Background. With promising antibiofilm properties, rifampicin is considered as a cornerstone in the complementary treatment of bone and joint infections. But, achieving an adequate concentration of rifampicin long-term in bone tissue is a challenge. Long-term systemic administration also comes with concomitant side effects. Thus, local delivery of rifampicin in a carrier to ensure the high local concentration of antibiotic in surgical site after intervention due to infection could be a valuable alternative. However, an ideal platform for local delivery of rifampicin is still lacking. A calcium sulphate/hydroxyapatite (CaS/HA) (Cerament, Bonesupport AB, Sweden) biomaterial was used as a local delivery platform. Here we aimed 1) to evaluate the injectability of CaS/HA hand-mixed with rifampicin at various concentrations up to maximum one daily dose used systemically in clinical practice 2) to test a clinically used and commercially available mixing device containing the biphasic ceramic with rifampicin. Materials & Methods. Three different concentrations (100 mg, 300 mg and 600 mg) of rifampicin powder (Rifampicin Ebb, Sanofi S.P.A, Italy) diluted in 5 mL of mixing solution (C-TRU, Bonesupport AB, Sweden) were used. Rifampicin solution was mixed to the CaS/HA powder and the injectability of the CaS/HA plus rifampicin composite was evaluated by extruding 250 µL of paste manually through a graduated 1 mL syringe connected to an 18G needle (Ø=1.2 mm, L=4 cm). Mixing was done with a spatula for 30 s at 22°C ±1°C. Total weight of the paste before and after extrusion were measured. To normalize the amount of composite that remained in the needle and syringe tip after injection, the mean of the paste extruded from the syringe at 3 min was calculated for the tested concentrations (normalized value). Injectability (%) was calculated by dividing the weight of the paste extruded from the syringe with normalized value. Each test was repeated for three times at various time points (3, 5, 7 and 9 min). Additionally, 300 mg rifampicin was chosen to mix with the CaS/HA in a commercially available mixing system, which is used clinically. Results. All three combinations of CaS/HA plus rifampicin (100 mg, 300 mg & 600 mg) could be completely extruded from 1 mL syringes at 3 min. At 5 min, 100 mg & 300 mg could still be injected, whereas 600 mg was uninjectable or solidified. At 7 min, rifampicin 100 mg & 300 mg showed 34% and 11% of injectability respectively. At 9 min, no injectability was observed. The material was completely set within 15 minutes with all concentrations. With commercial mixing system, at the recommended injection time of 4 min, 78% of the CaS/HA plus rifampicin (300 mg) composite could be injected. Conclusions. The injectability was reduced with the increasing concentration of rifampicin. CaS/HA plus rifampicin (100 mg and/or 300 mg) could be used by hand mixing and transferred to a syringe or by using an available mixing system containing the ceramic. For higher concentrations of rifampicin, the rheological properties of the ceramics have to be modified for injectability

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

We developed a novel silorane-based biomaterial (SBB) for use as an orthopedic cement. SBB is comprised of non-toxic silicon-based monomers, undergoes non-exothermic polymerization, and has weight-bearing strength required of orthopedic cements. We sought to compare the antibiotic release kinetics of this new cement to that of commercially available PMMA bone cement. We also evaluated each material's inherent propensity to support the attachment of bacteria under both static and dynamic conditions. One gram of either rifampin or vancomycin was added to 40g batches of PMMA and SBB. Pellets were individually soaked in PBS. Eluate was collected and tested daily for 14 days using HPLC. Compressive strength and modulus were tested over 21 days. Bioassays were used to confirm the bioactivity of the antibiotics eluted. We measured the growth and maturation of staphylococcus aureus (SA) biofilm on the surface of both PMMA and SBB disks over the course of 72 hours in a static well plate and in a dynamic biofilm reactor (CDC Biofilm Reactor). N=4 at 24, 48, and 72 hours. A luminescent strain of SA (Xen 29) was employed allowing imaging of bacteria on the discs. SBB eluted higher concentrations of vancomycin than did PMMA over the course of 14 days (p<0.001). A significant 55.1% greater day 1 elution was observed from SBB. Silorane cement was able to deliver rifampin in clinically favorable concentrations over 14 days. On the contrary, PMMA was unable to deliver rifampin past day 1. The incorporation of rifampin into PMMA severely reduced its mechanical strength (p<0.001) and modulus (p<0.001). Surface bacterial radiance of PMMA specimens was significantly greater than that of SBB specimens at all time points (p<0.05). The novel silorane-based cement demonstrated superior antibiotic release and, even without antibiotic incorporation, demonstrated an innate inhabitation to bacterial attachment and biofilm

