Acta Biomaterialia 10 (2014) 4518–4524

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Rifampicin–fosfomycin coating for cementless endoprostheses: Antimicrobial effects against methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) Volker Alt a,b,⇑, Kristin Kirchhof c, Florian Seim a,b, Isabelle Hrubesch a,b, Katrin S. Lips b, Henrich Mannel c, Eugen Domann d, Reinhard Schnettler a,b a

Department of Trauma Surgery Giessen, University Hospital of Giessen-Marburg, Campus Giessen, 35385 Giessen, Germany Laboratory of Experimental Trauma Surgery Giessen, Justus-Liebig-University Giessen, 35394 Giessen, Germany c Biomet Deutschland GmbH, 14167 Berlin, Germany d Institute of Medical Microbiology, University Hospital of Giessen-Marburg, Campus Giessen, 35392 Giessen, Germany b

a r t i c l e

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Article history: Received 17 February 2014 Received in revised form 7 May 2014 Accepted 9 June 2014 Available online 16 June 2014 Keywords: Infection Prosthesis Staphylococcus aureus MRSA

a b s t r a c t New strategies to decrease infection rates in cementless arthroplasty are needed, especially in the context of the growing incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections. The purpose of this study was to investigate the antimicrobial activity of a rifampicin–fosfomycin coating against methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA in a rabbit infection prophylaxis model. Uncoated or rifampicin–fosfomycin-coated K-wires were inserted into the intramedullary canal of the tibia in rabbits and contaminated with an inoculation dose of 105 or 106 colony-forming units of MSSA EDCC 5055 in study 1 and MRSA T6625930 in study 2, respectively. After 28 days the animals were killed and clinical, histological and microbiological assessment, including pulse-field gel electrophoresis, was conducted. Positive culture growth in agar plate testing and/or clinical signs and/or histological signs were defined positive for infection. Statistical evaluation was performed using Fisher’s exact test. Both studies showed a statistically significant reduction of infection rates for rifampicin–fosfomycin-coated implants compared to uncoated K-wires (P = 0.015). In both studies none of the 12 animals that were treated with a rifampicin–fosfomycin-coated implant showed clinical signs of infection or a positive agar plate testing result. In both studies, one animal of the coating group showed the presence of sporadic bacteria with concomitant inflammatory signs in histology. The control groups in both studies exhibited an infection rate of 100% with clear clinical signs of infection and positive culture growth in all animals. In summary, the rifampicin–fosfomycin-coating showed excellent antimicrobial activity against both MSSA and MRSA, and therefore warrants further clinical testing. Ó 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

1. Introduction Infections in total arthroplasty such as total knee and total hip arthroplasty are devastating situations with a negative impact both on the quality of life for the patient and on the cost to the healthcare system [1]. Frequently, surgical treatment to exchange the infected prosthesis is the only option for treatment of the infection. However, failure rates with reinfection or persistence of the infection of this extensive surgical treatment of 20% have been reported [2].

⇑ Corresponding author at: Department of Trauma Surgery Giessen, University Hospital of Giessen-Marburg, Campus Giessen, 35385 Giessen, Germany. E-mail address: [email protected] (V. Alt). http://dx.doi.org/10.1016/j.actbio.2014.06.013 1742-7061/Ó 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

The virulence of methicillin-resistant Staphylococcus aureus (MRSA) has turned this pathogen not only into the most deadly bacteria in North America [3] but also into a complex problem in the context of total joint infections. Previous reports have shown that the treatment outcome for patients with infections with multiresistant bacteria such as MRSA is significantly worse compared to infections with non-multiresistant bacteria with higher recurrence of infection of up to 61%, resulting in resection arthroplasty or even amputation [4,5]. Therefore, all efforts should be undertaken to optimize infection prophylaxis in total joint arthroplasty, including prophylaxis against MRSA. The principle of local delivery of antibiotics by antibioticloaded bone cement was introduced by Buchholz and Engelbrecht [6] and was intended to optimize infection prophylaxis by high concentrations of the antibiotic in direct vicinity to the implant

