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Introduction
  • Epidemiology 
    • incidence   
      • primary joint replacement
        • 1-2% TKA vs. 0.3-1.3% THA
      • revision joint replacement
        • 5-6% TKA vs. 3-4% THA
    • risk factors 
      • pre-operative
        • active infection
          • local cutaneous, subcutaneous, deep-tissue or joint infection 
          • systemic septicemia
        • previous local surgery/prior local infection 
      • postoperative
        • immune suppression
          • immunosuppressant drugs
            • anti-TNF agents (e.g. infliximab, etanercept, adalimumab, certolizumab, golimumab)
            • antimetabolites (e.g leflunomide)
            • corticosteroids
          • immunosuppressive conditions (dysplasia or neoplasia)
            • poorly controlled diabetes mellitus (HBA1c >7)
            • chronic renal disease
            • acute liver failure
            • malnutrition (eg. albumin <3.5; total serum leukocytes <800)
            • HIV (CD4 counts <400)
        • inflammatory arthropathy
          • rheumatoid arthritis
          • psoriasis
          • ankylosis spondylitis
        • lifestyle factors
          • morbid obesity
          • smoking
          • excessvice alcohol consumption
          • intravenous drug use
          • poor oral hygiene 
  • Pathophysiology
    • most common bacterial organism include
      • staphylococcus aureus 
      • staphylococcus epidermidis
      • Coagulase-negative Staphylococcus (chronic infections)
    • most common fungal pathogen 
      • Candida species (e.g. Candida albicans)
  • Prophylaxis
    • screening
      • screen and optimize risk factors
      • nasal mupirocin for decolonization of nasal MSSA/MRSA
      • routine urine cutures NOT warranted pre-operatively, unless history or symptoms of UTI
      • stop DMARDs 4-6 weeks prior to surgery  
      • revision joint replacement 
        • normalized ESR, CRP off antibiotics
    • operatively
      • pre-operative skin cleansing with antiseptic wash
      • systemic antibiotics 
        • administered within 30 minutes to incision, and >10 minutes prior to tourniquet
        • continued for 24 hours after surgery 
      • operative room
        • vertical laminar airflow systems 
        • limit hospital personal OR traffic in-and-out of room
    • post-operatively
      • antibiotics prior to dental work is dependant on host risk factors 
Classification
  • Time of onset
    • Acute infection
      • infection within 3-6 weeks from surgery
        • CDC definition < 90 days from date of joint replacement
      • biology
        • usually confined to joint space
        • no invasion into prosthetic-bone interface
        • no biofilm production
    • Chronic infection
      • infection more than 3-6 weeks from surgery
        • CDC definition > 90 days from date of joint replacement
      • biology
        • biofilm created by all bacteria forms on implant within four weeks
          • composition
            • 15% cells and 85% polysaccharide layer (glycocalyx) 
            • glycocalyx allows biofilm to adhere to prosthesis and sealoff infection and protect bacteria from host immune system
          • consequence
            • no method exists to safety remove biofilm and eradication is difficult
            • prosthetic explant indicated with infection >4 weeks due to biofilm
          • infection has invaded prosthetic-bone interface
  • Source of infection
    • Direct invasion
      • sinus tract into joint capsule
      • wound dehiscence
    • Hematogenous infection
      • infection in a longstanding infection-free joint secondary to another infection (eg. dental work, infected gallbladder)
Presentation
  • History
    •  may have history of the following
      • recent or active bacteremia
      • multiple local surgeries
      • skin/epithelial tissue penetration (eg. IV drug use, colonoscopy, dental work, ulceration, wound complication)
  • Symptoms
    • persistent pain and stiffness at site of arthroplasty is associated with infection in >90% of patients
    • acute onset with swelling, tenderness, and drainage 
    • chronic infections show pain and more subtle symptoms
      • function deteriorates over time
      • pain worsens over time
  • Physical exam
    • inspection
      • sinus tract to the joint is a definite infection
