Aims. Flucloxacillin is commonly administered intravenously for perioperative antimicrobial prophylaxis, while oral administration is typical for prophylaxis following smaller traumatic wounds. We assessed the time, for which the free flucloxacillin concentration was maintained above the minimum inhibitory concentration (fT > MIC) for methicillin-susceptible Staphylococcus aureus in soft and bone tissue, after intravenous and oral administration, using microdialysis in a porcine model. Methods. A total of 16 pigs were randomly allocated to either intravenous (Group IV) or oral (Group PO) flucloxacillin 1 g every six hours during a 24-hour period. Microdialysis was used for sampling in cancellous and cortical bone, subcutaneous tissue, and the knee joint. In addition, plasma was sampled. The flucloxacillin fT > MIC was evaluated using a low MIC target (0.5 μg/ml) and a high MIC target (2.0 μg/ml). Results. Intravenous administration resulted in longer fT > MIC (0.5 μg/ml) compared to oral administration, except for cortical bone. In Group IV, all pigs reached a concentration of 0.5 μg/ml in all compartments. The mean fT > MIC (0.5 μg/ml) was 149 minutes (95% confidence interval (CI) 119 to 179; range 68 to 323) in subcutaneous tissue and 61 minutes (95% CI 29 to 94; range 0 to 121) to 106 minutes (95% CI 76 to 136; range 71 to 154) in bone tissue. In Group PO, 0/8 pigs reached a concentration of 0.5 μg/ml in all compartments. For the high MIC target (2.0 μg/ml), fT > MIC was close to zero minutes in both groups across compartments. Conclusion. Although intravenous administration of flucloxacillin 1 g provided higher fT > MIC for the low MIC target compared to oral administration, concentrations were surprisingly low, particularly for bone tissue. Achievement of sufficient bone and soft tissue flucloxacillin concentrations may require a dose increase or continuous administration. Cite this article: Bone Joint Res 2021;10(1):60–67

Aim. Flucloxacillin is conventionally administered intravenously for perioperative prophylaxis, while oral administration is typical for bacterial inoculation prophylaxis following smaller traumatic wounds. We aimed to assess the time, for which the free flucloxacillin concentration was maintained above the minimum inhibitory concentration (fT>MIC) for meticillin-susceptible Staphylococcus aureus in soft and bone tissue, after intravenous and oral administration, using microdialysis in a porcine model. Method. 16 pigs were randomly allocated to either intravenous (Group IV) or oral (Group PO) flucloxacillin 1 g every 6 h during 24 h. Microdialysis was used for sampling in cancellous and cortical bone, subcutaneous tissue, and the knee joint. In addition, plasma was sampled. The flucloxacillin fT>MIC was evaluated using a low MIC target (0.5 μg/mL) and a high MIC target (2.0 μg/mL). Results. Intravenous administration resulted in longer fT>MIC (0.5 μg/mL) compared to oral administration, except for cortical bone. In Group IV all pigs reached a concentration of 0.5 μg/mL in all compartments. The mean fT>MIC (0.5 μg/mL) was 149 min in subcutaneous tissue and 61–106 min in bone tissue. In Group PO 0/8 pigs reached a concentration of 0.5 μg/mL in all compartments. For the high MIC target (2.0 μg/mL), fT>MIC was close to 0 min in both groups across compartments. Conclusions. Although intravenous administration of flucloxacillin 1g provided higher fT>MIC for the low MIC target compared to oral administration, concentrations were surprisingly low, particularly for bone tissue. Achievement of sufficient bone and soft tissue flucloxacillin concentrations may require a dose increase or continuous administration. Acknowledgement. The study was supported by the following grants: Sofus Carl Emil Friis Foundation, Aase & Ejnar Danielsens Foundation, the Augustinus Foundation, Direkt⊘r Emil Hertz og hustru Inger Hertz Foundation, and the Novo Nordisk Foundation

