RIF combinations compared with CaS/HA-VAN/GEN alone. The S. aureus strains developed resistance to RIF when biofilms were subjected to CaS/HA-RIF alone but not with combinations of CaS/HA-VAN/GEN+RIF. Enhanced antibiofilm effects without development of RIF resistance indicates that biphasic CaS/HA loaded with VAN or GEN could be used as a carrier for RIF for additional local delivery in clinically demanding DBIs. Acknowledgement: We deeply acknowledge the Royal Fysiographic Society of Lund, Landshövding Per Westlings Minnesfond and the Stina and Gunnar Wiberg fond for financial support

The aim of our project is to develop resorbable nanostructured composite layer with controlled elution of antibiotics for implants survival rate enhancement. The nanostructured layers are expected to be used especially in the case of known systemic or local (joint) inflammation. This layer can provide a bone tissue/implant (titanium alloy) bioactive interface improving the physiological healing process and eliminating the risk of bacterial orthopedic infections. The main aim of this study was to verify whether the local concentration of released vancomycin exceeded the minimum inhibitory concentration (MIC) for vancomycin-resistant Staphylococcus aureus (VRSA, >16 mg/l). The layer is composed of collagen (type I, isolated form calf skin), hydroxyapatite nanoparticles and vancomycin hydrochloride (10 wt%). The stability of collagen was enhanced by EDC/NHS cross-linking. The in vitro release of vancomycin and crystalline degradation products from optimally cross-linked layers was investigated. An elution method and a high performance liquid chromatographic assay were employed to characterize the in vitro release rates of the vancomycin and its crystalline degradation antibacterial inactive products over a 21-day period. During the whole experimental period, the level of released vancomycin was high above the MIC for VRSA. The maximum average concentration was obtained between day 4 and day 8 and it reached 265 mg/l. At the end of the experiment (day 21), an average concentration of 104 mg/l was detected. Our study confirmed the prophylactic effects of studied vancomycin-loaded nanostructured layers

Vancomycin -impregnated bonechips from a human morselized femoral head allograft (BCs) are used in orthopaedic surgery to treat infections. Literature suggests that bonechips can be efficient vancomycin carriers, but due to the diversity in the type of bonechips, of impregnation and of method used to evaluate AB release, there are no uniform guidelines. We performed an in vitro study to examine the release of vancomycin from solution-impregnated deepfrozen processed bonechips. Quantification was performed using a fully validated chromatographic method. Results were compared with the elution-profile from Osteomycin®, a commercially available lyophilised processed bonegraft. Different vancomycine impregnation-concentrations and impregnation-durations of frozen processed bonechips were investigated. After impregnation, bonechips were rinsed with saline in order to determine only the absorbed vancomycin. Elution was performed in newborn calf serum at 37°C. Eluted vancomycin concentrations were determined using Ultra Performance Liquid Chromatography – Diode Array Detection (UPLC-DAD). In addition an elution study was performed on the commercially available Osteomycin®, bone chips containing vancomycine. Using processed frozen bonechips, an impregnation-concentration of minimum 100 mg/mL during 10 minutes delivers the desired local concentration (therapeutic window 25 – 1000 mg/L) for 3 days. Longer impregnation time at this concentration had no effect. Osteomycin®: delivers the desired local concentration for 8 days in our experimental setting. Literature suggests that freshfrozen BCs can be used as carrier for vancomycin through solution-impregnation [1,3]. There is however much less information on the carrier-capacities of frozen processed bonechips, a type used in our hospital. Our impregnation-protocol was based on that of Mathyssen et al., but with direct quantification of elution concentrations. Impregnation with vancomycine 100 mg/mL during 10 minutes results in a release above the desired concentration for 3 days, which seems too short when treating bone-infections. Osteomycin®, shows a substantially longer elution [2]. Vancomycin-solution impregnation of frozen processed bonechips may not be sufficient to obtain the desired release-characteristics for the treatment of bone-infections

Aims. Biofilm formation is intrinsic to prosthetic joint infection (PJI). In the current study, we evaluated the effects of silver-containing hydroxyapatite (Ag-HA) coating and vancomycin (VCM) on methicillin-resistant Staphylococcus aureus (MRSA) biofilm formation. Methods. Pure titanium discs (Ti discs), Ti discs coated with HA (HA discs), and 3% Ag-HA discs developed using a thermal spraying were inoculated with MRSA suspensions containing a mean in vitro 4.3 (SD 0.8) x 10. 6. or 43.0 (SD 8.4) x 10. 5. colony-forming units (CFUs). Immediately after MRSA inoculation, sterile phosphate-buffered saline or VCM (20 µg/ml) was added, and the discs were incubated for 24 hours at 37°C. Viable cell counting, 3D confocal laser scanning microscopy with Airyscan, and scanning electron microscopy were then performed. HA discs and Ag HA discs were implanted subcutaneously in vivo in the dorsum of rats, and MRSA suspensions containing a mean in vivo 7.2 (SD 0.4) x 10. 6.   or 72.0 (SD 4.2) x 10. 5.   CFUs were inoculated on the discs. VCM was injected subcutaneously daily every 12 hours followed by viable cell counting. Results. Biofilms that formed on HA discs were thicker and larger than those on Ti discs, whereas those on Ag-HA discs were thinner and smaller than those on Ti discs. Viable bacterial counts in vivo revealed that Ag-HA combined with VCM was the most effective treatment. Conclusion. Ag-HA with VCM has a potential synergistic effect in reducing MRSA biofilm formation and can thus be useful for preventing and treating PJI. Cite this article:Bone Joint Res. 2020;9(5):211–218

Introduction. The utility of vancomycin powder application into the surgical site has recently shown efficacy in decreasing infections in patients undergoing thoracolumbar spine surgery. The effect on polyethylene wear after intraoperative placement of vancomycin powder at the surgical site of total joint replacements has not been determined. The purpose of this study is to compare wear behavior of material couples of Cobalt Chromium Alloy (CoCr) on ultra high molecular weight polyethylene (UHMWPE) to identical wear couples with vancomycin powder added prior to the start of wear simulation. Methods. A custom-designed six-station wear simulator was used to establish in vitrowear characteristics of CoCr on UHMWPE on test articles fabricated from materials identical to total knee implants. Three stations included vancomycin powder added to the 36% bovine calf serum solution used in each station. Cyclic articulation simulations were run for 10 million cycles (Mc) at 4 ± 0.3 Hz under a constant axial load of 89N over 25 degrees of flexion-extension. UHMWPE wear was measured using photography, stereomicroscopic examination, and gravimetric measurements at the end of 0.5, 1, 2.5, 5, and 10 Mc. Results. After photographic and stereomicrographic examination, no significant differences between the UHMWPE wear mark length, width, and area of the vancomycin group and the control group were found at any of the time points. There was no gravimetrically detectable difference in the amount of wear between the two groups. The vancomycin test group lost an average of 0.13 ± 0.07 after 2.5 MC and similarly the control test group lost an average of 0.13 ± 0.15 mg (p = 0.95). Discussion. The addition of vancomycin powder to CoCr on UHMWPE wear simulator demonstrated no detrimental effects on the prostheses in vitro. Topical vancomycin powder may have a role in infection prevention after total joint arthroplasty. A well designed clinical study is needed to further elucidate this role

Aim. Most orthopedic infections are due to the microbial colonization of abiotic surfaces, which evolves into biofilm formation. Within biofilms, persisters constitute a microbial subpopulation of cells characterized by a lower metabolic-activity, being phenotipically tolerant to high concentrations of antibiotics. Due to their extreme tolerance, persisters may cause relapses upon treatment discontinuation, leading to infection recalcitrance hindering the bony tissue regeneration. Using isothermal microcalorimetry (IMC), we aimed to evaluate in vitro the presence of persisters in a methicillin-resistant Staphylococcus aureus (MRSA) biofilm after treatment with high concentrations of vancomycin (VAN) and their ability to revert to a normal-growing phenotype during incubation in fresh medium without antibiotic. Moreover, the ability of daptomycin to eradicate the infection by killing persisters was also investigated. Method. A 24h-old MRSA ATCC 43300 biofilm was exposed to 1024 µg/ml VAN for 24h. Metabolism-related heat of biofilm-embedded cells, either during or after VAN-treatment, was monitored in real-time by IMC for 24 or 48h, respectively. To evaluate the presence of VAN-derived “persisters” after antibiotic treatment, beads were sonicated and detached free-floating bacteria were further challenged with 100xMIC VAN (100 µg/ml) in PBS+1% Cation Adjusted Mueller Hinton Broth (CAMHB).. Suspensions were plated for colony counting. The resumption of persister cells' normal growth was analysed by IMC on dislodged trated cells for 15h in CAMHB. Activity of 16 µg/ml daptomycin was assessed against persister cells by colony counting. Results. When incubated with 1024 µg/ml VAN, MRSA biofilm produced undetectable heat, suggesting a strong reduction of cell viability and/or cellular metabolism. However, the same samples re-inoculated in fresh medium produced a detectable and delayed metabolism-related heat signal, similarly to that generated by persister cells. The following exposure to 100xMIC VAN resulted in neither complete killing nor bacterial growth, strongly supporting the hypothesis of a persistent phenotype. IMC analysis indicated that VAN-treated biofilm cells resumed normal growth with a ∼3h-delay, as compared to the untreated growth control. Daptomycin treatment yielded a complete eradication of persister cells selected after VAN treatment. Conclusions. Hostile environmental conditions (e.g. high antibiotic bactericidal concentrations) select for persister cells in MRSA biofilm after 24h-treatment in vitro. A staggered treatment vancomycin/daptomycin allows complete biofilm eradication. These results support the use in clinical practice of a therapeutic regimen based on the combined use of antibiotics to kill persisters and eradicate MRSA biofilms. IMC represents a suitable technique to detect persisters and characterize in real-time their reversion to a metabolically-active phenotype