      • warmth, redness, or swelling  
      • low grade fever
    • motion
      • limited by pain and swelling
Imaging
  • Radiographs
    • findings  
      • periosteal reaction 
      • scattered patches of osteolysis
      • generalized bone resorption without implant wear
      • transcortical sinus tracts
      • implant loosening
  • Bone scan
    • modalitity
      • Tc-99m (technetium) detects inflammation and In-111 (indium) detects leukocytes
      • triple scan can differentiate infection from fracture or bone remodeling
    • indications
      • if infection is suspected, but cannot be confirmed by aspiration or blood work
    • sensitivity and specificity
      • 99% sensitivity and 30% to 40% specificity
  • Positron emission tomography (PET)
    • indication
      • may help to identify areas of high metabolic activity using fluorinated glucose
    • sensitivity and specificity
      • 98% sensitivity and 98% specificity
MSIS Criteria
  • Musculoskeletal Infection Society (MSIS) analyzed the available evidence to propose a new definition for prosthetic joint infections
    • Major criteria (diagnosis can be made when [1] major criteria exist)
      1. sinus tract communicating with prosthesis, or
      2. pathogen isolated by culture from 2 separate tissue/fluid samples from the affected joint
    • Minor criteria (diagnosis can be made when [4/6] of the following minor criteria exist)
      1. elevated ESR (>30mm/h) or CRP (>10mg/L)
      2. elevated synovial WBC (>1,100cells/ul for knees, >3,000cells/ul for hips)
      3. elevated synovial PMN (>64% for knees, >80% for hips)
      4. purulence in affected joint
        • this finding alone is insufficient
          • fluid from metal-metal articulation, gout, etc. can resemble pus
      5. pathogen isolation in 1 culture
      6. >5 PMN per hpf in 5 hpf at x400 magnification (intraoperative frozen section of periprostehtic tissue)
Studies
  • Labs
    • Blood panel
      • WBC
        • not specific or sensitive
    • ESR and CRP  
      • CRP
        • physiology
          • peaks 2-3days after surgery
          • returns to normal at 21 days (3 weeks)
        • normal range
          • acute (< 6 weeks from surgery) = <100 mg/L
          • chronic (> 6 weeks from surgery)= <10 mg/L
      • ESR 
        • physiology
          • peaks 5-7 days after surgery
          • returns to normal 90 days (3 months)
        • normal range
          • acute (< 6 weeks from surgery) = no consences
          • chronic (> 6 weeks from surgery)= <30 mm/hr
    • Serum interleukin-6 (IL-6, normal <10pg/mL)
      • physiology
        • peaks 8-12h after surgery
        • returns to normal 48-72h after surgery (3 days)
        • less commonly followed, but can monitor and follow the progress of infection
      • outcomes
        • has been shown to have the highest correlation with periprosthetic joint infection
        • sensitivity 100%, specificity 95%
        • false positives
          • RA
          • multiple sclerosis
          • AIDS
          • Paget's disease of bone
  • Joint aspiration
    • indications
      • whenever there is a strong suspicion in order to confirm the diagnosis 
    • lab order request
      • cell count and differential
      • crystals
      • gram stain
      • cultures and specificity
    • outcomes
      • cell count and differential
        • lowest serologic values suggestive of infection   
          • synovial WBC >1,100 cells/ul and PMN >64% in knees
            • synovial WBC >27,800 cells/ul in the first 6 weeks after TKA suggestive of infection
          • WBC >3,000 cells/ul and PMN >80% for hips
      • gram stain  
        • stain for bacteria in sample
        • specificity > sensitivity
          • positive test would be indicative of infection, however a negative test does not rule out infection
      • repeat aspiration 
        • indicated in cases of inconclusive aspirate and peripheral lab data  
    • other tests
      • alpha-defensin immunoassay test 
      • leukocyte esterase colorimetric strip test
  • Peri-operative analysis
    • microbiology
      • definitive diagnosis can be made if the same organism is obtained by repeat aspirations or at least 3 of 5 periprosthetic  specimens obtained at surgery
        • complications
          • false-positive rate is 8%
          • tissue sample better than swabs