Cephalasporin antibiotics have been commonly used for prophylaxis against surgical site infection. To prevent Clostridium difficile, the preferential use of agents such as flucloxacillin and gentamicin has been recommended. The aim of this study was to investigate the bone penetration of these antibiotics during hip and knee arthroplasty, and their efficacy against Staphylococcus aureus and S. epidermidis. Bone samples were collected from 21 patients undergoing total knee arthroplasty (TKA) and 18 patients undergoing total hip replacement (THA). The concentration of both antibiotics was analysed using high performance liquid chromatography. Penetration was expressed as a percentage of venous blood concentration. The efficacy against common infecting organisms was measured using the epidemiological cut-off value for resistance (ECOFF). The bone penetration of gentamicin was higher than flucloxacillin. The concentration of both antibiotics was higher in the acetabulum than the femoral head or neck (p=0.007 flucloxacillin; p=0.021 gentamicin). Flucloxacillin concentrations were effective against S. aureus and S. epidermis in all THAs and 20 (95%) TKAs. Gentamicin concentrations were effective against S.epidermis in all bone samples. Gentamicin was effective against S. aureus in 11 (89%) femoral samples. Effective concentrations of gentamicin against S. aureus were only achieved in 4 (19%) femoral and 6 (29%) tibial samples in TKA. Flucloxacillin and gentamicin was found to effectively penetrate bone during arthroplasty. Gentamicin was effective against S. epidermidis in both THA and TKA, while it was found to be less effective against S. aureus during TKA. Bone penetration of both antibiotics was less in TKA than THA

SIGN guidelines advise the use of flucloxacillin and gentamicin instead of cefuroxime as antibiotic prophylaxis for elective hip and knee arthroplasty. It is our impression that this change in practice has been associated with an increased risk of acute kidney injury (AKI). During a twelve month period we examined the incidence of AKI sequentially in four groups of patients: cefuroxime prophylaxis (n = 46); high dose flucloxacillin (5-8g) with single shot gentamicin (n = 50); low dose flucloxacillin (1-4 g) with single shot gentamicin (n = 45); and finally cefuroxime again (n = 52). There were no statistically significant differences by chi-square tests for age, gender, operation (hip or knee), ASA, anaesthesia, baseline serum creatinine, hypertension, diabetes or pre-operative medication. The proportion of patients in each antibiotic group with any form of AKI by RIFLE criteria was: cefuroxime group 1 (9%), high dose flucloxacillin (52%), low dose flucloxacillin (22%), cefuroxime 2 (14%) (p < 0.0001 by chi-square test). Odds ratios (OR) for AKI derived from a multivariate logistic regression model and assigning an OR of 1 to cefuroxime group 1 was: high dose flucloxacillin 14.5 (95% CI, 4.2, 50.2); low dose flucloxacillin 3.0 (0.8-10.9) and cefuroxime group 2 1.9 (0.5, 7.4). Three patients in the high dose flucloxacillin group required temporary haemodialysis. We have shown a strong association between high dose prophylactic flucloxacillin and subsequent development of AKI. We have no reason to believe that this was confounded by any of the co-variates we measured

In September 2011 our departmental protocol for peri-operative prophylactic antibiotic administration was altered from cefuroxime to gentamicin/flucloxacillin, in response to reported links between cephalosporin use and Clostridium difficile (C. diff) infection. As both gentamicin and flucloxacillin are known to be nephrotoxic in some patients, we investigated whether the new regimen increases the risk of Acute Kidney Injury (AKI) in patients undergoing elective and trauma hip and knee surgery, classified by severity (AKI Network criteria). The incidence of C. diff was noted. 10 out of 202 (5%) patients receiving cefuroxime (group A) developed AKI, compared with 23 of 210 (11%) patients receiving gentamicin and flucloxacillin (group B) (p=0.012). The severity of the renal injury was higher in the group B patients with 16 sustaining stage II/III AKI, whereas in Group A only one patient sustained a stage II injury and none stage III. The increased AKI rate in group B was observed equally in hip fracture patients and elective hip/knee replacement patients. However, 3 of 80 (4%) patients with hip fractures who received doses of cefuroxime developed C. diff, with none in the other groups (p=0.04). The choice of prophylactic antibiotics depends on a careful assessment of benefits and risks. Our data suggests that whereas hip fracture patients may have benefitted from the protocol change with reduced C. diff incidence, elective hip and knee replacement patients sustained additional harm. Different antibiotic regimens may be appropriate for these two groups