Purpose: This study investigates the synergistic use of fusidic acid with vancomycin, and linezolid in poly-methylmethacrylate (PMMA) cement for the treatment of orthopedic MRSA and MRSE infections. Alone, Vancomycin is typically eluted in limited quantities from cement. The purpose of this study was to. combine FA and Vancomycin, and Linezolid alone in PMMA cement and characterize antibiotic elution, and. to improve drug release using polyethylene glycol (PEG) and NaCl in PMMA cement. Method: Standardized 1g pellets of Palacos cement were manufactured containing Vancomycin and FA or Linezolid at increasing concentrations in three batches: without additive, with increasing concentrations of PEG, and with increasing concentrations of NaCl. The pellets were incubated in phosphate buffered saline and sampled at regular intervals. Drug analysis was performed with high pressure liquid chromatograpy. Results: Total drug release at 2.5% loading of Vancomycin alone was 0.84% and of FA was 2.35%. Linezolid showed comparable release profiles. Vancomycin and FA combined yeilded Vancomycin release of 6.2% and FA of 8.4%. The addition of 30% PEG increased release of Vancomycin and Fusidic Acid by six-fold. The addition of 18% NaCl increased total Vancomycin release by 11-fold but had no effect on FA release. Conclusion: Linezolid, Vancomycin and FA can be combined in PMMA and have favorable release profiles. The addition of PEG and NaCl dramatically increases the release of antibiotics, with the exception of FA and NaCl. These strategies may be useful in the management of MRSA/MRSE infections

Introduction. Calcium sulphate is a resorbable void filler that can be used for local antibiotic delivery. Results from clinical studies on chronic osteomyelitis thus treated with local vancomycin have already been published. Despite significant exposure to this drug, there are no pharmacokinetic studies published so far. Based on observations in our patients, a model predicting vancomycin serum and wound fluid levels and toxicity potential is presented. Methods. Following implantation of Osteoset® added with vancomycin, serum and wound fluid concentrations of this antibiotic have been monitored systematically. The pharmacokinetic analysis was performed using a non-linear mixed-effects model based on a one-compartment model with first-degree absorption. Results. Data from 43 patients treated between October 2006 and August 2010 were analysed. Serum concentrations remained far below the usually accepted trough levels of 10 mg/L, and were still acceptable in two cases of post-operative renal failure. Wound fluid concentrations around 1,000 mg/l were observed for the first 7–10 days, and remained above usual minimal inhibitory concentrations for approximately a month. Discussion and Conclusion. This is the first pharmacokinetic exploration of calcium sulphate added with vancomycin for local antibiotic therapy. The systemic exposure to vancomycin is low and appears safe even after implantation of up to 6 g vancomycin, except in case of markedly impaired renal function. Wound fluid concentrations of vancomycin appear extremely interesting for further studies

Deep periprostheses infection is a devastating complication that occurred in 8 to 20% of patients treated by en bloc resection and prosthetic reconstruction for bone sarcomas. The systemic safety of high dose vancomycin loaded spacer has been investigated but rarely the elution of vancomycin in vivo. The aim of the study is to evaluate the elution of vancomycin into the site of the excision arthroplasty to see if effective bactericidal activity can be obtained. Patients and Methods: From 2006 to 2008, 16 consecutive patients were managed by prosthetic exchange procedure using high dose vancomycin loaded cement. Patients were males :7, females :9. Average of age at the time of surgery was 22 years. Antibiotic-loaded methylmethacrylate cement beads were prepared by adding 4 g of vancomycin powder to a 40 g pack of Palacos R cement in the operative place immediately before the operation. We used 4 G vancomycin per batch of 40 G cement and generally used 2 to 4 batches of cement in one spacer depending of the size and length of resection. The average dose of vancomycin was 7.5 G (4–14.5). The wounds were closed with absorbable mono-filaments sutures over one suction drain. Intravenous antibiotics excluding vancomycin were given for 6 to 24 weeks. Patients biological values and the concentrations of vancomycin in the blood and in the aliquots of suction drainage were checked daily until removal of drain. Vancomycin was measured by fluorescent polarization immunoassay on the AxSYM analyzer (Abbott). Results: the serum concentration of vancomycin remained in all patients under 2 μg/ml confirming the systemic safety of the method. Local concentration of vancomycin depended of the dose of vancomycin used and decreased quickly during the first week: half life :2.25 days. For a dose of 10 G vancomycin, the average concentration in the liquid from the drain was :. d1 :725μg/ml. d2 :510 μg/ml. d3 :346 μg/ml. on day 10, its remained over 35μg/ml vancomycin in the aliquot of the drain. These results should be compared to the bactericidal concentration of vancomycin for staphylococcus aureus:10 to 20 μg/ml for usual organisms, 20 to 40 for resistant organisms. We had no reported cases of allergy, toxicity or intolerance. Conclusion : high dose vancomycin spacers result in very low serum concentration without risk of systemic toxicity. In the operative wound, very high concentration are obtained, 10 to 20 fold bactericidal concentration for staphylococcus aureus. Additional studies are needed, with longer follow-up to evaluate the clinical efficacy of this method

Background. Vancomycin and fosfomycin are antibiotic commonly used in Methicillin-resistant Staphylococcus aureus (MRSA) infection. This study compares the efficacy of articulating cement spacer implegnated with vancomycin and articulating cement spacer implegnated with fosfomycin to inhibit MRSA. Methods. Vancomycin implegnated articulating cement spacers and Fosfomycin implegnated articulating cement spacers were immersed in sterile phosphate buffered saline(PBS) and then incubated at 37 C. The samples were collected and change daily. Aliquots were tested for MRSA inhibition by disc diffusion method. The inhibition zones diameters were measured. Results. Vancomycin group showed an MRSA inhibition zone up to four weeks. However, Fosfomycin group showed inhibition zone in day 3 in some samples but after that no sample had the potential to inhibit MRSA. Conclusion. In this experiment. Vancomycin impregnated articulating cement spacers showed longer efficacy to inhibit MRSA when compared to Fosfomycin

The aim of the study is to evaluate the effect of acrylic cement CMW1 (DePuy) containing 2,5% of gentamicin and addition of 5 % and 10 % of respective vancomycin, meropeneme and ceftriaxone on growth inhibition of reference strains of MRSA, E. faecalis, S. aureus, P. aeruginosa and E. coli. From every portion of investigated acrylic cement CMW1 discs were cut with a diameter of 15mm and a thickness of 5mm, average weight 1.365 g (+/− 0,257g). Inoculum was prepared with the reference strains: MR3 S. aureus methicillin-resistant (MRSA), ATCC 29219 E. faecalis, ATCC 25923 S. ureus, ATCC 27853 P. aeruginosa and ATCC 25922 E. coli. A colonies of bacteria taken from a 18-hour culture on solid medium were addend to tubes with sterile physiological saline solution to obtain a density of 0.5 McFarland (5 × 105 CFU / ml). The suspension was distributed evenly over the Mueller-Hinton (MH) medium (Biomerieux, France). Prepared discs of CMW1 cement were put with a sterile forceps on the plate with a dry medium. The plates were incubated aerobically at 24 hr and the temp. 37°C. After 24 hours the diameter of zone of inhibition of bacterial growth on a plate was measured (in mm) and average size of the inhibition zone was calculated. The CMW1 cement inhibited to a comparable degree growth of reference strains with the exception of E. faecalis. The addition of vancomycin increased by 1/5 inhibitory potential of CMW1 cement on growth of MRSA, S. aureus, P. aeruginosa and E. coli. and significantly for E. faecalis. Changing the concentration of vancomycin, meropeneme and ceftriaxone from 5% to 10% do not increased the inhibitory potential of CMW1 cement on the growth of MRSA, S. aureus, P. aeruginosa, E. coli and E. faecalis. Addition of meropeneme increased inhibitory potential of CMW1 cement against MRSA by 1/3, P. aeruginosa and E. coli by ½, E. faecalis by 3/4 and against S. aureus by 100%. Addition of ceftriaxone to CMW1 cement increased the inhibiting of the growth of MRSA similiarly to 5% and 10% of vancomycin, E. faecalis as meropeneme 5% and 10 %, while the growth of S. aureus and P. aeruginosa, less than meropeneme. Addition of antibiotics to acrylic cement increased its antibacterial properties. Increase if vancomycine concentrations from 5 to 10% had no stronger antibacterial effect

Two-stage exchange revision is the gold standard in treating an infected total hip arthroplasty. The new emerging gold standard appears to be using an antibiotic impregnated spacer made from polymethylmeta-crylate (PMMA) bone cement between two stages. However, a consensus has not been reached on the antibiotic to use in the cement and its dose. Vancomycin an aminoglycoside is widely used for this purpose in the PMMA cement in doses such as 3 to 9 gr per 40 gr polymer powder. The purpose of this study was to see if Vancomycin is as effective in safer low doses of 1 gr per 40 gr polymer powder.Between 1997 and 2002, twenty-six patients were treated for an infected hip arthroplasty with a two-stage exchange arthroplasty using a Vancomycin impregnated polymethylmetacrylate (PMMA) bone cement spacer. During the first stage all prosthetic material was removed and after debridement, irrigation an articulating spacer was made from PMMA cement (Surgical Simplex, Howmedica, Rutherford, NJ, USA). One gram of Vancomycin HCl (Vancomycin, Eli Lilly, USA) powder was added to each 40 gr polymer powder prior to curing the cement. After the first stage parenteral antibiotics were administered for six weeks. When erythrocyte sedimentation rate and the CRP returned to a normal level, the patient underwent the second stage were a cementless prosthesis was inserted. Intra-operative cultures and frozen sections obtained during the second stage were negative in all patients indicating successful treatment of the infection. Mean follow up after the second stage was 36 (range 24 to 74) months. Two patients had a reinfection after four months. These two patients were infected with gram-negative micro-organisms. This gave us a 92 percent infection eradication rate at 3 years. None of the patients suffered from Vancomycin related side effects.In this study we used a lower dose (1 gr per 40 gr polymer powder) of Vancomycin in the PMMA spacer instead of the commonly used 3 to 9 gr per 40 gr polymer powder. The reason for this was our concerns for nephrotoxicity and allergic reactions frequently associated with use of Vancomycin. Antibiotics are used in cement spacers as a disinfecting agent and sterilizer of dead spaces. As Vancomycin is highly effective when used in PMMA due to its elution dynamics and thermostability we believed it would be effective even in low doses. In all patients the infection appeared to be cured after the first stage. This was demonstrated with negative intraoperative cultures and frozen sections. However, we had two reinfections in patients that initially were infected with gram-negative organism, which Vancomycin is not as effective. Despite this we were able to sterilize the infected hip with a low dose approach in the first stage. Vancomycin is effective in low dose when used in PMMA cement spacers for infected total hip arthroplasties. This approach will decrease potential serious side effects of Vancomycin

