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Proposed passive immunization is designed to be given to patients prior to revision total joint replacement
After preclinical toxicology studies, the immunization could be in clinical trials by the end of 2014.
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This month’s 4 Questions interview offers some hope for a new approach on how to reduce the devastating effects of Methicillin-resistant Staphylococcus aureus (MRSA) infections following a joint replacement. Edward M. Schwarz, PhD, the Burton Professor of Orthopaedics and Rehabilitation at the University of Rochester Medical Center, is an immunologist. He has presented interesting and encouraging results from his laboratory where they are working toward a passive vaccine that could be effective against both Methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA. It is my pleasure to bring his innovative work to the attention of Orthopedics Today readers.
Douglas W. Jackson, MD
Chief Medical Editor
Douglas W. Jackson, MD: Among the American population who undergo total joint replacement surgery, what percentage will have an infection from MRSA and what are the current limitations in our treatments?
Edward M. Schwarz, PhD: U.S. infection rates for primary total joint replacement (TJR) surgery remain at 1% to 2% despite significant efforts to decrease infections. About 80% of these infections are caused by Staphylococcus aureus, and half of these are MRSA. Treatment options are limited, and usually involve removal of the prosthesis and vancomycin therapy. If the patient recovers from this serious infection, and the bone has not been destroyed by osteomyelitis, then the patient can undergo a revision TJR surgery. Unfortunately, these often get re-infected, as the failure rate of revision TJR for MRSA osteomyelitis has been reported as high as 30% to 50%. It these cases the patient’s joint may be lost, and salvage outcomes include joint fusion, amputation and Girdlestone arthroplasty.
Jackson: What innovative work and methodology has your group used to explore alternatives to antibiotics for implant infections?
Schwarz: As an immunologist, my lab has been working towards a passive vaccine that would be effective against both MSSA and MRSA, which cause most TJR infections. Our approach has been to develop a mouse model of implant-associated osteomyelitis that closely mimics the microbial pathogenesis seen in the clinical situation. In these mice, a stainless steel pin is contaminated with S. aureus, and is surgically implanted through the tibia. This results in a highly reproducible localized infection with sequestrum and involucrum formation. The mice never get septic or die. Thus, we reasoned that they must be protecting themselves via host immunity. To test this hypothesis, we evaluated the antibodies in the mice before and after infection.
Edward M. Schwarz
Jackson: Your group has identified an antibody that interferes with MRSA bacterial division. What is your understanding of how it works?
Schwarz: We discovered that mice mount a specific antibody response against glucosaminidase (Gmd), which is an enzyme that is responsible for digesting the bacterial cell wall during binary fission. We believe there are two direct mechanisms by which the antibody could interfere with bacterial growth. The first is by crosslinking the bacteria together and forcing them to grow as large clumps, which we demonstrated by showing that the antibody can precipitate S. aureus out of liquid culture. The second is that it inhibits the enzyme activity and forces the bacteria to grow in long chance that cannot separate, which we showed by scanning electron microscopy. There are two other in vivo mechanisms by which the antibody can inhibit or kill MRSA.
The first is by opsonophagocytosis in which the antibody binds to Gmd on the surface of the bacteria and facilitates its uptake by white blood cells. The second, and perhaps most unique for antibodies against S. aureus, is that it might inhibit Gmd in the middle of binary fission when the new cell wall is not completely covering the dividing bacteria. This would make the bacteria susceptible to complement lysis, which is generally thought to be impossible for S. aureus.
Jackson: What are the implications for immunization development and a realistic time table for clinical use if it is as beneficial as it could be?
Schwarz: The proposed passive immunization is specifically designed to be given to revision TJR patients prior to surgery, and potentially high-risk patients (i.e., obese, diabetic, immune compromised), but not the general population like the flu vaccine. We are now testing the anti-Gmd monoclonal antibodies in mice to identify a lead candidate for clinical development. If this and the preclinical toxicology studies go perfectly, then the passive immunization could be in clinical trials by the end of 2014.
For more information:
- Edward M. Schwarz, PhD, is the Burton Professor of Orthopaedics, and Director, Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Ave., Box 665, Rochester, NY 14642; 585-275-3063; fax: 585-275-1121; email: edward_schwarz@urmc.rochester.edu.
- Disclosure: Schwarz is a paid consultant of MedImmune Inc. and his lab has osteomyelitis research funding from the National Institutes of Health, the AOTruama Foundation and Codevax LLC.