Introduction. Acute renal dysfunction (ARD) following orthopaedic surgery is known to increase morbidity, mortality, and length of hospital stay. The aim of this study was to compare the incidence of new acute post-operative renal dysfunction between two cohorts of elective orthopaedic surgical patients receiving either cefuroxime or a combination of gentamicin and flucloxacillin as prophylactic antibiotic regimes. The study was initiated following a change in antibiotic prophylaxis within our unit from cefuroxime to gentamicin and flucloxacillin. Method. Using a standardised data collection tool we retrospectively reviewed medical records of 238 patients who had received 1.5g of cefuroxime (TKR: n = 128; THR: n=110). This data was compared to prospectively collected data from 254 patients (TKR=117 THR=137) who had received Flucloxacillin 2g and Gentamicin (with the dose based on height). Primary outcome measure for the study was the RIFLE criteria which grades renal impairment: 0-Nil, 1-Risk, 2-Injury, 3-Renal failure. Results. In a cohort of 238 patients who underwent arthroplasty and were administered cefuroxime, there were 4 patients (1.68%) who developed renal impairment. All 4 patients were grade 1 RIFLE (Risk) and all resolved by day 3 post-op. Of the 254 patients who received the new antibiotic regime of Flucloxacillin and Gentamicin, 24 (9.45%) had new onset renal impairment. 12 were RIFLE grade 1 (Risk), 7 RIFLE Grade 2 (Injury) and 5 were Grade 3 (Renal Failure) (p=0.0001, Fishers exact test). 7 of these patients remained in acute renal impairment between day 5 and day 7 post-op. Discussion. Patients who received the combination of Flucloxacillin and Gentamicin had a significant increased risk of renal impairment which was also likely to be more severe and last longer. Following analysis of this study we have now reverted back to Cefuroxime for antibiotic prophylaxis

Aims. Here we used a mature seven-day biofilm model of Staphylococcus aureus, exposed to antibiotics up to an additional seven days, to establish the effectiveness of either mechanical cleaning or antibiotics or non-contact induction heating, and which combinations could eradicate S. aureus in mature biofilms. Methods. Mature biofilms of S. aureus (ATCC 29213) were grown on titanium alloy (Ti6Al4V) coupons for seven days and were subjected to the following treatments or their combinations: antibiotics, mechanical cleaning, or heat shock by induction heating of 60°C for one minute. Experiments were repeated at least five times. Results. In the untreated biofilm, growth up to 1.8×10. 11. colony-forming units (CFU)/cm. 2. was observed. Treatment with ciprofloxacin, flucloxacillin, vancomycin, cefuroxime, and amoxicillin all with rifampicin gave 6.0 log, 6.1 log, 1.4 log, 4.8 log, and 3.6 log reduction in CFU/cm. 2. , respectively. Mechanical cleaning alone resulted in 4.9 log reduction and induction heating in 7.3 log reduction. There was an additional effect of ciprofloxacin, flucloxacillin, and induction heating when used in combinations. There was no additional effect for mechanical cleaning. No bacterial growth could be detected after induction heating followed by seven days of ciprofloxacin with rifampicin. Conclusion. Mechanical cleaning, antibiotics, and non-contact induction heating reduced the bacterial load of mature S. aureus biofilms with approximately 5 log or more as a single treatment. The effect of mechanical cleaning on mature S. aureus biofilms was limited when used in combination with antibiotics and/or induction heating. Cite this article: Bone Joint Res 2022;11(9):629–638

Aim. The current antibiotic treatment of periprosthetic joint infection (PJI) is optimized by measuring concentrations in plasma. However, it remains unclear whether effective concentrations of the antibiotics are reached at the site of PJI. Nonetheless, adequate target site concentrations are important to achieve effective eradication of the micro-organism. In order to determine the efficacy of cefuroxime and flucloxacillin in synovial fluid, synovial tissue and bone tissue in relation to the minimal inhibitory concentration (MIC) of the pathogen causing the PJI, we perform a pharmacokinetic/pharmacodynamic (PK/PD) study. Therefore, we aimed to develop validated analytical methods for analysis of cefuroxime and flucloxacillin in synovial fluid, synovial tissue and bone tissue. Method. Blank samples of synovial fluid, synovial tissue and bone tissue were obtained by orthopedic surgeons during surgery. For validation the samples of each matrix were spiked with both cefuroxime and flucloxacillin. Synovial tissue and bone tissue was pulverized with a mikro-dismembrator. Samples were kept frozen at −20°C until analysis. After a sample preparation quantification of cefuroxime and flucloxacillin in each matrix was performed on the ultra-performance convergence chromatography-tandem mass spectrometry (UPC2-MS/MS). Stable-isotope-labeled meropenem-d6 served as internal standard. The linearity, limits of quantification, accuracy and precision and carry-over were determined for all methods separately. The methods were validated according to the European Medicine Agency (EMA) and Food and Drug Administration (FDA) guidelines on bioanalytical method validation. Results. These methods were successfully validated for cefuroxime and flucloxacillin quantification in all matrices according to the EMA and FDA guidelines. The limits of quantification were adequate to cover potential cefuroxime and flucloxacillin concentration in synovial fluid, synovial tissue and bone tissue as described in literature, with a range of 1–100mg/L for synovial fluid and 1–20 µg/g for synovial tissue and bone tissue (r >0.995). Accuracy and within-run precision were validated according to acceptance values (RSD <15%). Carry over was less than 20%. Matrix effects and recovery were investigated for synovial fluid. The results were within the range of 80–120%. Conclusions. The results of the validation fall within the limits of quantification according to the EMA and FDA guidelines. Therefore, these methods can be applied during a PK/PD study to discover the exposure of antibiotics in synovial fluid, synovial tissue and bone tissue at the site of infection in patients with a PJI

