Dr. Patel will discuss the importance of accurate diagnosis of prosthetic joint infection and its management. She will focus on the pathogenesis, clinical presentation, and definition of arthroplasty failure, and will discuss diagnostic strategies.
Robin Patel, M.D.
Director of the Initial Processing and Media Laboratory
Director of the Bacteriology Laboratory
Division of Clinical Microbiology
Mayo Clinic, Rochester, Minnesota
Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.
Our speaker for this program is Dr. Robin Patel, Director of the Initial Processing and Media Laboratory and Director of the Bacteriology Laboratory in the Division of Clinical Microbiology at Mayo Clinic in Rochester, Minnesota. Dr. Patel will discuss the importance of accurate diagnosis of prosthetic joint infection and its management. She will focus on the pathogenesis, clinical presentation, and definition of arthroplasty failure, and will discuss diagnostic strategies.
Total Hip and Knee Replacement Procedures United States 1990-2006
Thank you Sharon. Before beginning, I have the following disclosures. I have an unlicensed US patent pending for a method and an apparatus for sonication, but I have foregone my right to receive royalties in the event that the patent is licensed. I have had funding from the Mayo Clinic, the National Institutes of Health, the Scoliosis Research Society, the Orthopaedic Research and Education Foundation, and the Arthritis Foundation.
The numbers of primary total hip and knee arthroplasties have been increasing over the past decade, with nearly 800,000 performed in the United States in 2006. It is estimated that over 3 million primary total knee and over 500,000 primary total hip arthroplasties will be performed annually in the United States by the year 2030.
Prosthetic Hip and Knee Infections United States 1990-2004
Hip and knee arthroplasty are most common. Shoulder, elbow, wrist, ankle, and temporomandibular, metacarpophalangeal and interphalangeal joint replacement are less commonly performed. Prosthetic joints improve quality of life, but may fail due to aseptic loosening, infection, dislocation, prosthesis or bone fracture, and other causes, necessitating revision or resection arthroplasty. Prosthetic joint infection, although uncommon is the most serious complication occurring in approximately 2% of knee and 1% of hip arthroplasties.
Surgical Management of Prosthetic Hip or Knee Infection
As shown in this figure, the number of cases of prosthetic joint infection is increasing. Patient-related risk factors for prosthetic joint infection include prior revision arthroplasty or prior same site prosthetic joint infection, tobacco abuse, obesity, rheumatoid arthritis, malignancy, immunosuppression, and diabetes. Surgical risk factors include simultaneous bilateral arthroplasty, operative time greater than 2.5 hours, and allogeneic blood transfusion. Post-operative risk factors include wound-healing complications (such as superficial infection, hematoma, delayed healing, wound necrosis, dehiscence), atrial fibrillation, myocardial infarction, urinary tract infection, prolonged hospital stay and, Staphylococcus aureus bacteremia. The cost of treating prosthetic hip infection is estimated at $59,677 per episode.
Common Causes Hip and Knee Arthroplasty Infection
It is important to accurately diagnose prosthetic joint infection as its management differs from the management of other causes of arthroplasty failure. The goal of treatment is to cure infection, prevent recurrence, and achieve a pain-free, functional joint. This can best be achieved by a multidisciplinary team including an orthopaedic surgeon, clinical microbiologist, and infectious disease specialist.
Antimicrobial agents alone, without surgical intervention, ultimately usually fail. The quality of surgical debridement is critical. A general approach to surgical management is outlined, although different centers and surgeons may use slightly different strategies. Chronic infections require resection arthroplasty either as a one-stage, with removal and reimplantation of the prosthesis during the same surgical procedure, or a two-stage, with removal of the prosthesis and systemic antimicrobial agents with subsequent prosthesis reimplantation exchange. Patients with symptoms of prosthetic joint infection for fewer than three weeks, who present with early postoperative or hematogenous infection, and who have a well-fixed, functioning prosthesis, without a sinus tract, and with appropriate microbiology represent a select group potentially amenable to debridement and retention of the prosthesis. When unacceptable function is anticipated following surgery or the infection has been refractory to multiple surgical attempts at cure, resection arthroplasty with creation of a pseudarthrosis for hips (a Girdlestone procedure) or arthrodesis for knees may be considered. If the patient is not a surgical candidate, antimicrobial suppression may be considered; this approach is unlikely to cure infection, so antimicrobial agents are often continued indefinitely.
Unusual Causes of Prosthetic Joint Infection
Staphylococcus aureus and coagulase-negative Staphylococci account for more than half of prosthetic hip and knee infection cases. Propionibacterium acnes is a common cause of shoulder arthroplasty infection. Approximately 20% of Prosthetic Joint Infection cases are polymicrobial, most commonly involving methicillin-resistant Staphylococcus aureus or anaerobes. Approximately 7% of cases are culture-negative, often in the context of prior antimicrobial therapy.