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and in the adjacent tissue, while at the same time minimizing systemic concentrations and systemic side effects. Clinical data from the Norwegian Arthroplasty Register show a significant reduction of infection rates in primary cemented hip arthroplasty [7] when comparing systemic antibiotics plus antibiotic-loaded bone cement to systemic antibiotics plus antibiotic-free bone cement. In cementless arthroplasty, which is performed without bone cement, the local delivery of antibiotics is currently not possible. Coating the surface of cementless implants with antibiotics or other anti-infective agents is an interesting and promising option for this complex problem. Alt and co-workers were the first to reveal the successful in vivo antimicrobial activity of an antibiotic coating for cementless prostheses coated with combined gentamicin–hydroxyapatite layers [8]. Since then, several articles have been published on the in vivo results of a number of other coatings for cementless joint implants such as tobramycin–periapatite [9], vancomycin [10], minocycline–rifampicin [11,12], teicoplanin–clindamycin [13] and various silver coatings [14,15] or cationic steroidal antimicrobial coating [16]. New developments for coating of orthopaedic implants should target solutions that cover the most relevant bacteria strains for implant-associated infections such as Staphylococci including MRSA and gram-negative strains, e.g. Pseudomonas aeruginosa and Escherichia coli. Rifampicin is a bactericidal antibiotic that fulfils this requirement by inhibiting bacterial RNA polymerase with both extracellular and intracellular activity which is superior compared to vancomycin and teicoplanin [17]. One of the drawbacks of rifampicin use is the fast development of resistance in case of monotherapy, and therefore it should only be used with a second antibiotic agent [18]. Fosfomycin can act as ‘‘second antibiotic agent’’ in combination with rifampicin as it has been shown to exhibit excellent antibiotic activity against gram-negative and gram-positive strains including MRSA [19,20]. The synergistic effects of rifampicin and fosfomycin have been reported for systemic use [21], and this systemic combination was recently found to be highly effective in an in vivo subcutaneous implantassociated foreign body infection model [22]. The aim of this work is to investigate the in vivo antimicrobial effects of rifampicin–fosfomycin-coated titanium K-wires in an implant-associated bone infection prophylaxis model against methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA. 2. Materials and methods Two studies for antimicrobial testing of rifampicin–fosfomycincoated K-wires were undertaken, using an MSSA in the first and an MRSA in the second study. All experiments were approved before surgery by the local animal committee (RP Thüringen, Erfurt, Germany, Registration No. 14-002/07). 2.1. Study design 2.1.1. Study 1: MSSA Study 1 included 12 3 month old New Zealand White Rabbits. Inoculation doses of 105 or 106 colony-forming units (CFUs) of MSSA EDCC 5055 were used for this study. Six animals received a rifampicin–fosfomycin-coated K-wire. Three of these were inoculated with 105 and the remaining three rabbits with 106 CFUs. In the control group, in which the uncoated K-wire was inserted, three animals received an inoculation dose of 105 and three of 106 CFUs. One animal of the control group with an inoculation dose of 105 CFUs was precluded from the study because of anatomical deformity of the lower limb.

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2.1.2. Study 2: MRSA A similar study design was chosen for study 2. Inoculation doses of 105 or 106 CFUs of MRSA T6625930 were used to contaminate the intramedullary canal of the tibia. In six animals a rifampicin– fosfomycin-coated K-wire was implanted. Three of these rabbits were inoculated with 105 and three with 106 CFUs. In the control group, in which the uncoated K-wire was used, three animals were inoculated with 105 and three with 106 CFUs. In the control group one animal with an inoculation dose of 105 CFUs died during surgery due to anesthesia complications.