Background. Treatment of staphylococcal prosthetic joint infection (PJI) usually consists of surgical debridement and prolonged rifampicin combination therapy. Tailored antimicrobial treatment alternatives are needed due to frequent side effects and drug-drug interactions with rifampicin combination therapy. We aimed to assess the effectiveness of several alternative antibiotic strategies in patients with staphylococcal PJI. Methods. In this prospective, multicenter registry-based study, all consecutive patients with a staphylococcal PJI, treated with DAIR or one-stage revision surgery between January 1. st. , 2015 and November 3. rd. , 2020, were included. Patients were treated according to a predefined protocol for PJI. Antimicrobial treatment strategies differed between centers, which was accepted and used as pseudorandomization. Depending on the hospital patients were admitted to, they were treated with either a long-term rifampicin strategy (consisting of 12 weeks rifampicin combination therapy) ore one of several short-term rifampicin strategies, consisting of only five days of rifampicin combination treatment, started immediately postoperative, followed by clindamycin, flucloxacillin or vancomycin monotherapy. Patients were stratified in different groups, depending on the used antimicrobial strategy. Cox proportional hazards models were used to compare outcome between the groups. Results. Two hundred patients were included and, based on the antimicrobial treatment, stratified in one long-term rifampicin group (n=23) or one of the three short-term rifampicin groups: clindamycin (n=56), flucloxacillin (n=47), vancomycin (n=26), other (n=48). Outcome of PJI after DAIR or one-stage exchange was not statistically different between patients treated with long-term rifampicin combination therapy and patients treated with clindamycin or flucloxacillin monotherapy including only five days of rifampicin combination therapy. Moreover, treatment duration was four weeks shorter in the clindamycin-based and flucloxacillin-based groups. Adjusted hazard ratios for failure for patients treated with either flucloxacillin or clindamycin were almost equal to patients treated with long-term rifampicin combination therapy (aHR 1.21, 95%CI 0.34–4.40). Conclusions. A short-term rifampicin strategy with either clindamycin or flucloxacillin and only five days of rifampicin was found to be as effective as traditional long-term rifampicin combination therapy. A randomized controlled trial is needed to further address efficacy and safety of alternative treatment strategies for staphylococcal PJI

Aim. There is a lack of data supporting the use of doxycycline as a single agent after removing infected orthopaedic metalwork. We evaluated the efficacy and safety of doxycycline compared with other single antibiotic regimens used at our specialist orthopaedic hospital. Methods. A retrospective observational study including all adult patients diagnosed with an orthopaedic metalwork infection due to staphylococci. All patients were managed with the removal of metalwork, and multiple intraoperative samples were sent for culture, followed by the administration of at least four weeks of oral antibiotics. Antibiotic selection was on the recommendation of an infection consultant. Infection outcome was assessed as the proportion of patients meeting the OVIVA Trial definition of definite failure at follow-up. The probability of definite failure for doxycycline and the alternatives group was estimated using the Kaplan-Meier survival method. All adverse drug reactions (ADR) during treatment were analysed. Results. Seventy-nine orthopaedic metalwork infections were identified between July 2017 and July 2021. Forty-four were prosthetic joints, and 35 were fracture-related metalwork. In 54 cases, the infecting organism was Staphylococcus aureus, and 25 were due to coagulase-negative staphylococci. Forty-four were treated with doxycycline 100mg 12 hourly, and 35 were treated with alternatives (flucloxacillin 1g 6-hourly n=21 and clindamycin 450mg 6-hourly n=14). Overall, 70 patients (88.6%) were infection-free after a median follow-up of 23 months (IQR, 19 – 44). 38 (82.3%) were infection-free in the doxycycline group compared with 32 (91.4%) patients treated with alternatives. Of the failures in the alternatives group, all 3 received flucloxacillin. Survival analysis showed no significant difference in time to treatment failure between doxycycline and alternative antibiotics. Eighteen patients experienced an ADR: 2 nausea, one rash and one vaginal candidiasis due to doxycycline. Four diarrhoea, one reflux, two rashes and one headache due to clindamycin; 1 nausea and five diarrhoea due to flucloxacillin. Four patients required discontinuation therapy, two due to clindamycin and two due to flucloxacillin. Conclusions. In our cohort of patients, doxycycline monotherapy was an effective and well-tolerated oral option for treating staphylococcal infection following debridement and removal of orthopaedic metalwork