In addition to the organisms shown on the prior slide, an ever-expanding list of bacteria and fungi, some of which are shown on this slide, cause the remainder of cases of Prosthetic Joint Infection.
Criteria for Diagnosis of Prosthetic Joint Infection
The pathogenesis of Prosthetic Joint Infection involves the formation of microbial biofilms. Bacteria, typically inoculated at the time of implantation, adhere to the implant and enter into a phenotypically unique, biofilm state in which they are relatively protected from conventional antimicrobial agents and the host immune system. In this biofilm state, they grow slowly and elaborate an extracellular polymeric matrix. As mentioned, in the biofilm state, they are relatively resistant to antimicrobial agents and the host immune system. However, the immune system is attracted to the site of infection, and this can result in destruction of tissues surrounding the prosthesis and the finding, for example, of acute inflammation in periprosthetic tissues.
Prosthetic Joint Infection Clinical Presentation
Although there is no universally accepted definition of prosthetic joint infection, criteria listed have been applied in a number of studies and have been recently summarized in the references publication. The criteria include the presence of at least one of the following:
- Acute inflammation on histopathological examination of periprosthetic tissue, or
- Sinus tract communicating with the prosthesis, or
- Gross purulence in the joint space, or
- Isolation of the same microorganism from multiple cultures of joint aspirates or intraoperative periprosthetic tissue specimens and/or in significant amounts from prosthesis sonicate.
C-Reactive Protein Erythrocyte Sedimentation Rate
The most frequent symptom of prosthetic joint infection is pain. In infection caused by virulent bacteria, patients typically present with local and systemic signs and symptoms. In contrast, chronic infection is generally characterized by subtle signs and symptoms, often not suggestive of infection, such as persistent pain alone, accompanied by loosening of the prosthesis at the bone-cement interface, and sometimes by sinus tract formation with discharge. Infections due to hematogenous seeding of the implant can occur at anytime postoperatively, typically presenting with sudden onset of joint pain.
In the absence of underlying inflammatory conditions, C-reactive protein is the most useful preoperative blood test. Although C-reactive protein and erythrocyte sedimentation rate are both elevated after uncomplicated arthroplasty surgery, C-reactive protein returns to preoperative levels earlier than does the erythrocyte sedimentation rate. We recently examined preoperative C-reactive protein and erythrocyte sedimentation rate in 582 patients with knee, hip or shoulder implant failure. Both were statistically significantly higher in the groups with prosthetic knee or hip infection compared to those with aseptic implant failure. However, in the shoulder implant group, the erythrocyte sedimentation rate was not significantly different in the groups with prosthetic shoulder infection versus aseptic shoulder implant failure, and the C-reactive protein was minimally elevated in the former compared to the latter group.
We examined the data separated by erythrocyte sedimentation rate and C-reactive protein based on standard cutoffs of >30 mm/h and >10 mg/L, respectively, as well as cutoffs we optimized using receiver operating curve analysis. C-reactive protein performed better than erythrocyte sedimentation rate for detection of prosthetic hip implant infection, but neither test performed well for detection of prosthetic shoulder implant infection. Overall, therefore, C-reactive protein is preferred to erythrocyte sedimentation rate, but neither test performs well for the diagnosis of prosthetic shoulder infection.
18F-fluoro-2-deoxyglucose Positron Emission Tomography/Computed Tomography Increased Activity Around the Bone-Prosthesis Interface
Plain radiographs are inaccurate for diagnosis; periprosthetic radiolucency, osteolysis, and/or migration may be present in either prosthetic joint infection or aseptic loosening. Computed tomography and magnetic resonance imaging are hampered by artifacts produced by the prostheses, although non-ferromagnetic (such as titanium or tantalum) implants are associated with minimal artifacts and provide good magnetic resonance imaging resolution for soft-tissue abnormalities. Bone scans; including those performed as three-phase studies, are sensitive for detecting failed implants but cannot be used to determine the cause of failure, and may remain abnormal for more than a year after implantation. Combined bone and gallium scans offer improvement over bone scan alone; however, labeled leukocyte imaging combined with bone scan has the best accuracy.
Synovial Fluid Leukocyte/Differential Prosthetic Knee
Newer imaging strategies, such as antigranulocyte scintigraphy with monoclonal antibodies and hybrid imaging, such as positron emission tomography combined with computed tomography, which is shown here, are under investigation. In this patient (whose images were also shown on the prior slide), Staphylococcus epidermidis and Finegoldia magna were isolated from periprosthetic tissue.
