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What is on the horizon for periprosthetic joint infection?

Issue: July 2012

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Periprosthetic joint infection continues to pose a challenge to practicing orthopedic surgeons. In my opinion, periprosthetic joint infection is the challenge of the decade, placing an immense burden on patients, society and the health care system. Orthopedics Today convened a group of internationally recognized leaders to discuss this important topic with a special emphasis on new developments and recent innovations.

Javad Parvizi, MD, FRCS
Moderator

Javad Parvzi, MD, FRCS: What is periprosthetic infection?

Carl A. Deirmengian, MD: Periprosthetic infection occurs when pathogenic organisms establish residence around a joint replacement, interacting with the host to generate unwanted clinical consequences. Although most periprosthetic infections are caused by gram positive bacteria, a wide variety of infecting organisms have been reported. The host response may vary from chronic, low-grade local inflammation to acute, fulminant systemic sepsis. The local clinical consequences may be as subtle as chronic pain, or as obvious as loose implants with severe periarticular bone loss.

Parvizi: How does the body respond to an infecting organism?

Edward M. Schwarz, PhD: Mammals, including humans, have evolved a complex array of immediate responses (innate immunity) and specific responses to a particular pathogen that develop over time (adaptive immunity), which involve cells, immunoglobulins and a large number of soluble factors (cytokines and chemokines).

In the case of osteomyelitis, of which approximately 80% is caused by Staphylococcus aureus, the innate response commences when the bacteria contacts toll-like receptors (TLRs) on host cells that specifically recognize the components of the cell wall. TLRs then sound the alarm by signaling for the production of chemokines and cytokine that stimulate vasodilation, migration and activation of phagocytic leukocytes (neutrophils, macrophages and dendritic cells) that engulf and kill the bacteria. While the neutrophils often die at the infection site in this process of bacterial clearance, the macrophages and dendritic cells carry pieces of the lysed bacteria (antigens) to the draining lymph node, where they are presented to generate specific T-cells and B-cells for the adaptive immune response to clear chronic infection and provide immunological memory to prevent reinfection by the same pathogen.

In some instances, the pathogen enters the parenchymal cells to establish a latent infection, and in so doing, evaded the innate immune response. An example of this is the recent reporting of S. aureus infection of osteoblasts during chronic osteomyelitis. Host immunity for these intracellular infections is dependent on cytotoxic T-cells from the adaptive response, which recognizes bacterial antigens expressed on the surface of infected cells, and subsequently kills them.

Some microbes bind to necrotic tissue or medical implants following infection, and produce a biofilm that cannot be cleared by the host. In these cases, survival of the host is believed to be dependent on perpetual innate and adaptive responses to prevent sepsis from bacteria that leach out of the biofilm on a daily basis, in an effort to colonize distal tissues. Many believe that specific circulating antibodies against the bacteria produced from B-cells are critical for this protection, as they bind to the surface of the bacteria and facilitate opsonophagocytosis.

Parvizi: One of the challenges of diagnosing periprosthetic joint infection (PJI) relates to lack of an absolute test. Do you think we are getting closer to finding a test that will fulfill this criterion?

Deirmengian: I think we are getting close. The conceptual leap that has brought us closer is the idea that identification of both the organism and the host response are important. Although identification of the organism by culture was historically considered the primary diagnostic test, the recent literature has focused on tests that measure the host response, such as the synovial fluid white blood cell count, the erythrocyte sedimentation rate (ESR), and the C-reactive protein (CRP) concentration. Even though cultures, local cell counts and serum tests can provide a certain degree of accuracy, I believe that molecular technologies focusing on organism identification and the host response will soon supplant these tests and provide a more “absolute” diagnosis.

Parvizi: What are some recent developments in diagnosis of PJI?