Introduction: Purified plaster of Paris can be used as a resorbable carrier material for local antibiotic therapy. Clinical use already has been published with vancomycin and the aminoglycosides gentamycin and tobramycin. Calcium sulphate pellets with vancomycin can be manufactured during operation from Osteoset. ®. and vancomycin powder, whereas calcium sulphate with tobramycin is available as ready-to-use pellets under the brand name Osteoset T. ®. Results are promising. However, no data on systemic serum levels in humans have been published so far, despite well known toxicity issues of these antibiotics in systemic therapy. Methods: Following implantation of calcium sulphate with vancomycin or tobramycin, systemic serum levels of these antibiotics have been measured for up to 10 days, and prospectively gathered. Considering serum levels and renal function, pharmacokinetics have been estimated. Results: Between August 2006 and February 2008, calcium sulphate with vancomycin has been implanted in 15 patients, and with tobramycin in 12 patients. Whereas vancomycin levels remained very low, tobramycin levels close to the usually accepted trough levels could be observed at 24h post-operation. Conclusion: Vancomycin added to calcium sulphate has a safe systemic profile. On the contrary, significant serum levels of tobramycin can be measured more than 24h after implantation. Caution is mandatory when using this antibiotic, and explantation should be considered if levels too high are observed

This study aimed to determine the optimal formulation of antibiotic-loaded bone cement (ALBC) for periprosthetic joint infection (PJI) using both in vitro and in vivo models incorporating various combinations of gram-positive and gram-negative antibiotics. The in vitro antibiotic release characteristics and antibacterial capacities of ALBCs loaded with either 4 g of vancomycin or teicoplanin and 4 g of ceftazidime, imipenem, or aztreonam were measured against methicillin-susceptible S. aureus, methicillin-resistant S. aureus, coagulase-negative staphylococci, Pseudomonas aeruginosa and Escherichia coli. ALBC spacers with superior in vitro antibacterial capacity were then implanted into ten patients (five females and five males between 29 and 75 years of age) diagnosed with chronic hip/knee PJIs and antibacterial activities within joint fluid were measured. The average duration of ALBC spacer implantation was 80 days (range, 36–155 days). Antibiotic concentrations and antibacterial activities of joint fluid at the site of infection were measured during the initial period as well as several months following spacer implantation. Cement samples loaded with vancomycin/ceftazidime or teicoplanin/ceftazidime exhibited equal or longer antibacterial duration against test bacteria as compared with other ALBCs. Joint fluid samples exhibited antibacterial activity against the test microorganisms including ATCC strains and clinically isolated strains. There were no adverse systemic effects, infection at second stage re-implantation, or recurrent infection at final follow-up. Vancomycin/ceftazidime ALBC provided broad antibacterial capacity both in vitro and in vivo and was shown to be an effective and safe therapeutic measure in the treatment of hip/knee PJIs. We thank H.Y. Hsu for performing bioassay

The efficacy of saline irrigation for the treatment of periprosthetic infection (PJI) is limited in the presence of infected implants. This study evaluated the efficacy of vancomycin/tobramycin-doped polyvinyl alcohol (PVA)/ceramic composites (PVA-VAN/TOB-P) after saline irrigation in a mouse pouch infection model. 3D printed porous titanium (Ti) cylinders (400, 700 and 100 µm in pore size) were implanted into mice pouches, then inoculated with S. aureus at the amounts of 1X10. 3. CFU and 1X10. 6. CFU per pouch, respectively. Mice were randomized into 4 groups (n=6 for each group): (1) no bacteria; (2) bacteria without saline wash; 3) saline wash only, and (4) saline wash+PVA-VAN/TOB-P. After seven days, pouches were washed out alone or with additional injection of 0.2 ml of PVA-VAN/TOB-P. Mice were sacrificed 14 days after pouch wash. Bacteria cultures of collected Ti cylinders and washout fluid and histology of pouch tissues were performed. The low-grade infection (1X10. 3. CFU) was more significant in 400 µm Ti cylinders than that in Ti cylinders with larger pore sizes (700 and 1000 µm (p<0.05). A similar pattern of high-grade infection (1X10. 6. CFU) was observed (p<0.05). For the end wash, the bacteria burden (0.49±0.02) in saline wash group was completely eradicated by the addition of PVA-VAN/TOB-P (0.005±0.001, p<0.05). We noticed that 400 µm Ti cylinders have the highest risk of implant infection. Our data supported that the effect of saline irrigation was very limited in the presence of contaminated porous Ti cylinders. PVA-VAN/TOB-P was biodegradable, biocompatible, and was effective in eradicating bacteria retention after saline irrigation in a mouse model of low grade and high-grade infection. We believe that PVA-VAN/TOB-P represents an alternative to reduce the risk of PJI by providing a sustained local delivery of antibiotics

Introduction: It is common practice to use additional antibiotics in bone cement for revision hip surgery. Ideally antibiotic elution would initially be rapid and then reduce to zero in order to reduce the risk of antibiotic resistance developing. There is evidence that the addition of antibiotics to bone cement leads to deterioration in mechanical properties. We have carried out a study to see if the addition of vancomycin to Palacos R40G and Smartset GHV affects their in-vitro antibiotic elution and mechanical properties. Methods: Palacos R40G (contains 0.5g gentamycin per 40g mix) and Smartset GHV (contains 1g gentamycin per 40g mix) were used. 40g samples of the two cements with no additional vancomycin, 1g and 2g vancomycin were prepared by a standard method using vacuum mixing in a syringe. Antibiotic elution over a five week period was measured using an immunoassay method. Standard mechanical testing was carried out according to methods defined in ISO 5833. Results: Smartset GHV eluted double the quantity of gentamycin as Palacos R40G, as would be expected. Both cements eluted more gentamycin when vancomycin was added. Smartset appears to elute more vancomycin than Palacos initially and then shows a more rapid tailing off. The mechanical properties of the two cements were the same with no statistical differences found between them. Both showed deterioration in flexural strength with addition of increasing vancomycin. Discussion: Smartset may have improved qualities of antibiotic elution as compared with Palacos with similar mechanical properties. The presence of higher initial quantities of gentamycin does not lead to reduced mechanical properties

Objective. In the present study, we aimed to assess whether gelatin/β-tricalcium phosphate (β-TCP) composite porous scaffolds could be used as a local controlled release system for vancomycin. We also investigated the efficiency of the scaffolds in eliminating infections and repairing osteomyelitis defects in rabbits. Methods. The gelatin scaffolds containing differing amounts of of β-TCP (0%, 10%, 30% and 50%) were prepared for controlled release of vancomycin and were labelled G-TCP0, G-TCP1, G-TCP3 and G-TCP5, respectively. The Kirby-Bauer method was used to examine the release profile. Chronic osteomyelitis models of rabbits were established. After thorough debridement, the osteomyelitis defects were implanted with the scaffolds. Radiographs and histological examinations were carried out to investigate the efficiency of eliminating infections and repairing bone defects. Results. The prepared gelatin/β-TCP scaffolds exhibited a homogeneously interconnected 3D porous structure. The G-TCP0 scaffold exhibited the longest duration of vancomycin release with a release duration of eight weeks. With the increase of β-TCP contents, the release duration of the β-TCP-containing composite scaffolds was decreased. The complete release of vancomycin from the G-TCP5 scaffold was achieved within three weeks. In the treatment of osteomyelitis defects in rabbits, the G-TCP3 scaffold showed the most efficacious performance in eliminating infections and repairing bone defects. Conclusions. The composite scaffolds could achieve local therapeutic drug levels over an extended duration. The G-TCP3 scaffold possessed the optimal porosity, interconnection and controlled release performance. Therefore, this scaffold could potentially be used in the treatment of chronic osteomyelitis defects. Cite this article: J. Zhou, X. G. Zhou, J. W. Wang, H. Zhou, J. Dong. Treatment of osteomyelitis defects by a vancomycin-loaded gelatin/β-tricalcium phosphate composite scaffold. Bone Joint Res 2018;7:46–57. DOI: 10.1302/2046-3758.71.BJR-2017-0129.R2

With the dramatic improvement of conservative surgery in patients with bone sarcoma, infection becomes 1 of the most devastating complication, leading frequently to amputation. The aim of this monocentric study is to precise the influence of spacer loaded with high doses of vancomycin on late Results: PATIENTS From 1984 to 2007, we operated more than 600 patients (p)with bone sarcoma. Age of p. was 4,5 to 82 years (mean 25 y). Histology was osteosarcoma (304), Ewing (142), chondrosarcomas (148), fibrosarcomas or MFH (23), giant cell tumours in others. In 484 cases, p received chemotherapy, and radiotherapy in 50 cases. The mean follow-up from tumour removal is 15 years. 57 p suffered of deep infection of the material used to reconstruct the skeletal defect. We have seen also 3 p for recurrence of deep infection initially treated elsewhere. Altogether, we treated 60 patients for deep infections. Methods: 26 p had debridment and cleaning of the pros-thesis and long adapted antibiotherapy as first treatment. When ineffective (23/26), a removal of the prosthesis was performed with immediate replacing the new prosthesis in 19 cases. When infection recurred (16/19) and in all other patients the treatment included a two stages protocol with interposition of a spacer with antibiotic loaded cement during 4 to12 weeks. Until 2004, the spacer was made with gentamycin containing palacos mixed with conventional doses of antibiotics adapted to the germ. From 2004/6 we used high doses of vancomycin (4 g per batch of 40 g) with an average total dose of 11g of vancomycin per spacer. The new prosthesis was placed in a later time, when infection, cutaneous and muscular problems were solved. Results: At the last control, 15 were amputated, following a mean of 6 ineffective procedures. 45 p. benefited from conservation surgery but a new prosthesis could be inserted only in 43, following a mean of 3.2 surgical procedures, Analysis shows the bad prognostic value of initial radiotherapy, of distal locations, and of insufficient muscular coverage and the better efficacy of high dose antibiotics in spacer. Up to date, none of the high dose antibiotic loaded spacers was followed by amputation. Conclusion: Infection of massive prostheses is the most serious orthopaedic complication of limb salvage. Treatment must be preventive, avoiding any radiotherapy. Good prognostic factors are early removal of the prosthesis, effective antibiotherapy, improvement of the muscular coverage, and use of spacers with high dose vancomycin