2.2. Bacteria 2.2.1. Bacterial strains MSSA EDCC 5055 strain was used in a previous study for testing the antimicrobial effect of different gentamicin coatings for cementless endoprostheses in the same animal model [8]. MSSA EDCC 5055 is a clinical isolate from a patient with a wound infection. The isolate was identified by API biochemical characteristic testing (bioMerieux, Marcy L’Etoile, France), by sequencing the 16S rDNA gene, and by specific polymerase chain reactions (PCRs) to detect the femB and coa genes. This strain exhibited strong hemolytic activity and very strong biofilm formation capacity as published before [23] based on the technology of O’Toole et al. [24]. The MRSA T6625930 is a clinical isolate from a patient with a periprosthetic hip joint infection. It also shows in vitro biofilm formation. The strain was identified by sequencing the 16S rDNA gene, and by specific PCRs to detect the femB and mecA genes. To determine the minimal inhibitory concentration (MIC), bacterial colonies were picked out from blood–agar plates, mixed in a tube containing sterile saline and diluted to obtain a turbidity equivalent to the 0.5 McFarland test standard. Using a sterile swab, bacteria were streaked on Mueller–Hinton agar plates. MIC evaluator strips™ (OXOID, Wesel, Germany) were aseptically applied to the agar plates, which were further incubated overnight at 37 °C. MICs were read the following day. The MIC of MSSA EDCC 5055 against rifampicin was found to be 6 0.5 lg ml 1 and against fosfomycin 6 16 lg ml 1; the MIC of MRSA T6625930 against rifampicin was 6 0.5 lg ml 1 and against fosfomycin 6 8 lg ml 1. 2.2.2. Bacteria cultivation All bacteria were grown in brain heart infusion broth (BHI) at 37 °C under vigorous shaking for 16 h. The culture was diluted 1:50 in BHI and further incubated as described above for 4 h. The culture was diluted 1:10 in phosphate-buffered salie (PBS) and plated on BHI agar plates using a spiral plater for the enumeration of S. aureus in CFUs ml 1. Several suspensions with a final volume of 160 ll for inoculations with the required concentrations of 105 or 106 CFUs per 20 ll in BHI/20% glycerol were generated and stored at 80 °C until use. Each inoculation volume for the infection trial was 20 ll, equivalent to 105 or 106 CFUs. 2.3. Implants

c-sterilized titanium alloy Ti6Al4 V K-wires with a diameter of 2.0 mm that were either uncoated or coated with rifampicin–fosfomycin were used for the study (Fig. 1). All implants were provided by Biomet Deutschland GmbH (Berlin, Germany). The implants had a total length of 12 cm of which 10 cm were coated. The coating was applied via an ink-jet technology in analogy to a gentamicin coating as published before [8]. The concentrations of rifampicin and fosfomycin were 50 and 250 lg cm 2, respectively, with a total amount of 307 lg rifampicin and 1522 lg fosfomycin per implant.

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(0.1 mg kg 1 bodyweight). Surgery was carried out under aseptic conditions according to the previously published model [8]. No systemic antibiotics were utilized. After disinfection of the right lower limb, the knee region was draped in a sterile manner. The tibial tuberosity was approached via a 1 cm infrapatellar incision followed by splitting of the patellar tendon and opening of the distal part of the knee joint. The superior cortex of the tibial tuberosity was perforated and the K-wire was subsequently introduced into the intramedullary canal. The K-wire was driven to the distal part of the intramedullary canal and was shortened to fit the length of the tibia. Shortening was always performed in the non-coated proximal 2 cm of the implant. A 16G needle was also introduced into the intramedullary tibia canal next to the K-wire over which 20 ll of the suspension with the number of CFUs of S. aureus according to the study protocol were inoculated into the midshaft area of the intramedullary canal. After injection of the bacteria, 20 ll of the remaining inoculum was streaked out on agar plates to confirm the intended inoculation dose. The wound was closed and post-operative X-ray control was performed (Fig. 2). After 4 weeks the animals were killed under general anaesthesia (ketamine: 60 mg kg 1 bodyweight; T61: 4–5 ml intracardial). The tibiae were then harvested under sterile conditions. The K-wire was removed and the tibia was then sagitally cut. The lateral and the medial half were used for microbiological and histological evaluations, respectively. 2.5. Evaluation methods Fig. 1. Rifampicin–fosfomycin-coated K-wire (top) and uncoated titanium K-wire (bottom (a). Scanning electron microscope image of a rifampicin–fosfomycincoated Ti6Al4V alloy disc sample (K-wire and disc have the identical grit blasted surface finishing); 10,000-fold magnification, scale bar 1 lm (b).