Studies of Intrasurgical Frozen-Section Histopathologic Findings of Acute Inflammation in Prosthetic Joint Infection Diagnosis
The most useful pre-operative diagnostic test (where there is uncertainty) is joint aspiration for total and differential cell count and culture. Aspiration should not be performed through overlying cellulitis. A synovial fluid leukocyte count of more than 1.7x103/μl or a neutrophil percentage of more than 65% is consistent with prosthetic knee infection. Hip aspiration may require imaging guidance. A synovial fluid leukocyte count of more than 4.2x103/μl or a neutrophil percentage of more than 80% is consistent with prosthetic hip infection. These cutoffs are dramatically lower than those used to diagnose native joint infection. Synovial fluid culture has a sensitivity ranging of 56 to 75% and specificity of 95 to 100%, and to achieve ideal sensitivity and specificity should be performed by inoculation into a blood culture bottle. If an organism of questionable clinical significance is isolated, repeat synovial fluid aspiration for culture should be considered. Prior antimicrobial therapy reduces sensitivity.
Prospective Vortexing/Sonication Clinical Study Hip or Knee Implants
In cases where the diagnosis of Prosthetic Joint Infection has not been established preoperatively, assessment for acute inflammation on intraoperative frozen section provides rapid intraoperative assessment for Prosthetic Joint Infection, with sensitivities of 43-100% and specificities of 77-100% (using cutoffs varying from >5 to ³10 polymorphonuclear leukocytes per high power field).
Staphylococcus epidermidis Biofilm on Polycarbonate Coupons Scanning Electron Microscopy
Defining the pathogen(s) is critical to directing the antimicrobial regimen. If this has not been done preoperatively, it is important that appropriate specimens for microbiologic study be collected at the time of surgery. Antimicrobial therapy should be discontinued at least two weeks prior to collection of specimens for culture, and, at surgery, antimicrobial agents should be withheld until culture specimens have been collected. Cultures of sinus tract exudates are often positive due to microbial skin colonization, correlate poorly with surgically obtained specimens and should be avoided. Due to poor sensitivity, neither intraoperative swab cultures, nor periprosthetic tissue Gram stain are recommended.
Collection of multiple periprosthetic tissue specimens for aerobic and anaerobic bacterial culture is imperative because of the poor sensitivity of a single tissue culture, and to distinguish contaminants from pathogens. It has been demonstrated that, ideally, five or six specimens should be submitted for culture. In addition to prior systemic antimicrobial therapy, cultures may be falsely negative because of leaching of antimicrobial agents from antimicrobial impregnated cement, biofilm growth on the prosthesis surface, a low number of organisms in tissue, inappropriate culture media or inadequate culture incubation time, or prolonged transport to the laboratory. Fungal and/or mycobacterial cultures may be considered, but are not routinely recommended. Since microorganisms associated with Prosthetic Joint Infection attach to the prosthesis and persist as biofilm microorganisms, obtaining a sample from the prosthesis surface is useful for microbiologic diagnosis. Vortexing combined with sonication of the implant is a simple technique that can be performed in most microbiology laboratories and has been shown to be more sensitive than and as specific as multiple periprosthetic tissue cultures for diagnosing prosthetic hip, knee and shoulder infection as well as spine implant infection, provided that an appropriate cutoff for significant results is applied. This approach is particularly helpful in patients who have received prior antimicrobial therapy. Sonication in bags is not recommended due to contamination. This slide shows an outline of the procedure that we use for implant sonication. The implant is collected in a sterilized 1-liter, straight-sided, wide-mouthed polypropylene jar and transported to the laboratory. Four hundred milliliters of Ringer’s solution is added to the container. The container is vortexed for 30 seconds and then subjected to bath sonication for 5 minutes, followed by an additional vortexing for 30 seconds. In our original study we directly plated 0.5 ml of sonicate fluid to aerobic and anaerobic sheep blood agar plates, but we now concentrate the sonicate fluid hundred-fold by centrifugation and plate 0.1 ml of concentrated sonicate fluid.
Periprosthetic Tissue and Sonicate Fluid Culture
Sonication removes bacterial biofilms from surfaces as shown in this figure illustrating Staphylococcus epidermidis biofilm on polycarbonate coupons treated with soaking alone, scraping with a wooden stick or sonication as described on the prior slide.
Prospective Vortexing/Sonication Clinical Study Hip or Knee Implants
This slide shows periprosthetic tissue and sonicate fluid culture from the same patient. Note that there are much greater numbers of colonies growing from the sonicate fluid compared to the periprosthetic tissue specimen.
Definition of Prosthetic Hip and Knee Infection
We validated the vortexing/sonication technique by performing a prospective clinical trial of patients undergoing total hip or knee revision or resection for aseptic failure or presumed infection at our institution from August 2003 - December 2005. Those patients whose components were contaminated in the operating room, components did not fit in the container, in whom <2 tissues were cultured or who underwent partial revision were excluded from the study.