Objective. To assess the beneficial use of polypropylene mesh impregnated with vancomycin in an experimental model open fractures Gustilo IIIa in rabbits. Material and Method. We worked with 15 New Zeland White rabbits. All of them were carried out under general anaesthetic, a 5-cm incision longitudinal was made at the back of the right thigh. The femur was aproached and a fracture was performed with a shear, giving rise to a multifragment fracture. The wound remained open for 6 hours with the bone exposed, in a non-surgical ambient. Subsequently underwent surgical cleaning of the open fractures in two stages. The fracture was stabilized with an intramedular pin. The animals were sorted in 3 different therapeutic groups:. Group 1: (5 rabbits) without other treatment. Group 2: (5 rabbits) a polypropylene mesh was placed around the fracture. Group 3: (5 rabbits) a polypropylene mesh with vancomycin was placed around the fracture. The wound was closed with nylon stiches. Three weeks postoperative, the animals were intervened surgically under general anesthesia, after aseptic cure and placement of surgical fields, femoral bone biopsies, soft tissue and mesh were taken. The rabbits were sacrified. The samples were sent to pathology and bacteriology labs. Results. The bacteria isolated were as follows: Escherichia coli, Pasteurella multocida, Staphylococcus spp., Clostridium spp. Mamheinia spp. The Clostridium spp. is a common contaminant in the exposed fractures present in the environment. The Pasteurella mustocida is a microorganism present in the oral cavity of rabbits, as well as Escherichia coli is a germ present in the animal's digestive tract. Mannheimia spp. It is a beta-hemolytic organism, found in the nasal flora of these animals and their pathological role is not elucidated. Staphylococcus spp. is a germ that is found in the normal flora of the animals skin. Group 1 showed a relative risk for an infection. For Group 2 the relative risk was substantially greater than 1.4, while in Group 3, the relative risk was 0.6, significantly lower than the previous two groups. The results have shown a beneficial effect of the use of impregnated polypropylene mesh with vancomycin in this animal group. Conclusion. The use of polypropylene meshes with vancomycin could be useful in the treatment of muscle and ligamentary deficits in patients with open fractures Gustillo IIIa

Aim. The use of piperacillin/tazobactam with vancomycin as empirical antimicrobial therapy (EAT) for prosthetic joint infection (PJI) has been associated with an increased risk of acute kidney injury (AKI), leading to propose cefepim as an alternative since 2017 in our reference center. The present study compared microbiological efficacy and tolerance of these two EAT strategies. Method. All patients with PJI empirically treated by vancomycin-cefepim (n=90) were prospectively enrolled in an observational study, and compared with vancomycin-piperacillin/tazobactam-treated historical controls (n=117), regarding: i) the proportion efficacious empirical regimen (i.e., at least one of the two molecules active against the identified organism(s) based on in vitro susceptibility testing); and ii) the incidence of empirical therapy-related adverse events (AE), classified according to the Common terminology criteria for AE (CTCAE). Results. Among the 146 (67.3%) documented infections, the EAT was considered as efficacious in 99 (99.0%) and 66 (98.5%) in the piperacillin-tazobactam and cefepim-treated patients, respectively (p=0.109). The rate of adverse events, and in particular AKI, was significantly higher in the vancomycin-piperacillin/tazobactam (n=38 [32.5%] and 32 [27.6%]) compared to the vancomycin-cefepim (n=13 [14.4%] and 5 [5.7%]) group (p=0.003 and <0.001, respectively). Of note, sex, age, and the proportion of patients receiving other nephrotoxics were similar among piperacillin/tazobactam- and cefepim-treated patients. However, in comparison with patients receiving cefepim, a higher modified Charlson's comorbitidy index (4 [IQR, 3–5] versus 2 [IQR, 2–4], p<0.001) has to be acknowledged, mainly related to a higher prevalence of baseline chronic renal injury (n=62, 53.4% versus n=34, 38.6%; p=0.035). Conclusions. The empirical use of vancomycin-cefepim in PJI was as efficient as vancomycin-piperacillin/tazobactam, and was associated with a significantly lower incidence of AKI

Objectives. The objective of this study was to compare the elution characteristics, antimicrobial activity and mechanical properties of antibiotic-loaded bone cement (ALBC) loaded with powdered antibiotic, powdered antibiotic with inert filler (xylitol), or liquid antibiotic, particularly focusing on vancomycin and amphotericin B. Methods. Cement specimens loaded with 2 g of vancomycin or amphotericin B powder (powder group), 2 g of antibiotic powder and 2 g of xylitol (xylitol group) or 12 ml of antibiotic solution containing 2 g of antibiotic (liquid group) were tested. Results. Vancomycin elution was enhanced by 234% in the liquid group and by 12% in the xylitol group compared with the powder group. Amphotericin B elution was enhanced by 265% in the liquid group and by 65% in the xylitol group compared with the powder group. Based on the disk-diffusion assay, the eluate samples of vancomycin-loaded ALBC of the liquid group exhibited a significantly larger inhibitory zone than samples of the powder or the xylitol group. Regarding the ALBCs loaded with amphotericin B, only the eluate samples of the liquid group exhibited a clear inhibitory zone, which was not observed in either the xylitol or the powder groups. The ultimate compressive strength was significantly reduced in specimens containing liquid antibiotics. Conclusions. Adding vancomycin or amphotericin B antibiotic powder in distilled water before mixing with bone cement can significantly improve the efficiency of antibiotic release than can loading ALBC with the same dose of antibiotic powder. This simple and effective method for preparation of ALBCs can significantly improve the efficiency of antibiotic release in ALBCs. Cite this article: Bone Joint Res 2014;3:246–51

Two-stage revision surgery is the current gold standard for treating prosthetic joint infections (PJI). Between the first and the second stage gentamicin-loaded (G) spacers are widely used but the rate of gentamicin resistant staphylococci is increasing. The potential benefit of vancomycin + gentamicin-loaded (V/G) spacers has not yet been evaluated. The aim of our study was to compare the microbiological eradication and infection control rates in PJI treated with G- or V/G-spacers. 147 PJIs treated in our institution were retrospectively reviewed. From 2003 to 2009 G-spacers (Tecres®) were used (group G) and from 2010 to 2013 V/G-spacers (Group V/G). Gender, age, body mass index (BMI), co-morbidities, ASA score, type of infection, microorganisms isolated in the first and second stages, time between stages, infection outcome at last visit were collected. The 2 main outcome variables were microbiological eradication in the second stage (≤1 positive culture out of 6) and infection control after the second stage. Univariate and multivariate analysis were performed using SPSS®. There were 83 patients in group G and 63 in group V/G. The mean (SD) age was 71.5 (10.3) years and 54% were female. Groups were similar in gender, age, BMI, ASA score, time with spacer, microorganism isolated in the first stage, or type of infection (acute or chronic) (p>0.05). The presence of ≥2 positive cultures in the second stage was significantly higher in group G (23.2%) than in group V/G (6.7%, P<0.05). Logistic regression model identified polymicrobial infections (OR: 4.26, CI95%: 1.44–12.64) and the use of G-spacers (OR: 5.88, CI95%: 1.60–21.74) as independent predictors of failure in microbiological eradication. The global rate of infection control was 75% after a mean (SD) follow-up of 56 (32) months. Infection control was higher in chronic than acute PJI (83.6% vs 59.6%, P<0.05), when cultures during second stage were negative (81.5%) vs positive (61%, P<0.05), and there was a trend towards a higher control rate when V/G-spacers (82%) vs G-spacers (69.5%) were used (P=0.09). Multivariate analysis identified chronic PJI (OR: 5.43, CI95%: 2.20–13.51) and, at the limit of significance, the use of V/G spacers (OR: 2.36, CI95%: 0.97–5.71) as predictors of infection control. Vancomycin loaded spacers were significantly associated with a higher microbiological eradication and there was a trend towards a higher infection control than gentamicin loaded spacers

The incidence of infection after primary arthroplasty is low. However, with the increasing number of arthroplasties being performed the prevalence of infection is increasing. The pattern of infecting organisms following total joint arthroplasty has changed and gentamicin resistant organisms are becoming increasingly common. Vancomycin added to bone a cement carrier can, with adequate surgical debridement be very effective in the eradication of established resistant infection. We report the results of its use in 33 patients with 26 infected hip and 7 infected knee arthroplasies. 32 patients remain clinically and radiologically free of infection after a mean follow-up of 67 months. There was one recurrence of infection and there were three positive second stage cultures of uncertain significance. Vancomycin is potentially a very useful tool in the management of deep infection following arthroplasty surgery

Aims. The aims of this study were to compare the mean duration of antibiotic release and the mean zone of inhibition between vancomycin-loaded porous tantalum cylinders and antibiotic-loaded bone cement at intervals, and to evaluate potential intrinsic antimicrobial properties of tantalum in an in vitro medium environment against methicillin-sensitive Staphylococcus aureus (MSSA). Materials and Methods. Ten porous tantalum cylinders and ten cylinders of cement were used. The tantalum cylinders were impregnated with vancomycin, which was also added during preparation of the cylinders of cement. The cylinders were then placed on agar plates inoculated with MSSA. The diameter of the inhibition zone was measured each day, and the cylinders were transferred to a new inoculated plate. Inhibition zones were measured with a Vernier caliper and using an automated computed evaluation, and the intra- and interobserver reproducibility were measured. The mean inhibition zones between the two groups were compared with Wilcoxon’s test. Results. MSSA was inhibited for 12 days by the tantalum cylinders and for nine days by the cement cylinders. At day one, the mean zone of inhibition was 28.6 mm for the tantalum and 19.8 mm for the cement group (p < 0.001). At day ten, the mean zone of inhibition was 3.8 mm for the tantalum and 0 mm for the cement group (p < 0.001). The porous tantalum cylinders soaked only with phosphate buffered solution showed no zone of inhibition. Conclusion. Compared with cement, tantalum could release antibiotics for longer. Further studies should assess the advantages of using antibiotic-loaded porous tantalum implants at revision arthroplasty. Cite this article: Bone Joint J 2019;101-B:848–851

