Passive immunization with anti-glucosaminidase monoclonal antibodies protects mice from implant-associated osteomyelitis by mediating opsonophagocytosis of<i>Staphylococcus aureus</i>megaclusters

Varrone, John J.; Bentley, Karen L. de Mesy; Bello-Irizarry, Sheila N.; Nishitani, Kohei; Mack, Sarah K.; Hunter, Joshua G.; Kates, Stephen L.; Daiss, John L.; Schwarz, Edward M.

doi:10.1002/jor.22672

Cited by 78 publications

(137 citation statements)

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“…The monoclonal antibody reduced the expression of the effector molecule of the agr system, AgrC, and protected against infection. Another group showed that a monoclonal antibody to S. aureus glucosaminidase protects against implant-associated infections (25). In our study, we saw a significant effect on the various parameters in the rats passively immunized with antibody to PNAG and challenged with the ica − S. aureus strain when compared to the control group.…”

Section: Discussionsupporting

confidence: 57%

“…Additional studies using synthetic oligosaccharides of PNAG and dPNAG conjugated to carrier proteins confirmed the need to use only non-acetylated glucosamines for vaccination to achieve protective immunity (14,21), most likely via opsonic killing of bacteria. Thus, numerous investigations have consistently found an effect on infection and disease when opsonic antibody to PNAG is present due to either active or passive immunization (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

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Active and Passive Immunization Against Staphylococcus aureus Periprosthetic Osteomyelitis in Rats

Søe

Jensen

et al. 2017

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Active and Passive Immunization Against Staphylococcus aureus Periprosthetic Osteomyelitis in Rats

Søe

Jensen

et al. 2017

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“…These models are beneficial for studying the general etiology of osteomyelitis and biofilm formation [24] or systemic treatment strategies such as various antibiotic regimens [20] and immunization [26]. These pin implants are useful models for studying periprosthetic infection, but may be less relevant to trauma-related studies where plate stabilization of a bone defect is employed.…”

Section: Discussionmentioning

confidence: 99%

A novel murine model of established Staphylococcal bone infection in the presence of a fracture fixation plate to study therapies utilizing antibiotic-laden spacers after revision surgery

Inzana

Schwarz

Kates

et al. 2015

Bone

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Mice are the small animal model of choice in biomedical research due to the low cost and availability of genetically engineered lines. However, the devices utilized in current mouse models of implant-associated bone infection have been limited to intramedullary or trans-cortical pins, which are not amenable to treatments involving extensive debridement of a full-thickness bone loss and placement of a segmental antibiotic spacer. To overcome these limitations, we developed a clinically faithful model that utilizes a locking fracture fixation plate to enable debridement of an infected segmental bone defect (full-thickness osteotomy) during a revision surgery, and investigated the therapeutic effects of placing an antibiotic-laden spacer in the segmental bone defect. To first determine the ideal time point for revision following infection, a 0.7 mm osteotomy in the femoral mid-shaft was stabilized with a radiolucent PEEK fixation plate. The defect was inoculated with bioluminescent Staphylococcus aureus, and the infection was monitored over 14 days by bioluminescent imaging (BLI). Osteolysis and reactive bone formation were assessed by X-ray and micro-computed tomography (micro-CT). The active bacterial infection peaked by 5 days post-inoculation, however the stability of the implant fixation became compromised by 10–14 days post-inoculation due to osteolysis around the screws. Thus, day 7 was defined as the ideal time point to perform the revision surgery. During the revision surgery, the infected tissue was debrided and the osteotomy was widened to 3 mm to place a poly-methyl methacrylate spacer, with or without vancomycin. Half of the groups also received systemic vancomycin for the remaining 21 days of the study. The viable bacteria remaining at the end of the study were measured using colony forming unit assays. Volumetric bone changes (osteolysis and reactive bone formation) were directly measured using micro-CT image analysis. Mice that were treated with local or systemic vancomycin did not display gross pathology at the end of the study. While localized vancomycin delivery alone tended to decrease the bacterial burden and osteolysis, these effects were only significant when combined with systemic antibiotic therapy. This novel mouse model replicates key features of implant-associated osteomyelitis that make treatment extremely difficult, such as biofilm formation and osteolysis, and imitates the clinical practice of placing an antibiotic-laden spacer after infected tissue debridement. In addition, the model demonstrates the limitations of current PMMA spacers and could be an invaluable tool for evaluating alternative antimicrobial treatments for implant-associated bone infection.

