Implant infections caused by Staphylococcus aureus are difficult to treat due to biofilm formation, which complicates surgical and antibiotic treatment. We introduce an alternative approach using monoclonal antibodies (mAbs) targeting S. aureus and provide evidence of the specificity and biodistribution of S.-aureus-targeting antibodies in a mouse implant infection model. The monoclonal antibody 4497-IgG1 targeting wall teichoic acid in S. aureus was labeled with indium-111 using CHX-A”-DTPA as a chelator. Single Photon Emission Computed Tomography/computed tomographyscans were performed at 24, 72 and 120 h after administration of the ¹¹¹In-4497 mAb in Balb/cAnNCrl mice with a subcutaneous implant that was pre-colonized with S. aureus biofilm. The biodistribution of this labelled antibody over various organs was visualized and quantified using SPECT/CT imaging, and was compared to the uptake at the target tissue with the implanted infection. Uptake of the ¹¹¹In-4497 mAbs at the infected implant gradually increased from 8.34 %ID/cm³ at 24 h to 9.22 %ID/cm³ at 120 h. Uptake at the heart/blood pool decreased over time from 11.60 to 7.58 %ID/cm³, whereas the uptake in the other organs decreased from 7.26 to less than 4.66 %ID/cm³ at 120 h. The effective half-life of ¹¹¹In-4497 mAbs was determined to be 59 h. In conclusion, ¹¹¹In-4497 mAbs were found to specifically detect S. aureus and its biofilm with excellent and prolonged accumulation at the site of the colonized implant. Therefore, it has the potential to serve as a drug delivery system for the diagnostic and bactericidal treatment of biofilm.

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Additively manufactured (AM) porous titanium implants may have an increased risk of implant-associated infection (IAI) due to their huge internal surfaces. However, the same surface, when biofunctionalized, can be used to prevent IAI. Here, we used a rat implant infection model to evaluate the biocompatibility and infection prevention performance of AM porous titanium against bioluminescent methicillin-resistant Staphylococcus aureus (MRSA). The specimens were biofunctionalized with Ag nanoparticles (NPs) using plasma electrolytic oxidation (PEO). Infection was initiated using either intramedullary injection in vivo or with in vitro inoculation of the implant prior to implantation. Nontreated (NT) implants were compared with PEO-treated implants with Ag NPs (PT-Ag), without Ag NPs (PT) and infection without an implant. After 7 days, the bacterial load and bone morphological changes were evaluated. When infection was initiated through in vivo injection, the presence of the implant did not enhance the infection, indicating that this technique may not assess the prevention but rather the treatment of IAIs. Following in vitro inoculation, the bacterial load on the implant and in the peri-implant bony tissue was reduced by over 90% for the PT-Ag implants compared to the PT and NT implants. All infected groups had enhanced osteomyelitis scores compared to the noninfected controls.@en

Background and purpose — The long-term results of the 1-or 2-stage revision procedure and infection-free prosthesis survival in a tertiary referral center are unknown. In this retrospective observational study, the long-term results of infection control and infection-free prosthesis survival of the peri-prosthetic joint infection-related 1-and 2-stage revision procedure are evaluated. Furthermore, the merits of performing an antibiotic-free window in the 2-stage revision is evaluated. Patients and methods — All patients who received a 1-or 2-stage revision procedure of the hip or knee between 2010 and 2017 were included. Data was collected on patient and infection characteristics. The primary treatment aim was successful infection control without the use of antibiotic therapy afterwards. Infection-free survival analysis was performed using the Kaplan–Meier method with type of periprosthetic joint infection-related revision as covariate. Within the group of 2-stage revisions, use of an antibiotic-free window was selected as covariate. Results — 128 patients were treated for a periprosthetic joint infection-related revision procedure (81 hips and 47 knees). Successful infection control was achieved in 18 of 21 cases for the 1-stage and 89 out of 107 cases for the 2-stage revision procedure (83%) respectively after follow-up of more than 4 years. In addition, 2-stage revision procedure infection control was achieved in 52 of 60 cases with an anti-biotic-free interval and 37 of 45 cases without such interval (p = 0.6). The mean infection-free survival of the 1-stage revision was 90 months (95% CI 75–105) and 98 months (CI 90–106) for the 2-stage revision procedure. Interpretation — There seems to be no difference in infection control and infection-free survival between the 1-and 2-stage revision procedure. Second, an antibiotic-free window in the case of a 2-stage revision did not seem to influence treatment outcome. However, one must be cautious when interpreting these results due to confounding by indication and the small study population. Therefore, no definite conclusion can be drawn.

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Implant-associated Staphylococcus aureus infections are difficult to treat because of biofilm formation. Bacteria in a biofilm are often insensitive to antibiotics and host immunity. Monoclonal antibodies (mAbs) could provide an alternative approach to improve the diagnosis and potential treatment of biofilm-related infections. Here, we show that mAbs targeting common surface components of S. aureus can recognize clinically relevant biofilm types. The mAbs were also shown to bind a collection of clinical isolates derived from different biofilm-associated infections (endocarditis, prosthetic joint, catheter). We identify two groups of antibodies: one group that uniquely binds S. aureus in biofilm state and one that recognizes S. aureus in both biofilm and planktonic state. Furthermore, we show that a mAb recognizing wall teichoic acid (clone 4497) specifically localizes to a subcutaneously implanted pre-colonized catheter in mice. In conclusion, we demonstrate the capacity of several human mAbs to detect S. aureus biofilms in vitro and in vivo.