Introduction. To evaluate the clinical success and hip pain and function of patients with infected hip replacement treated by two-stage exchange using a temporary implant with high dose vancomycin added to the antibiotic cement at the first stage revision. Method. Thirty-three hips in 32 patients (median 67 yrs) underwent first stage revision using the PROSTALAC™ system (n=27) or a self-made system using an Elite long stem (n=6). Infection was diagnosed after 19 primary, 11 revision and 3 hemiarthroplasty hip replacements. Patients were reviewed regularly clinically and by questionnaire. The median follow-up was 3 years. Results. Five hips (15%) had repeat first stage for persistent infection. Twenty-four hips (73%) progressed to second stage. Five hips (15%) did not progress to second stage. Four hips (12%) underwent excision arthroplasty. There was a further one recurrence of infection (4%) requiring repeat two stage revision at 3 years. Patients reported, on average, minimal to no hip pain after second stage. The median Harris Hip Score (HHS) after first stage was 59, and at 2 years after second stage was 75. For comparison, the 2 year HHS in our patients that had undergone standard cemented femoral revision was 75. Conclusion. A temporary hip implant with high-dose vancomycin cement has improved our clinical management of infected hip replacement after the second stage THR. Patients report hip pain and function that compares to that achieved for standard revision hip replacement

Introduction. Antibiotic-loaded acrylic cement (ALAC) is employed in the treatment or prevention of infected total hip arthroplasty (THA). We have administered vancomycin (VCM) as the ALAC for the treatment of THAs with methicillin-resistant Staphylococcus aureus, or for the prevention of THAs with high risks. This study aimed to evaluate the serum concentration of VCM from ALAC in THA or cement beads. Methods. Between December 2013 and February 2014, 16 hips (16 patients) underwent application of the ALAC including VCM at our institution. Two hips were used for the treatment of infection, in the first stage of two-staged revision THAs (i.e., cement beads). Two hips were used for the both treatment and prevention of infection, in one-staged revision THAs. Twelve hips were used for the prevention of infection, in aseptic revision THAs or primary THAs with high risks. Patients were classified into two groups depending on the VCM concentration of ALAC, as follows: high-dose group (2 hips), average 4.4% (3.8–5.0%); low-dose group (14 hips), average 1.6% (1.3–2.5%). The amount of VCM placed as ALAC into the hip was calculated by using the remaining ALAC. The serum concentration of VCM was evaluated at 1 day, 4 days, 7 days, and 28 days after surgery. Statistical analysis was performed by using the t-test, and the differences were considered significant when the p value was <0.05. Results. Average amount of VCM placed as ALAC was 3.5 g (3.1–4.0 g) and 0.9 g (0.3–2.0 g) in the high- and low-dose groups, respectively. The average serum concentration of VCM (μg/mL) was 2.5 and 1.1 on day 1, 2.8 and 1.2 on day 4, 2.3 and 1.1 on day 7, and 1.9 and 1.0 on day 28, in the high- and low-dose groups, respectively. There were significant differences in the high- and low-dose groups on all days. Conclusions. Although the serum concentration of VCM in the high-dose group is significantly increased compared to that in the low-dose group, it is always under the effective blood concentration (5–10 μg/mL) and seem to be clinically safe. Further, we confirmed the continuous effect of ALAC, including VCM, because they were detected at 28 days. However, careful continued follow-up and further evaluation will be required

Aims: Evaluation of postoperative infections in T.H.R. and T.K.R., after randomized prophylactic use of Fusidic acid, Vancomycin and Cefuroxime and assessment of their side effects. Methods: From December 2000 to April 2002, 128 patients were operated on T.H.R. and T.K.R. in Orthopaedic Department of University of Patras (64 for T.H.R. and 47 for T.K.R.). Mean age was 66.5 years (range 45–90yrs.). The patients were categorized into three groups. In the first group was administrated Fusidic acid 500mg and Cefuroxime 1.5gr preoperatively and 2 doses of Fusidic acid 500mg postoperatively. The second group received Vancomycin 1gr and Cefuroxime 1.5gr preoperatively and 2 doses of Vancomycin 1gr postoperatively. The third group received Cefuroxime 1.5gr preoperatively and 2 doses of Cefuroxime 750mg postoperatively. Blood tests were systematically performed preoperatively, and the first and fifth postoperative day. Mean follow up was 8 months. Results: No deep wound infection was observed. Superficial infections developed 2 pt. (1.58%) of the first group, 2 pt. (1.58%) of the second group and 3 pt. (2.3%) of the third group. Temperature over 38.3° C attributed to another infection site was observed in 4 pt. of the first group, 2 pt. of the second group and 7 pt. of the third group, while temperature over 38.3° C with unknown origin was noted in 7,2,6 patients respectively. No side effect was recorded. Conclusions: The proper use of antibiotic prophylaxis according to pharmakokinetic and pharmakodvnamic properties combined with sterile surgical techniques, prevents early deep wound infections in T.H.R. and T.K.R. The use of specific antistaphylococcal agents is of no benefit in antimicrobial prophylaxis for the above operations

Aims: Evaluation of postoperative infections in T.H.R. and T.K.R., after randomized prophylactic use of Fusidic acid, Vancomycin and Cefuroxime and assessment of their side effects. Methods: From December 2000 to September 2002, 182 patients (43 males and 139 females), were operated on T.H.R. and T.K.R. in Orthopaedic Department of University of Patras. Mean age was 65.8 years (range 33–90yrs.). The patients were categorized into three groups (A, B and C). In group A was administrated Fusidic acid 500mg and Cefuroxime 1.5gr preoperatively and 2 doses of Fusidic acid 500mg postoperatively. Group B received Vancomycin 1gr and Cefuroxime 1.5gr preoperatively and 2 doses of Vancomycin 1gr postoperatively. Group C received Cefuroxime 1.5gr preoperatively and 2 doses of Cefuroxime 750mg postoperatively. Blood tests were systematically performed preoperatively, and the þrst and þfth postoperative day. Mean follow up was 10,5 months (range 2–21 months). Results: One patient of group B developed deep wound infection. Superþcial infections developed 2 pt. (3.2%) of group A, 2 pt. (3.9%) of group B and 2 pt. (2.8%) of group C. Temperature over 38.3û C attributed to another infection site was observed in 6 pt. (9.8%) of group A, 3 pt. (5.8%) of group B and 5 pt. (7.1%) of group C, while temperature over 38.3û C with unknown origin was noted in 7,3,8 patients respectively. No side effect was recorded. Conclusions: The proper use of antibiotic prophylaxis according to pharmakoki-netic and pharmakodynamic properties combined with sterile surgical techniques prevents early deep wound infections in T.H.R. and T.K.R. The use of speciþc anti-staphylococcal agents is of no beneþt in antimicrobial prophylaxis for the above operations

Aim. To evaluate the ability of different combinations of antibiotic loaded cement to inhibit bacteria growth and biofilm formation. Method. Cement beads were aseptically prepared using Palacos R (plain 40g PMMA cement) or Palacos R+G (40g PMMA cement containing industrially added 0.5g of gentamicin), with or without supplementary antibiotics as follows: Palacos R; Palacos R+G; Palacos R plus 1g / 2g daptomycin; Palacos R+G plus 1g / 2g of daptomycin; Palacos R plus 1g / 2g vancomcyin; and Palacos R+G plus 1g / 2g vancomycin. After production, each antibiotic loaded acrylic cement (ALAC) combination was allocated into two groups (group 1 and 2). The group 2 cement beads were initially eluted in broth at 37. o. C for 72hours then transferred to fresh broth containing a known concentration of bacteria. The group 1 samples were not eluted but directly immerse in culture broth containing bacteria. All samples were thereafter incubated at 37. o. C for 24 hours. After incubation, group 1 samples were visually assessed for bacterial growth, while for the group 2 samples, biofilm formation were quantified using ultrasonication and viable bacteria counting technique. Three proficient biofilm forming Staphylococcus epidermidis bacterial strains (1457, 1585-RA and 5179-R1) were used for all experiments and the bacteria counts were expressed as colony forming units / ml (CFU/ml). Results. In the group 1 samples, all the ALAC combinations were able to inhibit growth of all the three biofilm bacteria strains assessed except the gentamicin only samples in which biofilm growth were observed within 24hours. Meanwhile, in group 2, bacterial growth and biofilm formation by all three bacterial strains were observed on all the ALAC combinations, with the least biofilm formation being on the Palacos R+G plus 2g daptomycin combinations (mean CFU/ml: 1.04E +06) and the greatest on the gentamicin only cement (mean CFU/ml: 2.3E +07). Conclusions. Our study demonstrates that the highest antimicrobial activity of ALAC is seen in the first 24 hours. However, after 72 hours of antibiotic release, fresh bacterial exposure in fresh broth resulted in varying degrees of biofilm colonisation of all ALAC surfaces. Nonetheless, the overall biofilm formation was least on the gentamicin / daptomycin combinations and the results were statistically significant when compared to plain cement (p < 0.05, two tail t-test)

Aims

This study investigated vancomycin-microbubbles (Vm-MBs) and meropenem (Mp)-MBs with ultrasound-targeted microbubble destruction (UTMD) to disrupt biofilms and improve bactericidal efficiency, providing a new and promising strategy for the treatment of device-related infections (DRIs).