Staphylococcus aureus (SA), the predominant pathogen in human osteomyelitis, is known to persist by forming intracellular reservoirs, including in bone cells (Schwarz et al., 2019, Yang et al., 2018, Krauss et al., 2019, Gao et al., 2020, Bosse et al., 2005), promoting decreased antibiotic susceptibility. However, there are no evidence-based treatment guidelines for intracellular SA infections in osteomyelitis. We sought to address this by systematically reviewing the literature and, testing a selection of antibiotic treatments in a clinically relevant in vitro assay. We conducted a systematic review of the literature to determine the current evidence for the efficacy of antibiotics against intracellular SA infections relevant to osteomyelitis. For the antibiotics identified as potentially useful, we determined their minimal inhibitory concentration (MIC) against 11 clinical osteomyelitis SA- isolates. We selected those for further testing reported able to reach a higher concentration in the bone than the identified MIC against the majority of strains. Thus, rifampicin, oxacillin, linezolid, levofloxacin, oritavancin and doxycycline were tested in human SaOS-2-osteocyte infection models (Gunn et al., 2021) of acute (1d) or chronic (14d) infection to clear intracellular SA. Antibiotics were tested at 1x/4x/10x the MIC for the duration of 1d or 7d in each model. A systematic review found that osteoblasts and macrophages have mostly been used to test immediate short-term activity against intracellular SA, with a high variability in methodology. However, some extant evidence supports that rifampicin, oritravancin, linezolid, moxifloxacin and oxacillin may be effective intracellular treatments. While studies are ongoing, in vitro testing in a clinically relevant model suggests that rifampicin, oxacillin and doxycycline could be effectively used to treat osteomyelitic intracellular SA infections. Importantly, these have lower MICs against multiple clinical isolates than their respective clinically-achievable bone concentrations. The combined approach of a systematic review and disease-relevant in vitro screening will potentially inform as to the best approach for treating osteomyelitis where intracellular SA infection is confirmed or suspected

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

Background. Staphylococcus aureus is a human pathogen involved in implant-related infections. In these diseases, biofilm production is the key pathogenic event, and it increases antibiotic resistance of the organism. Because this phenomenon, local delivery of antibiotics could allows reaching high concentrations in the infected tissue without the secondary effects linked to systemic administration. Here we report the use of a ceramic biomaterial (SBA-15) as a carrier of antibiotics in order to deliver them directly in the infected tissue. Material and methods. SBA-15 discs were loaded with vancomycin, rifampin and a combination of both according to the protocol described by Molina-Manso et al. Loaded discs were introduced in a 0.5 McFarland suspension of S. aureus 15981 and incubated during 6 and 24 hours in order to develop a biofilm. After incubation, samples were sonicated during 5 minutes and 1:10 serial dilutions were performed in order to count viable bacteria. All experiments were performed in triplicate. Results. A statistically significant decrease in the number of viable bacteria was detected for all antibiotics at 6 hours, and also for vancomycin and the combination. Rifampin showed an increase in the number of viable bacteria at 24 hours. No differences were detected between vancomycin and the combination of antibiotics. Conclusion. SBA-15 can carry antibiotics that have effect on bacterial biofilm. The use of rifampin alone showed a loss of the effect after 24 hours of incubation, probably due to the selection of resistant mutants that nullify the effect of the antibiotic. No differences have been detected between vancomycin alone and its combination with rifampin in this experiment