2.5.1. Clinical assessment for infection The lower extremity and the adjacent knee and ankle joint were evaluated for any clinical signs of inflammation or swelling before harvesting of the bone. During dissection for bone harvest the soft tissue and after longitudinal section of the tibia the intramedullary cavity were assessed for pus, abscess formation and cortical lysis. 2.5.2. Microbiological assessment for infection The K-wires were removed carefully under sterile conditions and rolled out on BHI agar plates. For the bone samples, the bone marrow of one tibial half was removed and weighed. The bone marrow tissue sample was suspended in PBS and vortexed to disperse potential bacteria in the sample. The suspension was subsequently diluted (1:1, 1:10, 1:100) and 10 ll of each dilution were streaked on BHI plates and incubated at 37 °C for 24 h. The number of colonies was counted on each agar plate. In order to confirm the identity of the inoculated S. aureus and the S. aureus isolates on agar plates, randomly collected colonies from agar plates were genetically compared with the inoculated strains using PFGE and the CHEF-DR II system (Biorad, Munich, Germany) as described before [8]. 2.5.3. Histological evaluation The medial half of the tibia was immersed in 4% paraformaldehyde solution for 24 h and subsequently 5 lm longitudinal sections were cut using the grinding technique as previously described [8]. These sections were stained with toluidine blue and hematoxylin–eosin. The identification of bacteria with concomitant inflammatory signs such as sequester formation, presence of immune-competent cells, periost reaction and/or periosteal reaction was defined as infection.

Fig. 2. Postoperative X-ray of implanted rifampicin–fosfomycin-coated K-wire.

2.6. Statistical analysis 2.4. Surgery Anesthesia was performed using ketamine (60 mg kg 1 bodyweight), xylazine (6 mg kg 1 bodyweight) and atropine

Sample size calculation was based on the hypothesis that rifampicin–fosfomycin coating can reduce infection rates by 50% compared to standard implants (null hypothesis). This targeted 50%

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reduction of infection rate would indicate a great clinical success and was therefore considered as the target for statistical difference in the current study. Statistical analysis was done with Fisher’s exact test using a two sided v2-test using SPSS for Windows (version 21.0). Differences with a P-value < 0.05 were considered to be statistically significant. 3. Results 3.1. Study 1: MSSA Inoculation doses of 105 or 106 CFUs of MSSA EDCC 5055 were used for this study. Three of the five animals of the control group exhibited clear macroscopic infection signs such as subcutaneous abscess formation and/or knee joint empyema (Fig. 3A,B). In none of the animals that received a rifampicin–fosfomycin-coated implant were macroscopic infection signs found. All animals (5/5) that received an uncoated implant exhibited positive culture growth, whereas none of the six animals that were

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treated with a rifampicin–fosfomycin-coated implant showed positive culture growth. For the uncoated implant group, there was always positive culture growth for the implants and in four of five cases of the bone marrow samples as well. In all cases with positive culture growth PFGE identified the inoculated MSSA EDCC 5055, confirming this strain as the infection-causing organism. Histology showed bacteria with concomitant bone sequester formation and/or the presence of immune-competent cells close to the detected bacteria in all five animals of the control group (Fig. 4A,B). In five of the six animals of the rifampicin–fosfomycin group no bacteria were found (Fig. 4C,D). In one animal of this group with an inoculation dose of 105 CFUs of MSSA, EDCC 5055 bacteria with concomitant inflammatory signs were detected. Therefore, this animal was considered to be infected. Considering all evaluation methods, i.e. clinical, microbiological and histological analysis, the infection rate of the control group is 100% (infection in 5/5 animals), whereas only 16.7% (infection in 1/6 animals) of the animals of the rifampicin–fosfomycin group were infected. This reduction of the infection rate by rifampicin– fosfomycin coating is statistically significant (P = 0.015).