Aim To document an outbreak of Vancomycin Resistant Enterococci in an elective Orthopaedic Unit. To describe the clinical course of the affected patients and treatment options. To describe methods employed in eradicating endemicity following the outbreak and to evaluate the lessons learnt. Background VRE first appeared in the Microbiological literature in 1988. Very little is known about its effect in the Orthopaedic Realm. To our knowledge, this is the first report of a serious outbreak in such a unit and only the second reporting of peri-prosthetic VRE infection. Material and methods All patients in the unit over a 1/12 unit formed the cohort for the study. Following identification of the index case, samples were taken form all in-patients. Immediately a nurse specialist in infection control oversaw sampling of all patients. Microbiological data, Clinical Data and antimicrobial therapy data was collected on all positive patients. Rapid laboratory procedure were instituted, environmental screening was preformed and a dedicated cleaning team was formed. The assistance of a Clinical Microbiologist and an Environmental Microbiologist was sought. Results Following identification of the index case, 11 patietns had microbiological proven VRE. 1 patient had a VRE confirmed peri-prosthetic infection. This necessitated removal and appropriate anti-microbial therapy. However, this patient died. 2 pateints were found to have superficial wound infection, which resolved with oral Linezolid, while 8 patients showed colonization with the organism. No treatment was required other than clinical follow up and staged screening in these patients. The unit was closed for 9 weeks following the outbreak and deep cleaning resulted in eradication of endemicity. Conclusion Tracing of the index case and typing allowed us to confirm the source of the outbreak and to take steps to prevent a recurrence. Appropriate microbiological advice is essential in an outbreak situation, management of peri-prosthetic infection and follow up of affected cases. All protocols have been re-evaluated and retraining of all staff in good clinical hygiene has been undertaken. The speed of the outbreak and its devastating effect on a Joint Replacement Facility is alarming and should serve to aid other units in establishing preventative protocols and in preplanning their treatment options and an outbreak team

Aims. Delayed postoperative inoculation of orthopaedic implants with persistent wound drainage or bacterial seeding of a haematoma can result in periprosthetic joint infection (PJI). The aim of this in vivo study was to compare the efficacy of vancomycin powder with vancomycin-eluting calcium sulphate beads in preventing PJI due to delayed inoculation. Methods. A mouse model of PJI of the knee was used. Mice were randomized into groups with intervention at the time of surgery (postoperative day (POD) 0): a sterile control (SC; n = 6); infected control (IC; n = 15); systemic vancomycin (SV; n = 9); vancomycin powder (VP; n = 21); and vancomycin bead (VB; n = 19) groups. Delayed inoculation was introduced during an arthrotomy on POD 7 with 1 × 10. 5. colony-forming units (CFUs) of a bioluminescent strain of Staphylococcus aureus. The bacterial burden was monitored using bioluminescence in vivo. All mice were killed on POD 21. Implants and soft-tissue were harvested and sonicated for analysis of the CFUs. Results. The mean in vivo bioluminescence in the VB group was significantly lower on POD 8 and POD 10 compared with the other groups. There was a significant 1.3-log. 10. (95%) and 1.5-log. 10. (97%) reduction in mean soft-tissue CFUs in the VB group compared with the VP and IC groups (3.6 × 10. 3. vs 7.0 × 10. 4. ; p = 0.022; 3.6 × 10. 3. vs 1.0 × 10. 5. ; p = 0.007, respectively) at POD 21. There was a significant 1.6-log. 10. (98%) reduction in mean implant CFUs in the VB group compared with the IC group (1.3 × 10. 0. vs 4.7 × 10. 1. , respectively; p = 0.038). Combined soft-tissue and implant infection was prevented in 10 of 19 mice (53%) in the VB group as opposed to 5 of 21 (24%) in the VP group, 3 of 15 (20%) in the IC group, and 0% in the SV group. Conclusion. In our in vivo mouse model, antibiotic-releasing calcium sulphate beads appeared to outperform vancomycin powder alone in lowering the bacterial burden and preventing soft-tissue and implant infections. Cite this article: Bone Joint J 2024;106-B(6):632–638

Aims. High-energy injuries can result in multiple complications, the most prevalent being infection. Vancomycin powder has been used with increasing frequency in orthopaedic trauma given its success in reducing infection following spine surgery. Additionally, large, traumatic injuries require wound coverage and management by dressings such as negative pressure wound therapy (NPWT). NPWT has been shown to decrease the ability of antibiotic cement beads to reduce infection, but its effect on antibiotic powder is not known. The goal of this study was to determine if NPWT reduces the efficacy of topically applied antibiotic powder. Methods. Complex musculoskeletal wounds were created in goats and inoculated with a strain of Staphylococcus aureus modified to emit light. Six hours after contaminating the wounds, imaging, irrigation, and debridement and treatment application were performed. Animals received either vancomycin powder with a wound pouch dressing or vancomycin powder with NPWT. Results. There were no differences in eradication of bacteria when vancomycin powder was used in combination with NPWT (4.5% of baseline) compared to vancomycin powder with a wound pouch dressing (1.7% of baseline) (p = 0.986), even though approximately 50% of the vancomycin was recovered in the NPWT exudate canister. Conclusion. The antimicrobial efficacy of the vancomycin powder was not diminished by the application of NPWT. These topical and locally applied therapies are potentially effective tools that can provide quick, simple treatments to prevent infection while providing coverage. By reducing the occurrence of infection, the recovery is shortened, leading to an overall improvement in quality of life. Cite this article: Bone Joint Res 2021;10(2):149–155

Prophylactic antibiotics are important in reducing the risk of periprosthetic joint infection (PJI) following total knee arthroplasty. Their effectiveness depends on the choice of antibiotic and the optimum timing of their administration, to ensure adequate tissue concentrations. Cephalosporins are typically used, but an increasing number of resistant organisms are causing PJI, leading to the additional use of vancomycin. There are difficulties, however, with the systemic administration of vancomycin including its optimal timing, due to the need for prolonged administration, and potential adverse reactions. Intraosseous regional administration distal to a tourniquet is an alternative and attractive mode of delivery due to the ease of obtaining intraosseous access. Many authors have reported the effectiveness of intraosseous prophylaxis in achieving higher concentrations of antibiotic in the tissues compared with intravenous administration, providing equal or enhanced prophylaxis while minimizing adverse effects. This annotation describes the technique of intraosseous administration of antibiotics and summarizes the relevant clinical literature to date. Cite this article: Bone Joint J 2023;105-B(11):1135–1139

Aims. Despite recent literature questioning their use, vancomycin and clindamycin often substitute cefazolin as the preoperative antibiotic prophylaxis in primary total knee arthroplasty (TKA), especially in the setting of documented allergy to penicillin. Topical povidone-iodine lavage and vancomycin powder (VIP) are adjuncts that may further broaden antimicrobial coverage, and have shown some promise in recent investigations. The purpose of this study, therefore, is to compare the risk of acute periprosthetic joint infection (PJI) in primary TKA patients who received cefazolin and VIP to those who received a non-cephalosporin alternative and VIP. Methods. This was a retrospective cohort study of 11,550 primary TKAs performed at an orthopaedic hospital between 2013 and 2019. The primary outcome was PJI occurring within 90 days of surgery. Patients were stratified into two groups (cefazolin vs non-cephalosporin) based on their preoperative antibiotic. All patients also received the VIP protocol at wound closure. Bivariate and multiple logistic regression analyses were performed to control for potential confounders and identify the odds ratio of PJI. Results. In all, 10,484 knees (90.8%) received cefazolin, while 1,066 knees (9.2%) received a non-cephalosporin agent (either vancomycin or clindamycin) as preoperative prophylaxis. The rate of PJI in the cefazolin group (0.5%; 48/10,484) was significantly lower than the rate of PJI in the non-cephalosporin group (1.0%; 11/1,066) (p = 0.012). After controlling for confounding variables, the odds ratio (OR) of developing a PJI was increased in the non-cephalosporin cohort compared to the cefazolin cohort (OR 2.389; 1.2 to 4.6); p = 0.01). Conclusion. Despite the use of topical irrigant solutions and addition of local antimicrobial agents, the use of a non-cephalosporin perioperative antibiotic continues to be associated with a greater risk of TKA PJI compared to cefazolin. Strategies that increase the proportion of patients receiving cefazolin rather than non-cephalosporin alternatives must be emphasized. Cite this article: Bone Jt Open 2022;3(1):35–41

Aims. Current treatments of prosthetic joint infection (PJI) are minimally effective against Staphylococcus aureus biofilm. A murine PJI model of debridement, antibiotics, and implant retention (DAIR) was used to test the hypothesis that PlySs2, a bacteriophage-derived lysin, can target S. aureus biofilm and address the unique challenges presented in this periprosthetic environment. Methods. The ability of PlySs2 and vancomycin to kill biofilm and colony-forming units (CFUs) on orthopaedic implants were compared using in vitro models. An in vivo murine PJI model of DAIR was used to assess the efficacy of a combination of PlySs2 and vancomycin on periprosthetic bacterial load. Results. PlySs2 treatment reduced 99% more CFUs and 75% more biofilm compared with vancomycin in vitro. A combination of PlySs2 and vancomycin in vivo reduced the number of CFUs on the surface of implants by 92% and in the periprosthetic tissue by 88%. Conclusion. PlySs2 lysin was able to reduce biofilm, target planktonic bacteria, and work synergistically with vancomycin in our in vitro models. A combination of PlySs2 and vancomycin also reduced bacterial load in periprosthetic tissue and on the surface of implants in a murine model of DAIR treatment for established PJI. Cite this article: Bone Joint J 2020;102-B(7 Supple B):3–10