Infection is one of the most serious complications of orthopedic surgery, particularly in implant-related procedures. Minimum inhibitory concentration (MIC) for identified bacteria is an important factor for successful antibiotic treatment. We investigated the MIC of antibiotics in Staphylococcus species from orthopedic infections, comparing with isolates from respiratory medicine. Staphylococcus species isolated in our laboratory from January 2013 to July 2016 were retrospectively reviewed. The MIC of vancomycin (VCM), arbekacin (ABK), teicoplanin (TEIC), linezolid (LZD), and rifampicin (RFP) was reviewed. Differences in the MIC of each antibiotic in orthopedic and respiratory samples were determined. A total of 259 isolates were evaluated (89 orthopedic, 170 respiratory). Staphylococcus aureus was the most commonly identified species (58%). In comparison with orthopedic samples, the number of isolates with a VCM MIC <0.5 μg/ml in methicillin sensitive staphylococcus aureus (MSSA) was significantly higher in respiratory isolates, while a MIC of 2 μg/ml was significantly lower (P = 0.0078). The proportion of isolates with a VCM MIC of 2 μg/ml in methicillin-resistant coagulase-negative staphylococci (MRCNS) was significantly higher in orthopedic isolates than that seen in respiratory isolates of methicillin-resistant staphylococcus aureus (MRSA; P < 0.001). When comparing MRCNS and other orthopedic Staphylococci, the rate of RFP MIC >2 μg/ml in MRCNS isolates was significantly higher (P = 0.0058). The MIC of VCM in Staphylococcus species from orthopedic infection was higher than that of respiratory samples, particularly in MRCNS from implant-related samples. MRCNS showed a significantly higher rate of resistance for RFP versus other orthopedic isolates

We studied 51 patients with osteo-articular tuberculosis who were divided into two groups. Group I comprised 31 newly-diagnosed patients who were given first-line antituberculous treatment consisting of isoniazid, rifampicin, ethambutol and pyrazinamide. Group II (non-responders) consisted of 20 patients with a history of clinical non-responsiveness to supervised uninterrupted antituberculous treatment for a minimum of three months or a recurrence of a previous lesion which on clinical observation had healed. No patient in either group was HIV-positive. Group II were treated with an immunomodulation regime of intradermal BCG, oral levamisole and intramuscular diphtheria and tetanus vaccines as an adjunct for eight weeks in addition to antituberculous treatment. We gave antituberculous treatment for a total of 12 to 18 months in both groups and they were followed up for a mean of 30.2 months (24 to 49). A series of 20 healthy blood donors served as a control group. Twenty-nine (93.6%) of the 31 patients in group I and 14 of the 20 (70%) in group II had a clinicoradiological healing response to treatment by five months. The CD4 cell count in both groups was depressed at the time of enrolment, with a greater degree of depression in the group-II patients (686 cells/mm. 3. (. sd. 261) and 545 cells/mm. 3. (. sd. 137), respectively; p < 0.05). After treatment for three months both groups showed significant elevation of the CD4 cell count, reaching a level comparable with the control group. However, the mean CD4 cell count of group II (945 cells/mm. 3. (. sd. 343)) still remained lower than that of group I (1071 cells/mm. 3. (. sd. 290)), but the difference was not significant. Our study has shown encouraging results after immunomodulation and antituberculous treatment in non-responsive patients. The pattern of change in the CD4 cell count in response to treatment may be a reliable clinical indicator