Introduction. Introduction: Pin site infection is a common complication during treatment with a circular frame external fixator and increases time and support patients require from the limb reconstruction team. Wound swabs were not routinely sent by the clinical nurse specialists prior to this study, with most pin site infections treated as Staphylococcus aureus with flucloxacillin (clindamycin in penicillin allergy). The aim of this study was to ascertain whether routine sending of wound swabs in pin site infection would change antibiotic treatment. Materials & Methods. Materials and Method: Patients presenting at clinic or physiotherapy with clinical signs of pin site infection were assessed using the Maz Oxford Nuffield (MON) Pin Site Infection Grading System© (OUH, 2021). Antibiotics were commenced as per unit guidelines and swabs sent for microscopy, culture and sensitivity. Results. Results: There were forty patients treated with pin site infections. Swab results showed S. aureus in 60% (N=24), other organisms in 15% (N=6) and no growth or mixed skin organisms in 10% (N=10). Flucloxacillin was prescribed to 77.5% (n=31) of patients with the remaining 22.5% (n=9) of patients receiving clindamycin (due to allergy) or rifampicin and ciprofloxacin (due to a previous MRSA diagnosis). Antibiotic management was subsequently changed in only 5% (n=2) of patients due to one patient with a new MRSA diagnosis and one patient growing Enterobacter in three pin sites tested. Conclusions. Conclusion: This study has shown that routine swab testing of pin sites does not usually change antibiotic management but should still be used in multiple, severe or unresolving pin site infections

Background. We switched our antibiotic prophylaxis for elective hip and knee surgery from cefuroxime to flucloxacillin with single dose gentamicin in order to reduce the incidence of C. Diff diarrhoea. More patients subsequently appeared to develop acute kidney injury (AKI). Methods. During a twelve month period we examined the incidence of AKI sequentially in 198 patients undergoing elective hip or knee surgery: cefuroxime (n = 48); high dose flucloxacillin (median 8g) (n = 52); low dose flucloxacillin (median 4g) (n = 46); and cefuroxime again (n = 52). Results. There were no statistically significant differences between the four groups by chi-square tests for age, gender, nature of operation (hip or knee surgery), American Society of Anaesthesia (ASA) grade, mode of anaesthesia (spinal ± general anaesthetic v GA), baseline serum creatinine, pre-operative co-morbidity (hypertension, diabetes), pre-operative medication (NSAIDs, ACEI/ARBs or betablockers) and post-operative hypotension. Patients receiving high dose flucloxacillin required more vasopressors during surgery (p = 0.02 by Kruskal-Wallis test). The proportion of patients in each antibiotic group with any form of AKI by RIFLE criteria was: first cefuroxime group (8%), high dose flucloxacillin (52%), low dose flucloxacillin (22%), second cefuroxime (14%) (p < 0.0001). Odds ratios (OR) for AKI derived from a multivariate logistic regression model and arbitrarily assigning an OR of 1 to first cefuroxime group, were: high dose flucloxacillin 14.5 (95% CI, 4.2–49.7); low dose flucloxacillin 3.0(0.8–10.8); cefuroxime again 2.0(0.5–7.7). Three patients required temporary haemodialysis. Biopsies in two of these showed acute tubulo-interstitial nephritis. All three patients belonged to the high dose flucloxacillin group. None of the patients developed C Diff diarrhoea. Summary. We have shown a strong association between high dose flucloxacillin with single dose gentamicin prophylaxis and subsequent development of AKI which was not confounded by any of the co-variates we measured