    • histology
      • Intraoperative frozen section
        • indications
          • equivocal cases with elevated ESR and CRP or suspicion for infection
          • sensitivity 85% and specificity 90% to 95%  
          • >5 PMNs/hpf x 5 hpf is probable for infection
Treatment
  • Nonoperative
    • chronic suppressive antibiotic therapy
      • indications
        • unfit for surgery 
        • refuse surgery
        • systemic spread and maintain joint motion with symptomatic relief
      • outcomes
        • 10% to 25% success rate of eradication
        • 8% to 21% complication rate
  • Operative
    • polyethylene exchange with component retention, IV abx for 4-6 weeks 
      • indications
        • acute infection (<3 weeks after surgery)
        • acute hematogenous infection (weak literature, ideally <48-72hrs from symptom onset)
      • techniques
        • thorough tissue debridement and irrigation with large-volume of irrigant
      • outcomes
        • 50% to 55% success rate
        • implants must be removed if reinfection documented
        • Dependant of bacteria speciation  
    • one-stage replacement arthroplasty
      • indications
        • used more commonly in Europe for infected THA
        • no sinus tract, healthy patient and soft tissue, no prolonged antibiotic use, no bone graft
        • low-virulence organism with good antibiotic sensitivity
      • technique
        • use antibiotic-impregnated cement
      • advantages
        • lower cost and convenience with single procedure
        • earlier mobility
      • disadvantages
        • higher risk of continued infection from residual microorganisms
      • outcomes
        • variable success of 75-100%
    • two-stage replacement arthroplasty 
      • indications 
        • gold standard for an infected joint >4 weeks after arthroplasty
        • must be medically fit for multiple surgeries
        • requires adequate bone stock
        • requires confirmation of microbial eradication
          • benign clinical exam
          • normal labs (WBC, ESR, and CRP)
          • negative aspiration cultures
            • obtain repeat cultures at least two weeks after planned antibiotic course has been completed
      • techniques (see section below)
        • prosthesis removal, antibiotic spacer, IV antibiotics for 4-6 weeks and delayed reconstruction
      • outcomes
        • bilateral TKA resection arthroplasty followed by 6 weeks of antibiotics and bilateral reimplantation has excellent results at 2-year follow-up 
        • early reimplantation within 2 weeks has 35% success rate
        • delayed reimplantation >6 weeks has a 70-90% success rate
        • cementless reimplantation in the hip has better outcomes than cemented
    • resection arthroplasty
      • indications
        • poor bone and soft tissue quality
        • recurrent infections with multi-drug resistant organisms
        • medically unfit for multiple surgeries
        • failure of multiple previous reimplantations
        • elderly nonambulatory patients
      • disadvantages
        • short limb, poor function, and patient dissatisfaction
      • technique
        • remove all infected tissue and components with no subsequent reimplantation
      • outcomes
        • total knee success rate is 50% to 89%
        • total hip success rate is 60% to 100%
    • arthrodesis 
      • indications
        • reimplantation is not feasible due to poor bone stock 
        • recurrent infections with virulent organisms
      • outcomes
        • 71% to 95% success rate with bony fusion and infection eradication
    • amputation 
      • indications
        • total knee infections recalcitrant to other options
        • severe pain, soft tissue compromise, severe bone loss, or vascular damaged
      • technique
        • AKA
Techniques
  • Surgical debridement and polyethylene exchange
    • debridement
      • modular parts should be removed to remove fibrin layer between plastic and metal parts which acts as a nidus of infection
    • polyethylene exchange
      • be sure component available
  • Two-stage replacement arthroplasty
    • prosthetic explant
    • surgical debridement
      • must debride bone implant interface and soft tissues
    • antibiotic spacer and IV antibiotics
      • advantages of spacers
        • reduce joint dead space, provide stabilty, and deliver high dose antibiotics