After the implantation of endoprotheses or osteosynthesis devices, implant-related infections are one of the major challenges. The surface of implants offers optimal conditions for the formation of a biofilm. Effective carrier systems for the delivery of adequate therapeutics would reduce the concentrations needed for successful treatment and improve cure rates. In cancer diagnosis and therapy, magnetic nanoparticles are concentrated in the target area by an external magnetic field. For orthopaedic applications, in vitro examinations showed that the addition of a magnetic implant in combination with an external magnetic field could increase the amount of MNPSNPs that accumulated in direct vicinity to the implant. The present examinations implemented an electromagnet to increase magnetic field strength and should show if the in vitro set up can be transferred to an in vivo mouse model. Additionally, the loading capacity of the MNPSNPs with enrofloxacin and its release kinetics were determined. Fluorescein-isothiocyanate (FITC) was covalently attached to MNPSNPs. For the in vitro set up, a peristaltic pump was used to establish a closed circuit which contained the MNPSNP dispersion and a magnetic platelet. After 5 minutes fluid samples were taken from the area around the magnetic platelet and analysed using a microplate reader. For the in vivo set up, a BALB/c mouse was implanted subcutaneously with the metallic platelet at the hind leg. The MNPSNP dispersion was injected into the tale vein and the hind leg of the mouse was placed immediately in a magnetic field of 1.9 T. After one week the implant was retrieved and examined by confocal laser scanning microscopy (CLSM). Liver, spleen and kidneys of the mouse were examined by magnetic resonance imaging (MRI). The loading capacity of the MNPs with enrofloxacin was examined by quantification of the enrofloxacin content in the incubation and washing solution after incubation. The release kinetics weres tested in PBS using UV/Vis-spectrometry. The solution in the remaining tube contained no detectable MNPs while the concentration in the vicinity of the platelet was 150 µg/ml. The mouse showed no clinical adverse effects. The CLSM examination revealed a considerable accumulation of the MNPs at the implant surface. MRI could show neither accumulated MNPs nor changes of organ structure. The loading capacity of the MNPs for enrofloxacin was approximately 95 µg/mg. A burst release of nearly a third of the loaded antibiotic occurred within the first 6 hours followed by a further steady release. Conclusion. Loading and release of enrofloxacin showed appropriate results. For future studies antibiotics like rifampicin or vancomycin will be implemented. This first in vivo trial demonstrated an implant-directed targeting of the MNPs and successfully transferred the principle into an in vivo model so that a main study with statistically significant animal numbers has started including histological examinations

This longitudinal microCT study revealed the osteolytic response to a Staphylococcus epidermidis-infected implant in vivoand also demonstrates how antibiotics and/or a low bone mass state influence the morphological changes in bone and the course of the infection. Colonisation of orthopaedic implants with Staphylococcus aureusor S. epidermidisis a major clinical concern, since infection-induced osteolysis can drastically impair implant fixation or integration within bone. High fracture incidence in post-menopausal osteoporosis patients means that this patient group are at risk of implant infection. The low bone mass in these patients may exacerbate infection-induced osteolysis, or alter antibiotic efficacy. Therefore, the aims of this study were to examine the bone changes resulting from a S. epidermidisimplant infection in vivousing microCT imaging, and to determine if a low bone mass stateinfluences the course of the infection and the efficacy of antibiotic therapy. An in vivomodel system using microCT scanning [1], involving the implantation of either a sterile or a S. epidermidis-colonised PEEK screw into the proximal tibia of 24 week-old female Wistar rats, was used to investigate the morphological changes in bone following infection over a 28 day period. In addition, the efficacy of a combination antibiotic therapy (rifampin and cefazolin: administered twice daily from days 7–21 post-screw implantation) for affecting osteolysis was also assessed. A subgroup of animals was subjected to ovariectomy (OVX) at 12 weeks of age, allowing for a 12 week period for bone loss prior to screw implantation at 24 weeks. Bone resorption and formation rates, bone-implant contact and peri-implant bone volume in the proximity of the screw were assessed by microCT scanning at days 0, 3, 6, 9, 14, 20 and 28 days post-surgery. Following euthanasia at day 28, the implanted screw, bone and soft tissues were subjected to quantitative bacteriology as a measure of the efficacy of the antibiotic regimen. In non-OVX animals S. epidermidisinfection induced marked osteolysis, which peaked between 9 and 14 days post-screw implantation. Peak bone resorption was detected at day 6, before recovering to baseline levels at day 14. Infection also resulted in extensive deposition of mineralised tissue, initially within the periosteal region (day 9–14), then subsequently in the osteolytic region at day 20–28. Quantitative bacteriology indicated all non-OVX animals remained infected. Rifampin and cefazolin successfully cleared the infection in 5/6 non-OVX animals group although there was no difference observed in CT-derived bone parameters. OVX resulted in extensive loss of trabecular bone but this did not alter the temporal pattern of infection-induced osteolysis, or mineralised tissue deposition, which was similar to that observed in the non-OVX animals. Similarly, there was no difference in bacterial counts between non-OVX and OVX animals (39,005 colony-forming units (CFU) [range: 3,675–156,800] vs 37,665 CFU [range 3,250–84,000], respectively). Interestingly, antibiotic treatment was less effective in the OVX animals (3/5 remained infected), suggesting that antibiotics have reduced efficacy in OVX animals. This study demonstrates S. epidermidis-induced osteolysis displays a similar temporal pattern in both normal and low bone mass states, with comparable bacterial loads present within the localised infection site