Aim. Irrigation is a major step during debridement surgery in the context of Prosthetic Joint Infections (PJI), but its effects on biofilms are poorly described. The present study aims at evaluating the effect of PW alone or followed by antibiotics on MSSA and MRSA biofilms grown on Ti6Al4V coupons in-vitro. Method. Strains: 1 reference (MSSA: ATCC25923; MRSA: ATCC33591) and 2 clinical MSSA and MRSA isolated from PJI. Biofilm culture: Coupons were incubated for 24h at 37°C with bacteria (starting inoculum ∼6.6Log. 10. CFU/mL in TGN [TSB + 1% glucose + 2% NaCl]), under shaking at 50rpm. Treatment: Half of the coupons were irrigated with 50mL physiological serum from 5cm using a Stryker Interpulse; the coupons were then either analysed (ControlT0 and PWT0) or reincubated for 24h in TGN or TGN containing flucloxacillin (MSSA) or vancomycin (MRSA) at MIC or 20mg/L. Analysis: Coupons were rinsed twice with PBS. Biomass was measured by crystal violet (CV) assay. CFUs were counted after recovering bacteria from coupons using sonication and TSA plating. Results. Antibiotics alone: Flucloxacillin reduced CFU and biomass for ATCC25923 and 611 but not 578 (Fig b and d). Vancomycin had no statistically significant effects on CFUs for all MRSA and only a weak effect on biomass for 676. Irrigation alone markedly reduced CFUs and biomass for all strains but had no persistent effect after 24h reincubation in TGN. PW + antibiotics: Antibiotics prevented bacterial regrowth after PW when used at their MIC and further decreased CFUs when used at 20 mg/L. Conclusions. PW alone has a transient effect on coupon colonisation by S. aureus biofilms. Vancomycin at therapeutic concentrations is ineffective and flucloxacillin has a strain-dependent effect. In combination, these treatments show synergistic effects, indicating the importance of irrigation followed by high antibiotic doses for ODRI. For any figures or tables, please contact the authors directly

Osteoarticular infections (OAI) are a common cause of morbidity in children, and as opposed to adults is usually caused by haematogenous spread. The bacteriology of OAI in children is not well described in the South African context, therefore this study was designed to determine the bacteriology of OAI in our population. All patients that underwent surgery for the treatment of OAI over a 3-year period were identified and those with positive cultures where organisms were identified from tissue, pus, fluid or blood were included. Duplicate cultures from the same patient were excluded if the organism and antibiotic susceptibility profile was the same. Patients were categorised according to age and class of infection (Septic arthritis, acute osteomyelitis, fracture related infection, post-operative sepsis and chronic osteomyelitis) and organisms were stratified according to these categories. We identified 132 organisms from 123 samples collected from 86 patients. Most cultured organisms were from children older than 3-years with acute haematogenous septic arthritis, osteomyelitis, or both. Methicillin sensitive Staphylococcus aureus accounted for 56% (74/132) of organisms cultured. There were no cases of MRSA. The Enterobacterales accounted for 17% (22/132) of organisms cultured, mostly in the fracture related and post-operative infection groups. Of these, 6 each were extended spectrum B-lactamase producers and AmpC producers. There were no carbapenemase producing Enterobacterales. Kingella kingae was not isolated in any patient. Methicillin sensitive S. aureus is the most common infecting organism in paediatric OAI and an anti-staphylococcal penicillin such as cloxacillin or flucloxacillin is the most appropriate empiric treatment for haematogenous OAI in our environment. In fracture related or post-operative infections, Enterobacterales were more frequently cultured, and treatment should be guided by culture and susceptibility results

Introduction. Major trauma during military conflicts involve heavily contaminated open fractures. Staphylococcus aureus (S. aureus) commonly causes infection within a protective biofilm. Lactoferrin (Lf), a natural milk glycoprotein, chelates iron and releases bacteria from biofilms, complimenting antibiotics. This research developed a periprosthetic biofilm infection model in rodents to test an Lf based lavage/sustained local release formulation embedded in Stimulin beads. Method. Surgery was performed on adult rats and received systemic Flucloxacillin (Flu). The craniomedial tibia was exposed, drilled, then inoculated with S. aureus biofilm. A metal pin was placed within the medullary cavity and treatments conducted. Lf in lavage solutions: The defect was subject to 2× 50 mL lavage with 4 treatment groups (saline only, Lf only, Bactisure with Lf, Bactisure with saline). Lf embedded in Stimulin beads: 4 bead types were introduced (Stimulin only, Lf only, Flu only, Lf with Flu). At day 7, rats are processed for bioluminescent and X-ray imaging, and tibial explants/pins collected for bacterial enumeration (CFU). Results. Rats without treatments established a mean infection of 2×106 CFU/tibia. 4 treatment groups with a day 0, one-off lavage demonstrated >95% reduction in bacterial load 7 days post-op, with a reduction in CFU from 1×106/tibia down to 1×104/tibia. There was no statistically significant difference between each group (p = 0.55 with one way ANOVA). The stimulin bead experiments are ongoing and complete results will be obtained in the end of July. Conclusions. This research demonstrated a clinically relevant animal model of implanted metalware that establishes infection. No additional benefit was observed with a one-off, adjuvant Lf lavage during the initial decontamination of the surgical wound, compared with saline alone, and in combination with the antiseptic Bactisure. This animal model provides the foundation for future antibiofilm therapies