Deirmengian: Polymerase chain reaction-based (PCR) organism detection technologies and synovial fluid biomarker technologies have received the most recent attention in the literature and industry. PCR-based technologies detect organisms by amplifying their genomic material, potentially providing faster more accurate results than cultures. Additionally, several groups have now demonstrated the accuracy of synovial fluid biomarkers in detecting the specific host response to infection. Synovial fluid biomarkers outperform the ESR and serum CRP in the diagnosis of periprosthetic infection. In the future, I believe that we will screen patients for periprosthetic infection by testing for synovial fluid biomarkers, and then perform PCR-based testing to identify organisms in those patients who have infection.

Parvizi: Management of PJI consumes somewhere in the region of $600 million to $700 million of health care money each year. Do you see any strategies to help us make a difference in the rising incidence of PJI?

Sandra I. Berríos-Torres, MD: Implementation of effective surgical site infection (SSI) prevention strategies, like the ones in the Centers for Disease Control and Prevention’s (CDC) “Guideline for the Prevention of Surgical Site Infection, 1999” varies significantly across surgeons and facilities. Risk factors exist across the continuum of care. While the responsibility for prevention does not rest solely with surgeons, they should play a key leadership role. With our current knowledge base, to make a difference in the incidence of PJI, we must institute culture change and a multidisciplinary approach. This should include professional societies, surgical and perioperative nursing staff, infectious disease, infection control, quality improvement specialists and administrative leadership.

First, is a review of existing strategies that address modifiable patient and perioperative risk factors and identification of implementation gaps. Uniform implementation can make a difference even in procedures with a low incidence of SSIs. The updated guideline will augment our knowledge base with evidence-based strategies to add to the existing armamentarium. Knowledge gaps will be identified and used to develop an evidence-based research agenda that, over the next decade, could significantly advance the field in SSI prevention through research to include SSI risk factors, development of interventions, implementation of care bundles and basic science.

Parvizi: It is being discussed that the CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC) is in the process of revising the “Guideline for Prevention of Surgical Site Infection, 1999.” Can you please fill us in as to where you are with this process? When we should expect to see the updated guidelines?

Berríos-Torres: The updated guideline represents a transition from recommendations based on consensus opinion to a rigorous evidence-based, grade of recommendations assessment, development and evaluation methodology. In addition to CDC, HICPAC, its liaison and ex-officio members, there is representation by the American Academy of Orthopaedic Surgeons (AAOS), the Musculoskeletal Infection Society, the American College of Surgeons (ACS), the Surgical Infection Society-North America, and the Association of Perioperative Registered Nurses, in addition to academic experts in surgical site infection prevention, S. aureus colonization and biofilm. The University of Pennsylvania Health System’s Center for Evidence-based Practices provides the expertise in evidence-based methodology.

We are currently drafting evidence tables followed by grading of the evidence. Draft narrative summaries and recommendations will be posted to the Federal Register for 30 days of public comment and then CDC clearance. Progress to date is presented three times a year at publicly held HICPAC meetings. A schedule of upcoming meetings is available at www.cdc.gov/hicpac. AAOS and ACS leadership attended a November 2011 meeting. We encourage the orthopedic community to attend and take advantage of the opportunity to review and provide comments on the draft recommendations once posted to the Federal Register. We anticipate finalizing the guideline for publication in 2013.

Parvizi: In addition to the core section, providing recommendations deemed applicable across multiple surgical procedures, the updated guideline will now include a separate component section. The first of these is focused on prevention of SSIs in prosthetic joint arthroplasty. What was the impetus behind this move?

Berríos-Torres: Annually, more than 1.2 million prosthetic joint arthroplasties are performed in the United States. Despite the low incidence of SSIs in primary arthroplasties, there is a significant projected increase in both the number of arthroplasties and related SSIs. The associated morbidity, mortality and cost to treat these make the identification and implementation of SSI prevention strategies of paramount importance. The goal of this component section is to provide procedure-specific, evidence-based prevention strategies to supplement the core strategies and maximize the potential to further reduce the incidence of SSIs in a specific high-volume, high-burden procedure.

Updates to the component section are expected to be developed more frequently then those to the core section, and each update will target a different specialty and procedure. It is also an excellent opportunity to engage and expand on multidisciplinary collaborations between professional societies, academic and public health subject matter experts.