Summary Statement. Combination of antibiotics with N-acetylcisteine and sub-MIC concentration of erythromycin was evaluated in two collection and 16 clinical strains of staphylococci isolated from PJI. The results were strain-dependent, so it evidences the necessity of perform individual studies of biofilm susceptibility. Objectives. Staphylococci are the most common cause of prosthetic joint infections (PJI) (1), making the treatment of this disease difficult due to the increased resistance to antibiotics of biofilms. Combination between antibiotics and other compounds could be a good alternative. The aim of this study was to evaluate the effect of the combination of two compounds with nine antibiotics in biofilms formed by staphylococcal strains isolated from PJI. Methods. 16 clinical strains (8 S. aureus and 8 S. epidermidis) isolated from patients with PJI as well as 2 collection strains (S. aureus 15981 and S. epidermidis ATCC 35984) were tested against 9 antibiotics (rifampin, vancomycin, tigecycline, clindamycin, cotrimoxazole, ciprofloxacin, cloxacillin, daptomycin and fosfomycin) in combination with NAC 1024 μg/mL and erythromycin at subinhibitory concentration (0.12 μg/mL), which was established after the determination of MIC according to EUCAST recommendations. The Calgary Biofilm Device (CBD) was used to determine the susceptibility of the biofilms to these combinations. The Minimal Biofilm Eradication Concentration (MBEC) for the all the antibiotics alone was determined in a previous study. All the experiments were performed by triplicate. Results. All the S. aureus strains showed homogeneous results, and the addition of NAC or erythromycin at the tested concentrations has not a clear effect in the antibiotic susceptibility of the biofilm, although combination of tigecycline with NAC seems even to increase the MBEC in most cases. Almost all clinical strains were MRSA. Regarding S. epidermidis strains, the results were strain-dependant. The combination with NAC seems to increase the MBEC for rifampin and tigecycline in some strains. However, there was a slight MBEC decrease with cotrimoxazole, ciprofloxacin, cloxacillin, daptomycin and fosfomycin. Erythromycin combinations resulted to be successful only in a few cases, and there is no an apparent relationship between erythromycin resistance and combination results. It is especially remarkable that one strain (P-23.2) showed a slight decrease of the MBEC combining both substances with most of the antibiotics tested. Conclusion. None of the combinations tested was clearly effective against biofilms for all strains of both species. This heterogeneity showed the necessity of making an individual study of each strain. The search of new strategies to fight against PJI is mandatory and further investigation is needed

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.

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.

The treatment of chronic osteomyelitis often includes surgical debridement and filling the resultant void with antibiotic-loaded polymethylmethacrylate cement, bone grafts or bone substitutes. Recently, the use of bioactive glass to treat bone defects in infections has been reported in a limited series of patients. However, no direct comparison between this biomaterial and antibiotic-loaded bone substitute has been performed.

In this retrospective study, we compared the safety and efficacy of surgical debridement and local application of the bioactive glass S53P4 in a series of 27 patients affected by chronic osteomyelitis of the long bones (Group A) with two other series, treated respectively with an antibiotic-loaded hydroxyapatite and calcium sulphate compound (Group B; n = 27) or a mixture of tricalcium phosphate and an antibiotic-loaded demineralised bone matrix (Group C; n = 22). Systemic antibiotics were also used in all groups.

After comparable periods of follow-up, the control of infection was similar in the three groups. In particular, 25 out of 27 (92.6%) patients of Group A, 24 out of 27 (88.9%) in Group B and 19 out of 22 (86.3%) in Group C showed no infection recurrence at means of 21.8 (12 to 36), 22.1 (12 to 36) and 21.5 (12 to 36) months follow-up, respectively, while Group A showed a reduced wound complication rate.

Our results show that patients treated with a bioactive glass without local antibiotics achieved similar eradication of infection and less drainage than those treated with two different antibiotic-loaded calcium-based bone substitutes.

Cite this article: Bone Joint J 2014; 96-B:845–50.