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

Treatment of large bone defects represents a great challenge for orthopedic surgeons. The main causes are congenital abnormalities, traumas, osteomyelitis and bone resection due to cancer. Each surgical method for bone reconstruction leads its own burden of complications. The gold standard is considered the autologous bone graft, either of cancellous or cortical origin, but due to graft resorption and a limitation for large defect, allograft techniques have been identified. In the bone defect, these include the placement of cadaver bone or cement spacer to create the ‘Biological Chamber’ to restore bone regeneration, according to the Masquelet technique. We report eight patients, with large bone defect (for various etiologies and with an average size defect of 13.3 cm) in the lower and upper limbs, who underwent surgery at our Traumatology Department, between January 2019 and October 2020. Three patients were treated with both cortical and cancellous autologous bone grafts, while five received cortical or cement spacer allografts from donors. They underwent pre and postoperative radiographs and complete osseointegration was observed in all patients already undergoing monthly radiographic checks, with a restoration of length and range of motion. In our study, both the two stage-Masquelet and the cortical bone graft from a cadaver donor proved to be valid techniques in patients with very extensive defects to reconstruct the defect, restore the length, minimize implant left in situ and achieve complete functional recovery

Recent researches indicate that both M1 and M2 macrophages play vital roles in tissue repair and foreign body reaction processes. In this study, we investigated the dynamics of M1 macrophages in the induced membrane using a mouse femur critical-sized bone defect model. The Masquelet method (M) and control (C) groups were established using C57BL/6J male mice (n=24). A 3mm-bone defect was created in the right femoral diaphysis followed by a Kirschner wire fixation, and a cement spacer was inserted into the defect in group M. In group C, the bone defect was left uninserted. Tissues around the defect were harvested at 1, 2, 4, and 6 weeks after surgery (n=3 in each group at each time point). Following Hematoxylin and eosin (HE) staining, immunohistochemical staining (IHC) was used to evaluate the CD68 expression as a marker of M1 macrophage. Iron staining was performed additionally to distinguish them from hemosiderin-phagocytosed macrophages. In group M, HE staining revealed a hematoma-like structure, and CD68-positive cells were observed between the spacer and fibroblast layer at 1 week. The number of CD68-positive cells decreased at 2 weeks, while they were observed around the new bone at 4 and 6 weeks. In group C, fibroblast infiltration and fewer CD68-positive cells were observed in the bone defect without hematoma-like structure until 2 weeks, and no CD68-positive cells were observed at 4 and 6 weeks. Iron staining showed hemosiderin deposition in the surrounding area of the new bone in both groups at 4 and 6 weeks. The location of hemosiderin deposition was different from that of macrophage aggregation. This study suggests that M1 macrophage aggregation is involved in the formation of induced membranes and osteogenesis and may be facilitated by the presence of spacers

Treatment of bone infection often includes a burdensome two-stage revision. After debridement, contaminated implants are removed and replaced with a non-absorbable cement spacer loaded with antibiotics. Weeks later, the spacer is exchanged with a bone graft aiding bone healing. However, even with this two-stage approach infection persists. In this study, we investigated whether a novel 3D-printed, antibiotic-loaded, osteoinductive calcium phosphate scaffold (CPS) is effective in single-stage revision of an infected non-union with segmental bone loss in rabbits. A 5 mm defect was created in the radius of female New Zealand White rabbits. The bone fragment was replaced, stabilized with cerclage wire and inoculated with Staphylococcus aureus (MSSA). After 4 weeks, the infected bone fragment was removed, the site debrided and a spacer implanted. Depending on group allocation, rabbits received: 1) PMMA spacer with gentamycin; 2) CPS loaded with rifampin and vancomycin and 3) Non-loaded CPS. These groups received systemic cefazolin for 4 weeks after revision. Group 4 received a loaded CPS without any adjunctive systemic therapy (n=12 group1-3, n=11 group 4). All animals were euthanized 8 weeks after revision and assessed by quantitative bacteriology or histology. Covariance analysis (ANCOVA) and multiple regression were performed. All animals were culture positive at revision surgery. Half of the animals in all groups had eliminated the infection by end of study. In a historical control group with empty defect and no systemic antibiotic treatment, all animals were infected at euthanasia. There was no significant difference in CFU counts between groups at euthanasia. Our results show that treating an osteomyelitis with segmental bone loss either with CPS or PMMA has a similar cure rate of infection. However, by not requiring a second surgery, the use of CPS may offer advantages over non-resorbable equivalents such as PMMA