Aims. There is a considerable challenge in treating bone infections and orthopaedic device-associated infection (ODAI), partly due to impaired penetration of systemically administrated antibiotics at the site of infection. This may be circumvented by local drug administration. Knowledge of the release kinetics from any carrier material is essential for proper application. Ceftriaxone shows a particular constant release from calcium sulphate (CaSO. 4. ) in vitro, and is particularly effective against streptococci and a large portion of Gram-negative bacteria. We present the clinical release kinetics of ceftriaxone-loaded CaSO. 4. applied locally to treat ODAI. Methods. A total of 30 operations with ceftriaxone-loaded CaSO. 4. had been performed in 28 patients. Ceftriaxone was applied as a single local antibiotic in 21 operations and combined with vancomycin in eight operations, and in an additional operation with vancomycin and amphotericin B. Sampling of wound fluid was performed from drains or aspirations. Ceftriaxone concentrations were measured by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Results. A total of 37 wound fluid concentrations from 16 operations performed in 14 patients were collected. The ceftriaxone concentrations remained approximately within a range of 100 to 200 mg/l up to three weeks. The median concentration was 108.9 mg/l (interquartile range 98.8 to 142.5) within the first ten days. No systemic adverse reactions were observed. Conclusion. Our study highlights new clinical data of locally administered ceftriaxone with CaSO. 4. as carrier material. The near-constant release of ceftriaxone from CaSO. 4. observed in vitro could be confirmed in vivo. The concentrations remained below known local toxicity thresholds. Cite this article: Bone Joint Res 2022;11(11):835–842

Aims. Gram-negative periprosthetic joint infection (PJI) has been poorly studied despite its rapidly increasing incidence. Treatment with one-stage revision using intra-articular (IA) infusion of antibiotics may offer a reasonable alternative with a distinct advantage of providing a means of delivering the drug in high concentrations. Carbapenems are regarded as the last line of defense against severe Gram-negative or polymicrobial infection. This study presents the results of one-stage revision using intra-articular carbapenem infusion for treating Gram-negative PJI, and analyzes the characteristics of bacteria distribution and drug sensitivity. Methods. We retrospectively reviewed 32 patients (22 hips and 11 knees) who underwent single-stage revision combined with IA carbapenem infusion between November 2013 and March 2020. The IA and intravenous (IV) carbapenem infusions were administered for a single Gram-negative infection, and IV vancomycin combined with IA carbapenems and vancomycin was applied for polymicrobial infection including Gram-negative bacteria. The bacterial community distribution, drug sensitivity, infection control rate, functional recovery, and complications were evaluated. Reinfection or death caused by PJI was regarded as a treatment failure. Results. Gram-negative PJI was mainly caused by Escherichia coli (8/34), Enterobacter cloacae (7/34), and Klebsiella pneumoniae (5/34). Seven cases (7/32) involved polymicrobial PJIs. The resistance rates of penicillin, cephalosporin, quinolones, and sulfonamides were > 10%, and all penicillin and partial cephalosporins (first and second generation) were > 30%. Of 32 cases, treatment failed to eradicate infection in only three cases (9.4%), at a mean follow-up of 55.1 months (SD 25 to 90). The mean postoperative Harris Hip Score and Hospital for Special Surgery knee score at the most recent follow-up were 81 (62 to 91) and 79 (56 to 89), respectively. One patient developed a fistula, and another presented with a local rash on an infected joint. Conclusion. The use of IA carbapenem delivered alongside one-stage revision effectively controlled Gram-negative infection and obtained acceptable clinical outcomes with few complications. Notably, first- and second-generation cephalosporins and penicillin should be administrated with caution, due to a high incidence of resistance. Cite this article: Bone Joint J 2023;105-B(3):284–293

Aims. Debridement, antibiotics, and implant retention (DAIR) remains one option for the treatment of acute periprosthetic joint infection (PJI) despite imperfect success rates. Intraosseous (IO) administration of vancomycin results in significantly increased local bone and tissue concentrations compared to systemic antibiotics alone. The purpose of this study was to evaluate if the addition of a single dose of IO regional antibiotics to our protocol at the time of DAIR would improve outcomes. Methods. A retrospective case series of 35 PJI TKA patients, with a median age of 67 years (interquartile range (IQR) 61 to 75), who underwent DAIR combined with IO vancomycin (500 mg), was performed with minimum 12 months' follow-up. A total of 26 patients with primary implants were treated for acute perioperative or acute haematogenous infections. Additionally, nine patients were treated for chronic infections with components that were considered unresectable. Primary outcome was defined by no reoperations for infection, nor clinical signs or symptoms of PJI. Results. Mean follow-up for acute infection was 16.5 months (12.1 to 24.2) and 15.8 months (12 to 24.8) for chronic infections with unresectable components. Overall non-recurrence rates for acute infection was 92.3% (24/26) but only 44.4% (4/9) for chronic infections with unresectable components. The majority of patients remained on suppressive oral antibiotics. Musculoskeletal Infection Society (MSIS) host grade was a significant indicator of failure (p < 0.001). Conclusion. The addition of IO vancomycin at the time of DAIR was shown to be safe with improved results compared to current literature using standard DAIR without IO antibiotic administration. Use of this technique in chronic infections should be applied with caution. While these results are encouraging, this technique requires longer follow-up before widespread adoption. Cite this article: Bone Joint J 2021;103-B(6 Supple A):185–190

Aims. Induction heating is a noninvasive, nonantibiotic treatment modality that can potentially be used to cause thermal damage to the bacterial biofilm on the metal implant surface. The purpose of this study was to determine the effectiveness of induction heating on killing Staphylococcus epidermidis from biofilm and to determine the possible synergistic effect of induction heating and antibiotics. Methods. S. epidermidis biofilms were grown on titanium alloy (Ti6Al4V) coupons for 24 hours (young biofilm) and seven days (mature biofilm). These coupons with biofilm were heated to temperatures of 50°C, 55°C, 60°C, 65°C, 70°C, 80°C, and 90°C for 3.5 minutes and subsequently exposed to vancomycin and rifampicin at clinically relevant concentrations. Results. For the young biofilm, total eradication was observed at 65°C or higher for 3.5 minutes followed by 24 hours of vancomycin 10 mg/l and rifampicin 1 mg/l. For the mature biofilm, total eradication was observed at 60°C for 3.5 minutes followed by 24 hours of vancomycin 10 mg/l and rifampicin 1 mg/l. Total eradication was also observed at 60°C for 3.5 minutes followed by 24 hours of vancomycin 1 mg/l and rifampicin 1 mg/l followed by another thermal shock of 60°C for 3.5 minutes (two thermal shocks). Conclusion. Induction heating of Ti6Al4V coupons is effective in reducing bacterial load in vitro for S. epidermidis biofilms. Induction heating and antibiotics have a synergistic effect resulting in total eradication of the biofilm at 60°C or higher for clinically relevant concentrations of vancomycin and rifampicin. Cite this article:Bone Joint Res. 2020;9(4):192–199

Introduction and Objective. The rupture of the anterior cruciate ligament is a common sports injury and surgical reconstruction is often required to restore full function of the knee. Hamstring tendons are usually used as autografts. In addition to knee pain and stiffness, infections are feared complications after surgery. Incubation of the autograft in a vancomycin solution until implantation reduced the infection rate by about ten-fold. Recent studies showed no negative effect of vancomycin on the biomechanical properties of porcine tendons. A negative effect of high vancomycin concentrations on chondrocytes and osteoblast is reported, but the effect on tendon and tenocytes is not known. Materials and Methods. Rat Achilles tendons or isolated tenocytes were incubated with an increasing concentration of vancomycin (0 – 10 mg). Tendons were incubated for 0 – 40 minutes, while tenoyctes were incubated for 20 minutes followed by culturing for up to 7 days. Cell viability was assessed with PrestoBlue Assay and live/dead stain. The potential effect of vancomycin on the expression of tendon specific genes and extracellular matrix (ECM) genes was quantified. Possible structural changes of the tendon are analyzed. Results. Incubation of the tendons or tenocytes with 5 mg vancomycin for 20 minutes (clinical use) had no negative effects on the cell viability in the tendons or the isolated tenocytes, while incubation with the toxic control (ethanol) significantly reduced cell viability. Even twice the concentration and a longer incubation time had no negative effect on the cells in the tendons or the isolated cells. Vancyomycin did not affect the expression of Col1a1, Col3a1, and the tenocyte markers mohawk, scleraxis and tenomodulin. Conclusions. The results showed that clinical practice of wrapping the autograft in vancomycin did not impair the tenocyte viability. The expression of collagens and tenocyte markers was also not affected, neither in the incubated tendons nor in the isolated cells. This indicates that vancomycin had no effect on cell phenotype and the formation of the extracellular matrix, which, in addition to cell viability, is important for the performance of the autograft

Aim. Multispecies biofilms are associated with difficult periprosthetic joint infections (PJI), particularly if they have different antibiotic sensitivities. We aimed to determine if we could generate and kill a multispecies biofilm consisting of a Gram negative and Gram positive pathogen in-vitro with antibiotic loaded calcium sulfate beads containing single or combination antibiotics. Methods. To establish whether we could co-culture mixed species biofilms various combinations of Pseudomonas aeruginosa (PA), Enterococcus faecalis (EF), Staphylococcus aureus (SA) and Enterobacter faecalis (EF) were grown together on 316L stainless steel coupons and agar plates. Based on this screen we focused on PA + EF and challenged them with high purity calcium sulfate beads (Stimulan Rapid Cure) loaded with vancomycin (V), alone tobramycin (T) alone or vancomycin and tobramycin in combination (V+T). Bioluminescence, light imaging, plate count, confocal microscopy and scanning electron microscopy were used to quantify growth. Results. On 316LSS the V loaded bead reduced both EF and PA by approximately 2 logs compared to unloaded control beads. A T alone loaded bead eliminated PA from the dual species biofilm and caused a 2-log reduction in EF. The V+T-beads reduced PA by 9-logs and EF by 8.3 logs. In terms of total CFUs V+T beads reduced the bioburden by 8.4 logs compared to V or T alone. which resulted in 2.1 and 2.6 log reductions respectively. (* P<0.05, *** P<0.001). On agar PA dominated the culture for the unloaded and V loaded beads. However, when challenged with a T loaded bead both species were able to coexist and a zone of killing was generated in both species in the multispecies biofilms. However, this zone was smaller and included more tolerant variants than the zone generated by V+T-loaded beads. Conclusions. There were species proportion differences between biofilms grown on agar and 316LSS demonstrating the importance of growth conditions on species interactions. Antibiotics against strains with differing sensitivities can shift species interactions. High purity calcium sulfate beads containing tobramycin a broad-spectrum Gram positive and negative antibiotic vancomycin, a Gram-positive targeted antibiotic killed a larger percentage of a multispecies in an in-vitro biofilm than either single gram-specific antibiotic alone, demonstrating the advantage of using combination antibiotics for treating multispecies biofilms