Number of Microorganisms Detected by Sonicate Fluid Culture
Prosthetic hip and knee infection was defined as previously shown, but excluding microbiologic criteria. Patients had to have at least one of the following:
- Visible purulence of synovial fluid or intraoperatively, or
- Acute inflammation on histopathologic tissue examination; or
- The presence of a sinus tract communicating with the prosthesis.
Results Prosthetic Hip or Knee Infection
252 subjects with aseptic implant failure and 79 with prosthetic joint infection were enrolled. Sonicate fluid was not concentrated; 0.5 ml was plated on an anaerobic and aerobic sheep blood agar plate and incubated anaerobically and aerobically, respectively. This slide shows the quantity (and type) of microorganisms detected by sonicate fluid culture. Most of the prosthetic joint infection specimens yielded >100 colony forming units per plate, whereas most of the aseptic failure specimens yielded no growth or a small number of colonies. A cutoff of 5 colony-forming units of the same organism was determined to most accurately differentiate aseptic failure from infection.
Effect of Preoperative Antimicrobial Therapy on Culture Sensitivity in Patients with Prosthetic Hip or Knee Infection
The sensitivity of sonicate fluid culture (78.5%) was superior to that of tissue culture (60.8%). The sensitivity of synovial fluid culture was 56.3%. The specificities of sonicate fluid culture, tissue culture, and synovial-fluid culture were 98.8%, 99.2%, and 98.1%, respectively.
The sensitivity of tissue and sonicate fluid culture was reduced in patients receiving antimicrobial therapy. For tissue culture, the sensitivity decreased from 76.9% to 47.8% to 41.2% as the antimicrobial-free interval before surgery decreased from greater than 14 days, to 4 to 14 days, to 0 to 3 days, respectively. For sonicate fluid culture, the sensitivity was 82.1%, 87.0%, and 58.8% for the same time intervals, respectively. Sonicate fluid culture was more sensitive than tissue culture when antimicrobial agents were discontinued within 14 days before surgery (75% versus 45% respectively).
Prospective Clinical Study Shoulder Implants
Fourteen patients with prosthetic joint infection had positive sonicate fluid and negative tissue cultures. No patients with prosthetic joint infection had negative sonicate fluid cultures and positive tissue cultures. 48 patients with prosthetic joint infection had positive sonicate fluid and tissue cultures, with concordant results in 37. Five had an additional organism detected by sonicate fluid cultures, four had an additional organism detected by periprosthetic tissue cultures, and two had different organisms detected by the two techniques. Among the aseptic failure subjects there were three with positive sonicate fluid cultures and two different subjects with positive tissue cultures.
We recently published a similar prospective clinical trial of patients undergoing shoulder arthroplasty revision or resection for aseptic failure or presumed infection at our institution from August 2004 through November 2008. Those patients in whom <2 tissues were cultured, who underwent partial revision or whose sonicate fluid was not archived were excluded from the study.
Definition of Definite Prosthetic Shoulder Infection
Vortexing and sonication were performed as described in our hip and knee implant study except that after December 14, 2005, we introduced sonicate fluid concentration as shown on this slide. The implant was placed in a sterile jar and 400mL of Ringers solution was added. The implant in the jar was subjected to Vortexing for 30 seconds, sonication for 5 minutes, Vortexing for an additional 30 seconds, and then as mentioned.
Prospective Clinical Study Shoulder Implants
Prior to December 14, 2005, 0.5 mL was plated onto aerobic and anaerobic culture plates and after December 15, 2005, 0.1 mL of concentrated sonicate fluid was plated onto aerobic and anaerobic culture plates.
Shoulder Arthroplasty Infection
Patients were classified as having prosthetic shoulder infection if at least one of the following was present:
- Visible purulence surrounding the prosthesis, or
- Acute inflammation on histopathologic examination of permanent tissue sections, or
- A sinus tract communicating with the prosthesis.
- Aseptic failure was defined as failure that did not meet these criteria.
One hundred thirty-six patients undergoing arthroplasty revision or resection were studied; 33 had definite prosthetic shoulder infection and 101 had aseptic implant failure. Sonicate fluid culture was more sensitive than periprosthetic tissue culture for the detection of definite prosthetic shoulder infection (66.7 and 54.5%, respectively). The specificities were similar.
Propionibacterium acnes was the commonest species detected among culture-positive definite prosthetic shoulder infection cases by periprosthetic tissue culture as well as sonicate fluid culture.
Propionibacterium acnes was isolated in 7 cases, Staphylococcus epidermidis in 7 cases, Staphylococcus aureus in 4 cases, Pseudomonas aeruginosa in 1 case, Propionibacterium acnes plus a Corynebacterium species in 1 case, Propionibacterium acnes plus S. epidermidis in 1 case, and Finegoldia magna in 1 case.