In a new rabbit model of carbapenem-resistant Klebsiella pneumoniae knee-prosthesis infection, we studied the efficacy of colistin cement alone or in combination with systemic intramuscular (i.m.) injections of colistin. Seven days after infection, surgical debridement and removal of the infected prostheses were performed, and rabbits were randomly assigned to one of four different treatment groups of twelve rabbits: prosthesis replacement by drug-free cement spacer (control) prosthesis replacement by colistin-loaded cement spacer (3 MUI of colistin/40 g of cement) (colistin local), prosthesis replacement by drug-free cement spacer and i.m. colistin (12 mg/kg of body weight, three time a day for 7 days), or colistin local + i.m. We observed a statistically significant difference (p = 0.049) between the colistin local + systemic group and the control group in the criteria of number of rabbits with sterile bone under the total number of rabbits. Combination of systemic and local colistin could be an interesting therapeutic option to cure carbapenem-resistant Klebsiella pneumoniae peri prosthetic joint infection

Introduction. 20 cases of bone defect have been treated by the induced membrane technique avoiding allograft, microsurgery and amputation. Material and Methods. 9 cases of long bone defect (humerus and 2 bones arm) and 11 cases of bone defct at the hand have been included in this multicentric prospective study (3 centers). 11 cases were traumatic, 7 cases were septic non union and 2 cases were tumor. At hand level's bone reached at least one phalanx, and for long bone the mean defect was 5cm (3–11). All cases were treated by the induced membrane technique which consists in stable fixation, flap if necessary and in filling the void created by the bone defect by a cement spacer (PMMA). This technique needs a second stage procedure at the 2. nd. month where the cement is removed and the void is filled by cancellous bone. The key point of this induced membrane technique is to respect the foreign body membane which appeared around the cement spacer and which create a biologic chamber after the second time. Bone union was evaluated prospectively in each case by an surgeon not involved in the treatment by Xray and CT scan. Failure was defined as a non union at 1 year, or an uncontrolled sepsis at 1 month. Results. 3 cases failed to achieve bone union, 2 at hand level and 1 for long bone. No septic complications occured and all septic cases werre stopped. In 14 cases bone union was achieved with a delay of 5 months (1, 5–12). 2 biopsies allowed to proove us that osteoid tissue was created by the technic. At hand level all fingers have included. At shoulder and elbow level, function reached 75% of motion than controlateral side. Discussion. Masquelet first reported 35 cases of large bone defect of tibia non union treated by the induced membrane technic which allow to fill bone defect with cancellous bone alone. The cement spacer allows to induce a foreign body membrane which constitute a biological chamber. Works on animal model reported by Pellissier and Viatteau showed the properties of the membrane: secretion of growths factors (VEGF, TGFbéta1, BMP2) and osteoinductive activitie of the cells. The induced membrane seem to play the role of a neo periosteum. Using this technic is possible in emergency or in septic condition where bone defect can not been solved by shortening. This technic avoids to use microsurgical technic and the limit is the quantity of avalaible cancellous bone

Previous clinical studies have shown the efficacy of a foreign body-induced membrane combined with bone autograft for the reconstruction of traumatologic or pathologic large bone defects or, bone non union. This membrane, rich in mesenchymal stromal cells (MSC), avoids bone autograft resorption and promotes consolidation by revascularisation of the bone and secretion of growth factors. Reconstruction requires two different surgical stages: firstly, insertion of a cement spacer in the defect, and secondly, removal of the spacer, preservation of the foreign body-induced membrane and filling of the cavity by bone autograft. The optimal time to perform the second surgical stage remains unclear. So, we aimed to correlate bone healing and, phenotype and function of cells isolated from the induced membrane, in patients whose second surgery was performed on average after 6 months (i.e. beyond the recommended time of one month). Cell phenotype was determined by flow cytometry and cell function by: alkaline Phosphatase enzyme activity, secretion of calcium and von Kossa staining. Second, using histological and immunohistochemistry studies, we aimed to determine the nature and function of induced membrane over time. Seven patients were included with their consent. Results showed Treated patients achieved in all cases bone union (except for one patient) and in in vitro and histology and immunohistochemistry gave some indications which need to be completed in the future. First, patient age seemed to be an indicator of bone union speed and recurrent infection, appeared to influence in vitro MSC osteogenic potential and induced membrane structure. Second, we reported, in bone repair situation, the commitment over time in osteogenic lineage of a surprising multipotent tissue (induced membrane) able of vascularisation/ osteogenesis/ chondrogenesis at a precocious time. Finally, best time to perform the second stage (one month) could be easily exceeded since bone union occurred even at very late times