Parvizi: Can you tell us about your research in vaccination as a potential strategy for management of PJI?

Schwarz: Methicillin-resistant S. aureus (MRSA) is major problem in PJI, and multidrug resistant strains for which no antibiotic therapies are available are now merging. Recent reports on the long-term outcome of two-stage revision surgery for MRSA PJI indicated a greater than 50% failure rate. Thus, there is a need to develop additional therapeutic interventions such as passive immunization (intravenous infusion of protective antibodies against MRSA), particularly for immunocompromised patients and the elderly who are typically poor responders to active vaccines.

To address this, we have taken a parallel basic science and clinical research approach, which is currently funded by the AOTrauma Foundation’s Clinical Priority Program on Bone Infection. The preclinical research uses a novel murine model of implant-associated osteomyelitis in which a stainless steel pin is coated with bioluminescent S. aureus and implanted transcortically through the tibia. In this model, infection can be quantified longitudinally via bioluminescent imaging to assess vaccine efficacy. We also used this model to discover that mice protect themselves from this infection by mounting a specific IgG2b response against the peptidoglycan hydrolase, glucosaminidase (Gmd), an enzyme involved in cell wall digestion during binary fission. Due to the functional significance of the target and the finding that there is no genetic variation among clinical strains, we have commenced development of an anti-Gmd passive immunotherapy that is currently being investigated in various animal models. If this vaccine proves effective, it could proceed to clinical trials with PJI patients within 3 years.

The long-standing “immune proteome” theory posits that successful adaptive immunity against a particular pathogen occurs through the generation of antibodies against a specific constellation of antigens. Conversely, failure to generate these protective antibodies results in chronic infections and death of the host. While an immune proteome for S. aureus infections in humans has been proposed, it remains to be evaluated in PJI patients. Thus, our clinical research focuses on an international collaboration of more than 20 centers worldwide that will collect serum and S. aureus isolates from 500 patients at the time of septic implant removal (baseline), at the time of revision surgery and 1 year postoperatively. The sera will be evaluated for anti-S. aureus antibodies and correlated with the clinical outcome of the two-stage revision surgery to define the immune proteome.

Parvizi: What, in your opinion, are some of the most exciting developments in the field of infection and PJI in particular?

Schwarz: In addition to the MRSA vaccine work being done by many groups in addition to our research, there are several other lines of investigation that could lead to major innovations for PJI. The first is in the generation of more sophisticated patient registries supported by the Agency for Healthcare Research and Quality, which will generate patient- specific and clinical outcome data that may help better define patients at high risk for PJI who should receive greater care prior to, during and after surgery.

While it is well known that PJI patients are not a random population, and there are several comorbidities that are associated with higher infection rates (i.e., diabetes, obesity and immunosuppression), this information alone has not led to an effective algorithm on how to lower the overall PJI rate. Similarly, the development of hospital systems designed to lower PJI rates below the national average (1% to 2%) have been largely unsuccessful (i.e., Surgical Care Improvement Project measures). To address this, the Center for Medicare & Medicaid Innovation will be funding $30 million grants focused on the implementation of new health care systems that significantly reduce hospital re-admissions, of which infection is a major contributor. Thus, there is an expectation that a more comprehensive analysis of patient demographics and clinical practices may identify major insights that can be acted on to reduce infections and prevent the emergence of more virulent multidrug resistant strains.

Although the idea of antimicrobial coatings on medical devises has been pursued for decades, recent advances in smart implant design and synthetic antibacterial agents have spawned new enthusiasm that effective products may be on the horizon. One of the more promising technologies is a smart implant that has vancomycin, the most potent antibiotic against MRSA, covalently bonded to the implant. Animal studies have demonstrated the remarkable efficacy of these implants to prevent bacterial colonization and biofilm formation. Other coating technologies include novel synthetic antimicrobial peptides and ceragenins, such as cationic steroidal antimicrobial-13, which are designed to be eluted from a silicone polymer coating on implant. Although more rigorous safety and efficacy studies are needed, preliminary preclinical studies are promising.