Aim. Efficacious antibiotic treatment is crucial for managing and preventing orthopedic infections due to their complexity and associated risk of treatment failure. Previous reviews on antibiotic target tissue concentrations have primarily focused on static measurements, which may not accurately reflect the dynamic pharmacokinetic/pharmacodynamic (PK/PD) changes encountered in clinical settings. This review aimed to summarize the current literature on antibiotic distribution in orthopedically relevant tissues and settings using dynamic sampling methods. Method. In accordance with PRISMA guidelines, a literature search was conducted with a scientific librarian's assistance. PubMed and Embase databases were systematically searched using relevant MeSH terms, entries, and keywords. English-published studies between 2004 and 2023 involving systemic antibiotic administration and dynamic measurements were included. 4467 titles were identified. After title and abstract screening, 77 eligible studies remained. Results. The studies covered clinical and pre-clinical studies on both healthy and infected tissue. Dynamic measurements were obtained from various tissues including bone, intervertebral discs, joints, muscles, and subcutaneous tissue. Microdialysis was the predominant sampling method (98.70%, 76/77). Antibiotics like cefuroxime, linezolid, and vancomycin were extensively studied. Fluoroquinolones, tetracyclines, and most beta-lactams typically presented good tissue penetration in relation to relevant PK/PD-targets. In contrast, glycopeptides, macrolides, and flucloxacillin exhibited poorer penetration. Conclusions. This review provides valuable insights of antibiotic distribution in orthopedically relevant target tissues and settings, which may help improve dosing recommendations and treatment outcomes. Our findings are limited to the investigated dosing regimens and administration methods and depend on the chosen PK/PD target. Many antibiotics still require further research to address the significant knowledge gaps, such as the lack of dynamic evaluations for certain antibiotic types and further investigation across various orthopedic settings and tissues

Aim. Debridement, Antibiotics, Irrigation, and implant Retention (DAIR) is a surgical treatment protocol suitable for some patients with fracture related infection (FRI). Clinically relevant pre-clinical models of DAIR are scarce and none have been developed in large animals. Therefore, this project aimed to develop a large animal model for FRI including a DAIR approach and compare outcomes after 2 or 5 weeks of infection. Method. Swiss Alpine sheep (n=8), (2–6 years, 50–80 kg) were included in this study. This study was approved by cantonal Ethical authorities in Chur, Switzerland. A 2 mm osteotomy was created in the tibia and fixed with a 10-hole 5.5 mm steel plate. Subsequently, 2.5 mL of saline solution containing 10. 6. CFU/mL of Staphylococcus aureus MSSA (ATCC 25923) was added over the plate. Sheep were observed for 2 (n=3) or 5 weeks (n=5) until revision surgery, during which visibly infected or necrotic tissues were removed, and the wound flushed with saline. All samples were collected for bacterial quantification. After revision surgery, the sheep were treated systemically for 2 weeks with flucloxacillin and for 4 weeks with rifampicin and cotrimoxazole. After 2 further weeks off antibiotics, the animals were euthanized. Bacteriological culture was performed at the end of the study. Bone cores were isolated from the osteotomy site and processed for Giemsa & Eosin and Brown and Brenn staining. A radiographical examination was performed every second week. Results. Bacteriological evaluation of the retrieved samples during revision surgery showed no significant difference between the 2 vs 5 weeks infection periods in term of total CFU counts. At the end of the study, radiographical examination showed callus formation over the osteotomy site in both groups, although the osteotomy was not completely healed in either group. At euthanasia, the 2 weeks infection group showed a higher soft tissue burden compared to the 5 weeks group, whereby the infection in the 5 weeks group was primarily located in the bone and bone marrow. Conclusions. The large animal model of FRI and DAIR was successfully established. Bacteriological outcomes highlight that the increasing duration of the infection does not change the outcome but the location of the infection from a predominantly soft tissue infection to a deeper bone and intramedullary (IM) channel infection. The debridement of the IM channel could potentially reduce the infection burden by eliminating those bacteria not easily reached by systemic antibiotics, though is not practical using conventional techniques