      • disadvantages of spacers
        • potential local or systemic allergic reactions
        • increased chance of developing antibiotic-resistant organisms
        • only heat-stable antibiotics can be added to cement
      • static or dynamic (articulating) spacers can be used
      • advantages of static spacers
        • allow delivery of higher doses of antibiotics (not premade)
        • better wound healing (no joint motion)
      • advantages of articulating spacers  
        • decreased reimplantation exposure time
        • better maintenance of joint space and motion
        • decreased quad shortening
        • better patient satisfaction
        • both spacer types have equivalent functional outcomes and rate of infection recurrence
      • spacer antibiotics
        • each 40 g bag of cement should have 3 g of vancomycin and 4 g of tobramycin added
          • gentamycin may be substituted for tobramycin
        • elution of antibiotics depends on cement porosity, surface area (beads increase area), and antibiotic concentration 
        • must use heat stable antibiotics (vancomycin, tobramycin, gentamicin)
      • IV antibiotics
        • wait to administer intraoperatively until aspiration  and cultures taken
        • must be administered for 4 to 6 weeks after explant
        • initial empiric regimen
          • first-generation cephalosporin
          • vancomycin (if any of the following are true)
            • true allergic sensitivity to penicillin
            • prior history of or documented exposure to MRSA
            • unidentified organism
        • tailor the regimen based on microorganism and susceptibility testing
    • reimplantation
      • send tissue specimens for culture and frozen section pathology
      • implant only if all preoperative and intraoperative measures are acceptable
      • if intraoperative frozen section demonstrate acute inflammation, debride the wound, reapply cement spacer, and return later
      • when using cement, use antibiotic-impregnated cement
Local Antibiotics 
  • Properties
    • active against the organism
    • can be incorporated into delivery vehicle (PMMA)
    • thermo stable (will not denature during exothermic polymerisation reaction)
  • Choices
    • aminoglycosides (gentimicin, tobramycin)
      • effective against gram-negative bacilli
      • synergistic against gram-positive cocci (Staphylococcus, Enterococcus)
      • low risk of systemic toxicity
    • Vancomycin
      • effective against gram-positive cocci
      • excellent elution properties
  • Doses
    • low dose = 2g antibiotics:40g of cement
      • commercial antibiotic cement is low dose
        • Cobalt G-HV (Biomet)
        • Palacos R+G (Zimmer)
        • Simplex P (Stryker)
        • Cemex Genta (Exactech)
        • SmartSet GMV (Depuy)
        • VersaBone AB (Smith & Nephew)
    • high dose ≥ 3.6g antibiotics:40g of cement
      • highest doses without systemic toxicity
        • 12.5g tobramycin:40g cement
        • 10.5 vancomycin:40g cement
    • practical dose
      • vancomycin is 1g per vial, tobramycin is 1.2g per vial
      • use 3g vanco and/or 3.6g tobramycin in 40g cement
        • use extra liquid monomer (1.5-2 ampoules monomer : 1 bag cement)
  • Elution properties
    • rapid release in initial 24h
    • followed by rapidly decline in release rate
      • combination dosing (both tobramycin+vancomycin) increases release rate of antibiotics (more than if each were used alone)
    • low levels at 5 weeks
    • experimental models do NOT show difference in elution/concentrations in conventional wound closure vs negative-pressure wound therapy (NPWT)
  • Mixing
    • vacuum mixing 
      • removes air bubbles
      • enhances mechanical properties
      • may increase/decrease antibiotic elution rates
    • hand mixing
      • may lead to uneven distribution of antibiotics within cement and inconsistent release
    • sequence of ingredients
      • adding vancomycin powder after cement powder + liquid monomer mixed for 30s results in greater elution
  • Newer techniques
    • vancomycin powder directly into wounds (mostly in spine literature)
    • antibiotic cement coated IM nails
    • local antibiotics bonded to implant surface
Complications
  • Failure to eradicate infection
 

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