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Introduction: Debridement, antibiotics and implant retention (DAIR) procedures are effective treatments for acute postoperative or acute hematogenous periprosthetic joint infections. However, literature reporting on the effectiveness of DAIR procedures performed after a one- or two-stage revision because of a prosthetic joint infection (PJI) (PJI-related revision arthroplasty) is scarce. The aim of this study is to retrospectively evaluate the infection control after 1 year of a DAIR procedure in the case of an early postoperative infection either after primary arthroplasty or after PJI-related revision arthroplasty. Materials and methods: All patients treated with a DAIR procedure within 3 months after onset of PJI between 2009 and 2017 were retrospectively included. Data were collected on patient and infection characteristics. All infections were confirmed by applying the Musculoskeletal Infection Society (MSIS) 2014 criteria. The primary outcome was successful control of infection at 1 year after a DAIR procedure, which was defined as the absence of clinical signs, such as pain, swelling, and erythema; radiological signs, such as protheses loosening; or laboratory signs, such as C-reactive protein (CRP) (<10) with no use of antibiotic therapy. Results: Sixty-seven patients were treated with a DAIR procedure (41 hips and 26 knees). Successful infection control rates of a DAIR procedure after primary arthroplasty (n=51) and after prior PJI-related revision arthroplasty (n=16) were 69 % and 56 %, respectively (p=0.38). The successful infection control rates of a DAIR procedure after an early acute infection (n=35) and after a hematogenous infection (n=16) following primary arthroplasty were both 69 % (p=1.00). Conclusion: In this limited study population, no statistically significant difference is found in infection control after 1 year between DAIR procedures after primary arthroplasty and PJI-related revision arthroplasty.

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Background Implant associated infections such as periprosthetic joint infections are difficult to treat as the bacteria form a biofilm on the prosthetic material. This biofilm complicates surgical and antibiotic treatment. With rising antibiotic resistance, alternative treatment options are needed to treat these infections in the future. The aim of this article is to provide proof-of-principle data required for further development of radioimmunotherapy for non-invasive treatment of implant associated infections. Methods Planktonic cells and biofilms of Methicillin-resistant staphylococcus aureus are grown and treated with radioimmunotherapy. The monoclonal antibodies used, target wall teichoic acids that are cell and biofilm specific. Three different radionuclides in different doses were used. Viability and metabolic activity of the bacterial cells and biofilms were measured by CFU dilution and XTT reduction. Results Alpha-RIT with Bismuth-213 showed significant and dose dependent killing in both planktonic MRSA and biofilm. When planktonic bacteria were treated with 370 kBq of ²¹³Bi-RIT 99% of the bacteria were killed. Complete killing of the bacteria in the biofilm was seen at 185 kBq. Beta-RIT with Lutetium-177 and Actinium-225 showed little to no significant killing. Conclusion Our results demonstrate the ability of specific antibodies loaded with an alpha-emitter Bismuth-213 to selectively kill staphylococcus aureus cells in vitro in both planktonic and biofilm state. RIT could therefore be a potentially alternative treatment modality against planktonic and biofilm-related microbial infections.

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BACKGROUND: Widespread use and misuse of antibiotics have led to a dramatic increase in the emergence of antibiotic resistant bacteria, while the discovery and development of new antibiotics is declining. This has made certain implant-associated infections such as periprosthetic joint infections, where a biofilm is formed, very difficult to treat. Alternative treatment modalities are needed to treat these types of infections in the future. One candidate that has been used extensively in the past, is the use of ionizing radiation. This review aims to provide a historical overview and future perspective of radiation therapy in infectious diseases with a focus on orthopedic infections. METHODS: A systematic search strategy was designed to select studies that used radiation as treatment for bacterial or fungal infections. A total of 216 potentially relevant full-text publications were independently reviewed, of which 182 focused on external radiation and 34 on internal radiation. Due to the large number of studies, several topics were chosen. The main advantages, disadvantages, limitations, and implications of radiation treatment for infections were discussed. RESULTS: In the pre-antibiotic era, high mortality rates were seen in different infections such as pneumonia, gas gangrene and otitis media. In some cases, external radiation therapy decreased the mortality significantly but long-term follow-up of the patients was often not performed so long term radiation effects, as well as potential increased risk of malignancies could not be investigated. Internal radiation using alpha and beta emitting radionuclides show great promise in treating fungal and bacterial infections when combined with selective targeting through antibodies, thus minimizing possible collateral damage to healthy tissue. CONCLUSION: The novel prospects of radiation treatment strategies against planktonic and biofilm-related microbial infections seem feasible and are worth investigating further. However, potential risks involving radiation treatment must be considered in each individual patient.

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