Fig. 3. Macroscopic infection signs in an animal with an uncoated implant after MSSA contamination showing subcutaneous abscess formation (A) and knee empyema (B). Macroscopic appearance without infection signs in the subcutaneous tissue (C) and within the knee joint (D) in an animal treated with a rifampicin–fosfomycin-coated implant.

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Fig. 4. Histological evaluation of an animal that received an uncoated implant (control group) of the MSSA study with abscess formation (arrow) in the intramedullary canal (A) (scale bar: 1 mm). In detail histology (B): presence of bacteria (arrow) within the abscess surrounded by a wall of immune competent cells (arrow head) (scale bar 20 lm). Intact cortical and intact bone marrow structure of an animal of the rifampicin–fosfomycin group of the MSSA study (C) (scale bar: 200 lm) without signs of infection reactions in Haversian (arrow) or Volkmann channels (arrow head) and intact osteocytes (D) (scale bar: 50 lm).

Fig. 5. Macroscopic appearance of an animal treated with an uncoated implant after MRSA contamination with extensive pus formation in the knee joint infection signs in an animal with an uncoated implant after MRSA contamination showing knee empyema (A). Macroscopic appearance without infection signs within the knee joint (B) in an animal treated with a rifampicin–fosfomycin-coated implant.

3.2. Study 2: MRSA Three of five animals of the control group exhibited clear macroscopic infection signs such as subcutaneous abscess formation and/or knee joint empyema (Fig. 5). These were the animals that received the dose of 106 CFUs of MRSA T6625930. All animals of the rifampicin–fosfomycin group were free of macroscopic infection signs. As in study 1, all animals (5/5) that received an uncoated implant were found to have positive culture growth on the agar plates whereas none of the six animals that received a rifampicin–fosfomycin-coated implant showed positive culture growth.

PFGE confirmed the inoculated MRSA T6625930 in all cases with positive culture growth. Histological analysis identified bacteria with concomitant bone sequester formation and/or the presence of immunecompetent cells close to the detected bacteria in all five animals of the control group. One animal of the rifampicin–fosfomycin group with an inoculation dose of 106 CFUs MRSA T6625930 was also found to have sporadic bacteria in the bone marrow and cortical bone (Fig. 6) with concomitant inflammatory signs. Therefore, this animal was also considered to be infected. All five other animals of this group were free of bacteria based on histological assessment.

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Based on clinical, microbiological and histological evaluation, the infection rate of the control group and the rifampicin–fosfomycin coating group is 100% (infection in 5/5 animals) and 16.7% (infection in 1/6 animals), respectively, which also means a statistically significant reduction of the infection rate (P = 0.015) due to the rifampicin–fosfomycin coating. 4. Discussion The goal of antimicrobial coatings for cementless prostheses is to reduce infection rates. The rifampicin–fosfomycin coating tested here showed excellent antimicrobial activity against both MSSA and MRSA, with statistically significant reduction of infection rates compared to uncoated control implants. Currently, there is no published animal model for the assessment of the antimicrobial activity of antibiotic-coated K-wires to mimic the human situation after implantation of a cementless joint prosthesis. Animal models in orthopedics should in general try to target the human situation as accurately as possible [25]. This means for antimicrobial testing of implant coatings for cementless joint prostheses that the models should enable osseous implantation with joint contact of the coated device. Anatomical and biomechanical preconditions between bone and soft tissue are quite different, and therefore total joint implants intended for bone anchorage in the joint environment should be tested in osseous and not in soft tissue environment. Several studies concerning the in vivo antimicrobial activity of antibiotic-coated implants in animal models have been reported [8–16]. Gordon et al. [15] and Shimazaki et al. [14] used rat models with only subcutaneous implantation of the coated device, which hence exhibit the above-mentioned serious limitations. The other above-mentioned models [8–13,16] fulfil at least some important prerequisites for a more realistic testing of joint prostheses components as all of them allow for osseous implantation with intra-articular contact of the device. It is accepted that these models do not allow articulation between implants and therefore do not fully mimic the human joint arthroplasty situation. In these studies the implants coated with antibiotics such as minocycline– rifampicin [11,12], tobramycin–periapatite [9] or teicoplanin plus clindamycin [13] were challenged only against MSSA strains and not against MRSA. The reported activity of thermal sprayed silver-containing hydroxyapatite coating against MRSA was obtained as mentioned above only in a subcutaneous implantation model [14,15]. Sinclair et al. [16] found in vivo activity of a cationic steroidal antimicrobial coating which is not based on an antibiotic drug technology. Therefore, the present work with the rifampicin– fosfomycin coating is the first one that successfully shows the activity of an antibiotic coating in an implant-associated bone and joint infection model against MRSA. We have used this model previously for the assessment of the antimicrobial activity of gentamicin-coated implants [8]. This