Introduction: In patients presenting with an infected hip arthroplasty first-line antibiotics at our institution are Flucloxacillin and Fucidic Acid. It was observed that many patients needed their antibiotic regime changed once sensitivities became known. This was because of resistance to the first-line antimicrobial agents. This raised the question ‘How frequent is Flucloxacillin and Fucidic acid resistance in prosthetic hip infection and is there a more appropriate first-line antibiotic?’. Method: A computerised search of the Belfast Orthopaedic Information System (BOIS) identified all cases of infected hip arthroplasty from October 2001 to April 2005. All microbiology results of these patients were obtained and analysed to determine the infecting organism, sensitivity and resistance to Flucloxacillin, Fucidic acid and Teicoplanin. Results: BOIS identified forty cases of infected hip arthroplasty, 35 primary arthroplasties and 5 revision arthroplasties. Of the 40 patients 36 had positive cultures, 3 had no growth and there was missing data on one patient. Flucloxacillin sensitivity occurred in 25% of patients with 58% resistance. With regard to Fucidic Acid sensitivity was 47 % with 44% resistance. There were no cases of Teicoplanin resistance. Teicoplanin sensitivity occurred in 78% of patients and with analysis by organism susceptibility sensitivity would measure 92% (8% were not tested against Teicoplanin). Discussion: Flucloxacillin resistance is greater than sensitivity in infected hip arthroplasty in this study group. Fucidic Acid sensitivity and resistance are roughly equal. There are no cases of Teicoplanin resistance in our study population and with analysis with respect to the causative organism Teicoplanin sensitivity reaches 92%. It could be suggested therefore that the first-line agents of Flucloxacillin and Fucidic acid are inappropriate and that Teicoplanin may be a better choice

In 2011 health policy dictated a reduction in iatrogenic infections, such as Clostridium difficile (C. diff), this resulted in local change to antimicrobial policy in orthopaedic surgery. Previous antimicrobial policy was Cefuroxime, this was changed to Flucloxacillin and Gentimicin. Following this change an increased number of patients appeared to suffer from acute kidney injury (AKI). We initially evaluated the incidence of AKI pre and post antibiotic change and found a correlation between the Flucloxacillin and AKI. We then made changes to antibiotic policy to mitigate the increased rates of AKI and proceeded to evaluate the outcomes. In this prospective study all patients admitted with fracture neck of femurs were identified from the National Hip Fracture database and data obtained. The degree of AKI was classified according to the validated RIFILE criteria. Evaluation showed a 4 fold decrease, from 13% to only 3%, in AKI after introduction of the modified antibiotic policy. C.difficile continues to be non-existent since this change. Flucloxacillin obviously had a significant impact on this patient group. However, we have shown that with appropriate changes to antibiotic policy AKI associated morbidity can be significantly reduced. Dose dependent antibiotics will now be given based on weight and eGFR

In late 2011 there was a change in antimicrobial policy in orthopaedic surgery to reduce the Clostridium difficile (C. diff) rate, this was inducted top down from government, to PCT, to hospital trust. The previous antimicrobial policy was Cefuroxime, this was changed to Flucloxacillin and Gentimicin. Following this change it was noticed an increased number of patients appeared to suffer from acute kidney injury (AKI). This led us to evaluate the incidence of AKI pre and post antibiotic change and look at the causes behind this. In this retrospective study all patients admitted with fracture neck of femurs were identified from the National Hip Fracture database and data pulled. The degree of AKI was classified according to the validated RIFILE criteria. Evaluation showed 2–4 fold increase in AKI since antibiotic change. Although mortality was decreased in these patients, the incidence of AKI had increased significantly. However, C. difficile has been obliterated by this change. The investigation highlights potential problems with increased rates of AKI amongst NOF patients, since antibiotic change. Flucloxacillin may have significant impact on this patient group. Dose dependent antibiotics will now be given based on weight and eGFR. Further analysis of this new change needs to be evaluated