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“…The functions of these 14 proteins are very important for S aureus to establish orthopaedic infections. S aureus uses microbial surface components recognizing adhesive matrix molecules and determinant proteins to adhere to host tissue or to the implant surface [1], and they use autolysins (glucosaminidase and aminidase) during cell division [37]. The secreted proteins each interfere with some element of the host immunity and collectively act to thwart the immune response [32].…”

Section: Certain Antigens Predominate In the Immune Response Againstmentioning

confidence: 99%

A Diagnostic Serum Antibody Test for Patients With Staphylococcus aureus Osteomyelitis

Nishitani

Beck

Rosenberg

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Because immunity against Staphylococcus aureus has not been fully elucidated, there is no diagnostic test to gauge how robust a patient's host response is likely to be. Therefore, we aimed to develop a test for specific antibodies in serum with diagnostic and prognostic potential. Questions/Purposes We describe the development and validation of a multiplex immunoassay for characterizing a patient's immune response against 14 known S aureus antigens, which we then used to answer four questions: (1) Do certain antigens predominate in the immune response against S aureus? (2) Is there a predominant pattern of antigens recognized by patients and mice with infections? (3) Is the immunoglobulin G (IgG) response to any single antigen a useful predictor of ongoing S aureus infection? (4) Does measurement of the combined response against all 14 antigens provide a better predictor of ongoing infection? Methods A case-control study was performed. Sera were collected from 35 consecutive patients with S aureus culture-confirmed (methicillin-sensitive S aureus or methicillin-resistant S aureus) musculoskeletal infections The institution of one or more of the authors (EMS, SLK, JLD, CAB) has received, during the study period, funding from the National Institutes of Health, NIAMS (Bethesda, MD, USA) and (EMS, SLK, JLD) the AOTrauma Clinical Priority Program (Davos, Switzerland). One of the authors certifies that he (JLD) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of USD 10,000 to 100,000 from Telephus Medical LLC (San Diego, CA, USA) and an amount of less than USD 10,000 from Calorics Pharmaceuticals (Waltham, MA, USA). One of the authors certifies that he (EMS) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of USD 10,000 to 100,000 from Telephus Medical LLC (San Diego, CA, USA). One of the authors certifies that he (SLK) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of less than USD 10,000 from Surgical Excellence Healthcare Quality Consulting, and an amount of USD 10,000 to 100,000 from Sage Publications (Thousand Oaks, CA, USA) One of the authors certifies that he (CAB) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of USD 10,000 to 100,000 from the FDA (Silver Spring, MD, USA), and an amount of USD 10,000 to 100,000 from Boston Scientific (Marlborough, MA, USA), an amount of USD 10,000 to 100,000 from Lundbeck Inc (Deerfield, IL, USA), an amount of USD 10,000 to 100,000 from Patient-Centered Outcomes Research Institute (PCORI, Washington, DC, USA), and an amount of less than USD 10,000 from Auspex Pharmaceuticals (La Jolla, CA, USA). All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research 1 editors and board mem...

show abstract

Passive immunization with anti-glucosaminidase monoclonal antibodies protects mice from implant-associated osteomyelitis by mediating opsonophagocytosis ofStaphylococcus aureusmegaclusters

Cited by 78 publications

References 53 publications

Active and Passive Immunization Against Staphylococcus aureus Periprosthetic Osteomyelitis in Rats

Active and Passive Immunization Against Staphylococcus aureus Periprosthetic Osteomyelitis in Rats

A novel murine model of established Staphylococcal bone infection in the presence of a fracture fixation plate to study therapies utilizing antibiotic-laden spacers after revision surgery

A Diagnostic Serum Antibody Test for Patients With Staphylococcus aureus Osteomyelitis

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