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model reliably leads to implant-associated bone and knee joint infection in the uncoated control group with infection rates of 88% as shown previously [8] and 100% in this study with clear macroscopic signs of infection. Therefore, this model is suitable for the testing of antibiotic-coated implants for cementless arthroplasty. The rifampicin–fosfomycin coating exhibited excellent antimicrobial activity against both MSSA and MRSA with statistically significant reduction of infection rates compared to uncoated control implants in the current study. Moreover, the coating proved its antimicrobial performance when applying a relatively high concentration of bacteria in the inoculum, leaving behind only sporadic bacteria. In clinical practice the desired aim is to minimize the exposure to bacteria as much as possible (disinfection) so that the host defence is able to cope with the remaining bacteria. Therefore, the rifampicin–fosfomycin coating can serve as an important part of the prophylaxis concept enabling the disinfection of the wound in cementless arthroplasty. One limitation of the study is the small sample size number of only six animals per subgroup. Furthermore, the two animals lost were not replaced during the study. Therefore, the limited statistical power of the study should be kept in mind when interpreting the results. The transferability of preclinical experimental data into clinical practice always needs to be discussed. Currently, there are no antibiotic-coated implants in cementless arthroplasty available, which makes the comparison between results from animal models and clinical trials impossible. However, the principle of local delivery of antibiotics from implants has been clinically established in orthopedic surgery for antibiotic-loaded bone cement [7], and currently for gentamicin-coated intramedullary nails for tibia fractures [26]. In both cases preclinical testing in animal models showed the successful translation of the principle of local delivery of antibiotics by the antibiotic-loaded implants. For poly(methyl methacrylate) bone cement, the original preclinical studies in different animal models [27–29] revealed successful release of different antibiotics such as gentamicin on which the further clinical testing was based. The preclinical antimicrobial activity for gentamicin– poly-DL-lactic acid (PDLLA) coating has been established in a rat model [30,31]. which led to the development of a gentamicin– PDLLA-coated tibia nail for human application. This should pave the way for transferring results from experimental trials with adequate models into clinical practice in the context of local delivery of antibiotics in orthopedic surgery. 5. Conclusion There is a tremendous need for new strategies to improve infection prophylaxis and reduce infection rates in total joint replacement including cementless arthroplasty. The growing incidence of MRSA-related total joint infection, worsening the outcome after total joint infections, shows the importance of extending prophylaxis strategies against MRSA strains. The rifampicin–fosfomycin coating presented here shows excellent antimicrobial activity against MSSA and MRSA that warrants further clinical testing. Acknowledgement The study was supported by Biomet Deutschland GmbH. Appendix A. Figures with essential color discrimination

Fig. 6. Bacteria (arrow) in cortical erosion tunnels in a rifampicin–fosfomycintreated animal (scale bar: 20 lm).

Certain figures in this article, particularly Figs. 1 and 3–6, are difficult to interpret in black and white. The full color images can be found in the on-line version, at http://dx.doi.org/10.1016/ j.actbio.2014.06.013.

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Rifampicin-fosfomycin coating for cementless endoprostheses: antimicrobial effects against methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA).

New strategies to decrease infection rates in cementless arthroplasty are needed, especially in the context of the growing incidence of methicillin-re...
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