Aim. Infections represent a serious threat to the successful utilization of implants in modern medicine. Implant-associated infections are difficult to treat, because they involve biofilms that protect bacteria from the immune system and harbour antibiotic-tolerant persister cells. In this work, we developed an antibody-drug conjugate (ADC) containing the anti-neoplastic drug mitomycin C (MMC) as a novel treatment paradigm for implant-associated infections. MMC was chosen as it is a potent antimicrobial against biofilms and its synthesis into an ADC was chosen to alleviate toxicity. Following development and synthesis of the ADC, stability and release of MMC was measured. We then used the ADC to kill bacteria in suspension and in biofilms, in vitro and in vivo. Method. Mitomycin C was conjugated to a commercially available antibody against S. aureus via a disulfide linkage, with a drug release occurred via thiol-disulfide exchange. ADC as tested against S. aureus under various growth conditions (planktonic, persisters and biofilm). In vitro toxicity of ADC vs MMC was measured using a human cell line (MOLT-4). Finally, two independent in vivo experiments were performed in a murine implant-associated osteomyelitis model. In experiment one ADC treatment was compared NaCl, vancomycin and vancomycin + ADC (n=10 for all groups). Subsequently, ADC was compared to NaCl, the antibody used in the ADC construction, MMC and a novel ADC constructed with a non-S. aureus antibody (n=10 for all groups). All treatments were started day 7 post inoculation and were administered for 3 days. CFU enumeration was done following sonication to quantify bacterial load. Results. Drug release could be triggered on demand with N-acetyl cysteine and release occurred, once in contact with free thiols on S. aureus cell surface. The ADCs exhibited a concentration-dependent antimicrobial effect against S. aureus with doses exceeding 0.5 mg/l reducing amount of CFU to below detection limit (p< 0.001). 15 minutes exposure to ADC resulted in an approx. 2 log CFU/ml reduction compared to untreated biofilms (p < 0.01). In vivo ADC treatment was effective compared to NaCl treatment and the vancomycin treatment (p≤ 0.001). Further ADC and MMC treatment were comparable in efficacy, but both were superior than NaCl, pure antibody and the non-specific ADC (p≤ 0.05). Finally, in vitro cytotoxicity was significantly lower for ADC than MMC. Conclusions. In this study we have demonstrated that ADCs can be a novel treatment approach to combat implant-associated infections caused by S. aureus

The February 2024 Hip & Pelvis Roundup. 360. looks at: Trial of vancomycin and cefazolin as surgical prophylaxis in arthroplasty; Is preoperative posterior femoral neck tilt a risk factor for fixation failure? Cemented versus uncemented hemiarthroplasty for displaced intracapsular fractures of the hip; Periprosthetic fractures in larger hydroxyapatite-coated stems: are collared stems a better alternative for total hip arthroplasty?; Postoperative periprosthetic fracture following hip arthroplasty with a polished taper slip versus composite beam stem; Is oral tranexamic acid as good as intravenous?; Stem design and the risk of early periprosthetic femur fractures following THA in elderly patients; Does powered femoral broaching compromise patient safety in total hip arthroplasty?

The June 2024 Spine Roundup. 360. looks at: Intraoperative navigation increases the projected lifetime cancer risk in patients undergoing surgery for adolescent idiopathic scoliosis; Intrawound vancomycin powder reduces delayed deep surgical site infections following posterior spinal fusion for adolescent idiopathic scoliosis; Characterizing negative online reviews of spine surgeons; Proximal junctional failure after surgical instrumentation in adult spinal deformity: biomechanical assessment of proximal instrumentation stiffness; Nutritional supplementation and wound healing: a randomized controlled trial

The April 2024 Research Roundup. 360. looks at: Prevalence and characteristics of benign cartilaginous tumours of the shoulder joint; Is total-body MRI useful as a screening tool to rule out malignant progression in patients with multiple osteochondromas?; Effects of vancomycin and tobramycin on compressive and tensile strengths of antibiotic bone cement: a biomechanical study; Biomarkers for early detection of Charcot arthropathy; Strong association between growth hormone therapy and proximal tibial physeal avulsion fractures in children and adolescents; UK pregnancy in orthopaedics (UK-POP): a cross-sectional study of UK female trauma and orthopaedic surgeons and their experiences of pregnancy; Does preoperative weight loss change the risk of adverse outcomes in total knee arthroplasty by initial BMI classification?

Aim. Empiric antibiotic therapy for suspected pyogenic spondylodiscitis (SD) should be initiated immediately with severely ill patients and may also be necessary for culture-negative SD. The aim of this study was to infer an appropriate empiric antibiotic regimen by analyzing the antimicrobial susceptibility of isolated pathogens from microbiologically proven pyogenic spondylodiscitis. Method. We performed a retrospective review of adult patients with clinically proven SD treated at our level 1 trauma center between 2013 and 2020. Demographic data, radiologic findings, and treatment modalities were evaluated. The appropriateness of empiric antibiotic regimens was assessed based on the antibiograms of the isolated pathogens. Anamneses were used to distinguish between community-acquired (CA) and healthcare-associated (HA) pathogens, which included cases that had a hospital stay or invasive intervention in the past 6 months. Results. A total of 155 patients (male: N=88; female: N=67; mean age 66.1 ± 12.4 years) with SD were identified. In n= 74 (47.7%) cases, the infections were associated with the healthcare system (HA). N=34 (21.9%) patients suffered from sepsis. The lumbar spine was involved in 47.1% of the cases, the thoracic spine in 37.3%, and the cervical spine in 7.8%. In 7.8% of the cases, SD occurred in multiple spinal segments. N=96 (62.0%) patients were treated surgically. The mean hospital stay was 36.4 ± 36.3 days. Antibiograms of n=45 patients (HA: N=22; CA: N=23) could be retrospectively evaluated: The most frequently identified pathogens were Staphylococcus aureus (46.7%), Coagulase-negative Staphylococci (17.8%), Enterobacteriaceae (15.6%) and Streptococcus species (15.6%). Overall, 82.2% (HA: 68.2%; CA: 95.5%) of the isolated pathogens were sensitive to piperacillin/tazobactam, 77.8% (HA: 81.8%; CA: 72.2%) to vancomycin, 64.4% (HA: 68.2%; CA: 59.1%) to clindamycin, and 55.6% (HA: 36.4%; CA: 72.7%) to ceftriaxone. To a combination of vancomycin plus meropenem 97.8% of pathogens were sensitive (HA: 95.5%; CA: 100.0%), to vancomycin plus ciprofloxacin 91.1% (HA: 86.4%; CA: 95.7%), and to vancomycin plus cefotaxime 93.3% (HA: 90.9%; CA: 95.7%). In 14 cases, empiric antibiosis was adjusted based on the results of the antibiogram. Conclusions. Antibiotic resistance of CA SD pathogens differed significantly from HA SD. The identification of the pathogen and the analysis of its susceptibility guides the antibiotic therapy. Vancomycin in combination with a carbapenem, broad-spectrum cephalosporin, or fluoroquinolone may be appropriate for empiric treatment of HA SD

Aims. Biofilm-related infection is a major complication that occurs in orthopaedic surgery. Various treatments are available but efficacy to eradicate infections varies significantly. A systematic review was performed to evaluate therapeutic interventions combating biofilm-related infections on in vivo animal models. Methods. Literature research was performed on PubMed and Embase databases. Keywords used for search criteria were “bone AND biofilm”. Information on the species of the animal model, bacterial strain, evaluation of biofilm and bone infection, complications, key findings on observations, prevention, and treatment of biofilm were extracted. Results. A total of 43 studies were included. Animal models used included fracture-related infections (ten studies), periprosthetic joint infections (five studies), spinal infections (three studies), other implant-associated infections, and osteomyelitis. The most common bacteria were Staphylococcus species. Biofilm was most often observed with scanning electron microscopy. The natural history of biofilm revealed that the process of bacteria attachment, proliferation, maturation, and dispersal would take 14 days. For systemic mono-antibiotic therapy, only two of six studies using vancomycin reported significant biofilm reduction, and none reported eradication. Ten studies showed that combined systemic and topical antibiotics are needed to achieve higher biofilm reduction or eradication, and the effect is decreased with delayed treatment. Overall, 13 studies showed promising therapeutic potential with surface coating and antibiotic loading techniques. Conclusion. Combined topical and systemic application of antimicrobial agents effectively reduces biofilm at early stages. Future studies with sustained release of antimicrobial and biofilm-dispersing agents tailored to specific pathogens are warranted to achieve biofilm eradication. Cite this article: Bone Joint Res 2022;11(10):700–714

The June 2023 Spine Roundup. 360. looks at: Characteristics and comparative study of thoracolumbar spine injury and dislocation fracture due to tertiary trauma; Sublingual sufentanil for postoperative pain management after lumbar spinal fusion surgery; Minimally invasive bipolar technique for adult neuromuscular scoliosis; Predictive factors for degenerative lumbar spinal stenosis; Lumbosacral transitional vertebrae and lumbar fusion surgery at level L4/5; Does recall of preoperative scores contaminate trial outcomes? A randomized controlled trial; Vancomycin in fibrin glue for prevention of SSI; Perioperative nutritional supplementation decreases wound healing complications following elective lumbar spine surgery: a randomized controlled trial

The August 2024 Trauma Roundup. 360. looks at: Does topical vancomycin prevent fracture-related infections in closed fractures undergoing open reduction and internal fixation? A randomized controlled trial; Is postoperative splinting advantageous after upper limb fracture surgery?; Does suprapatellar nailing resolve knee pain?; Locking versus non-locking plate fixation in comminuted talar neck fractures: a biomechanical study using cadaveric specimens; Revolutionizing recovery metrics: PROMIS versus SMFA in orthopaedic trauma care; Dorsal hook plating of patella fractures: reliable fixation and satisfactory outcomes; The impact of obesity on subtrochanteric femur fracture outcomes; Low-dose NSAIDs (ketorolac) and cytokine modulation in orthopaedic polytrauma: a detailed analysis