Around 1% of total hip replacements are follow by prosthetic joint infection (PJI). There is uncertainty about best treatment method for PJI, and the most recent high quality systematic reviews in unselected patients indicates that re-infection rates following one-stage and two-stage revision arthroplasty are relatively similar. In the absence of evidence randomised controlled trials will help to identify the most clinically and cost-effective treatment for PJI. Before such trials are conducted, there is a need to establish reasons for current practice and to identify whether trials are feasible. This study aimed to deliver research that would inform trial design. Specifically, we aimed to characterise consultant orthopaedic surgeons' decisions about performing either one-stage or two-stage exchange arthroplasty for patients with PJI after hip replacement and to identify whether a randomised trial comparing one-stage with two-stage revision would be possible. Semi-structured interviews were conducted with 12 consultant surgeons from 5 high-volume National Health Service (NHS) orthopaedic departments in the UK. Surgeons were sampled on the basis that they perform revision surgery for PJI after hip arthroplasty and final sample size was justified on the basis of thematic saturation. Surgeons were interviewed face-to-face (n=2) or via telephone (n=10). The interview study took place before design of a multicentre prospective randomised controlled trial comparing patient and clinical outcomes after one-stage or two-stage revision arthroplasty. Data were audio-recorded, transcribed, anonymised and analysed using a thematic approach, with 25% of transcripts independently double-coded. Results: There is no standard surgical response to the treatment of PJI and surgeons manage a complex balance of factors when choosing a surgical strategy. These include multiple patient-related factors, their own knowledge and expertise, available infrastructure and the infecting organism. Surgeons questioned whether evidence supports the emergence of two-stage revision as a method. They described the use of loosely cemented articulating spacers as a way of managing uncertainty about best treatment method. All surgeons were supportive of a randomised trial to compare one-stage and two-stage revision surgery for PJI after hip replacement. Surgeons reported that they would put patients forward for randomisation when there was uncertainty about best treatment. Surgeons highlighted the need for evidence to support their choice of revision. Some surgeons now use revision methods that can better address both clinical outcomes and patients' quality of life, such as loosely cemented articulating spacers. Surgeons thought that a randomised controlled trial comparing one-stage and two-stage exchange joint replacement is needed and that randomisation would be feasible. The next stage of the work was to design a multi-centre randomised controlled trial, this has been achieved and the trial is now ongoing in the UK

Background. Antibiotic loaded bone cement spacers are used as an adjunct to treatment in 2-stage arthroplasty revisions. If release of the correct choice of antimicrobials is optimised, systemic therapy might be curtailed and emergence of resistance minimised. Aims: To determine the elution period of antimicrobials from bone cement with and without a copolymer, polyvinylpyrrolidone (PVP) and to limit resistance development by the use of two or more antimicrobials. Methods. Triclosan, gentamicin and clindamycin with and without (PVP) in CMW bone cement, was tested against six bacteria using serial plate transfer. Results. While there was little difference between clindamycin and clindamycin with PVP, and between gentamicin and gentamicin with PVP, there was marked enhancement of release of triclosan with PVP. Resistance developed when antimicrobials were used singly but not when used in combination. Conclusion. The addition of water soluble PVP was expected to enhance elution of antimicrobials from bone cement. This occurred with triclosan, a poorly water-soluble agent, but there was no significant difference for gentamicin and clindamycin, which as preferentially water -soluble. Other copolymers are being explored in an attempt to enhance their release. Triclosan used in combination extended the duration of activity against the test bacteria without development of resistance. Combinations of antimicrobials reduce the risk of paradoxical resistance in bone cement

Objectives

Thermal stability is a key property in determining the suitability of an antibiotic agent for local application in the treatment of orthopaedic infections. Despite the fact that long-term therapy is a stated goal of novel local delivery carriers, data describing thermal stability over a long period are scarce, and studies that avoid interference from specific carrier materials are absent from the orthopaedic literature.

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.

Objectives

The objective of this study was to determine if combining variations in mixing technique of antibiotic-impregnated polymethylmethacrylate (PMMA) cement with low frequency ultrasound (LFUS) improves antibiotic elution during the initial high phase (Phase I) and subsequent low phase (Phase II) while not diminishing mechanical strength.

We studied the effects of coating titanium implants with teicoplanin and clindamycin in 30 New Zealand White rabbits which were randomly assigned to three groups. The intramedullary canal of the left tibia of each rabbit was inoculated with 500 colony forming units of Staphylococcus aureus. Teicoplanin-coated implants were implanted into rabbits in group 1, clindamycin-coated implants into rabbits in group 2, and uncoated implants into those in group 3. All the rabbits were killed one week later. The implants were removed and cultured together with pieces of tibial bone and wound swabs. The rate of colonisation of the organisms in the three groups was compared.

Organisms were cultured from no rabbits in group 1, one in group 2 but from all in group 3. There was no significant difference between groups 1 and 2 (p = 1.000). There were significant differences between groups 1 and 3 and groups 2 and 3 (p < 0.001). Significant protection against bacterial colonisation and infection was found with teicoplanin- and clindamycin-coated implants in this experimental model.