• Deep infection of an orthopaedic prosthesis remains one of the most serious and costly complications of orthopaedic surgery. 
• Despite sophisticated prevention strategies infection rates of around 1–2% still persist in elective joint arthroplasty.
• Diagnosis and management is challenging for orthopaedic surgeons and some of the greatest difficulties involve choosing the optimal treatment method.
• At present there is significant debate as to the ideal treatment strategy for prosthetic joint infection (PJI) with considerable variation in both surgical and non-surgical management.
• An essential component of the care of patients with PJI is strong collaboration between all involved medical and surgical specialists.

Predisposing factors to infection

• The main factors predisposing towards PJI are advanced age, malnutrition, morbid obesity, uncontrolled diabetes mellitus, HIV infection at an advanced stage and nasal carriage of Staphylococcus aureus.
• Other factors include rheumatoid arthritis, psoriatic arthritis, prolonged surgery, blood transfusion and bilateral surgery. Any factor that delays surgical wound healing, such as haematoma, cellulitis or wound abscess also increases the risk of deep joint infection. 

• The common organisms responsible for PJI are Gram-positive such as coagulase negative staphylococcus, S. aureusand streptococcus. Gram-negative and fungal infections are less common but are increasingly seen in patients with multiple revisions and medical comorbidities.

Biofilm

• A biofilm can be defined as a layer-like aggregation of cells and cellular products attached to a solid surface or substratum. An established biofilm structure comprises microbial cells and extracellular polymeric substances (EPS), whichare produced by the microorganisms themselves. This EPS is a polymeric conglomeration of extracellular DNA, proteins and polysaccharides and provides an environment for the exchange of genetic material between cells.
• Biofilms undergo a five-stage developmental process: first, they form tenuous attachmentsto a surface; second, cells develop strong adhesionsto that surface; third, they form aggregates; fourth, these aggregates develop into a mature biofilm; and fifth, the biofilm disperses.
• Cells often disperse in still-associated clumps that are capable of seeding new surfaces and perpetuating an infection. Staphylococcus organisms tend to follow this pattern explaining the tendency for the development of satellite infections in patients with such infections.
• Quorum sensing is the ability of a bacterial colony to sense its size and, in response, to regulate its activity. At certain population densities, intercellular signals activate genes involved in biofilm differentiation.
• A biofilm cannot be treated with antibiotics as the dense extracellular matrix and outer layer of cells protect the interior microorganisms. This acts as a penetration barrier and in some cases antibiotic resistance can be increased a thousand-fold.
• Biofilms are also resistant to phagocytosis, and the phagocytes that attempt an assault on the biofilm may actually do more harm to surrounding tissues than to the biofilm itself.
• A biofilm is a complex structure composed of micro-organisms enveloped in macromolecules of glycocalyx and other protective structures. Attachment of bacteria to a surface involves cell-to-cell adhesion between microorganisms and the artificial surface (Figure 1).

Figure 1. Diagram showing biofilm development; (a and b) initial attachment of bacteria to the surface of the prosthesis, (c) bacterial replication and formation of an immature biofilm, (d) maturation of the biofilm and expansion of the bacteria, (e) resistance of the biofilm to systemic antibiotics and the patient’s immune system

• Biomaterials and other foreign materials are inanimate and are thus susceptible to bacterial colonisation. After implantation implants are coated by the body with a layer of protein and platelets. If bacteria reach the implant prior to this coating by the host’s cells, bacterial adhesion may progress to aggregation. In so doing these colonising microorganisms develop and slowly grow in a structure known as a biofilm. 
• Bacterial biofilms exhibit dramatically reduced (i.e. 500–5000 times) susceptibility to killing by antimicrobial agents as compared with free-floating (planktonic) cells of the same microorganism.
• A variety of potential mechanisms implicated in biofilm resistance to antimicrobial agents have been proposed including: restricted penetration through the biofilm matrix, antimicrobial destroying enzymes, quorum-sensing signaling systems, existence of altered growth rate (i.e. persister cells) inside the biofilm, stress response to hostile environmental conditions, and overexpression of genes.
• Existence within this bio?lm represents a survival mechanism by which microbes resist external and internal environmental factors, such as antimicrobial agents and the host’s immune system. 
• There are opportunities to target specific cells at different stages of development. Agents have been classified as “biofilm preventing,” “biofilm disrupting,” “biofilm bypassing” and “antibiofilm vaccines.”

• On the basis of clinical presentation, infections associated with prosthetic joints can be classified as: positive intraoperative culture, early postoperative infection, acute haematogenous and late chronic.

1. Early postoperative infection:

• Immediate postoperative period.
• The wound may be erythematous, swollen, discharging and tender. 
• It may be difficult to differentiate between a superficial or deep infection (deep to fascia). 
• Implant salvage remains possible at this stage.

2. Delayed onset infection:

• These probably originate at the time of surgery but a low virulence or inoculum delays the onset of symptoms. 
• Removal of the device is usually needed to eradicate the infection.
• These infections occur from 3 to 12 months post-surgery.
• Infecting organisms could include propionibacterium acnes, enterococci and coagulase-negative staphylococci.
• Presents with persistent joint pain whereas aseptic failures might present with pain on weight bearing and walking.

3. Haematogenous infection:

• Sudden, rapid deterioration in the function of an implant. 
• Most are some years down the line presenting with symptoms and signs similar to early postoperative infection. 
• It may be triggered by infection elsewhere, for example dental surgery, uro-sepsis, remote infection. 
• Implant salvage is possible if treatment is prompt.

4. Positive intraoperative culture:

• Infection diagnosed at theatre in unsuspected cases of infection undergoing revision for presumed aseptic loosening.

• A number of classification systems for PJI exist.
• In 1975 Coventry divided infection after total hip arthroplasty (THA) into three groups based on timing:³

• Type 1: Infection occurring in the first 30 days post-surgery.
• Type 2: Infection occurring at a period of 6–24 months after surgery.
• Type 3 Infection occurring greater than 24 months after surgery.

• Type 1 infections can usually be diagnosed clinically – continuous pain usually, fever, erythematous, swollen, tender and fluctuant wound. Type 1 infection is due either to infected haematoma or to the deep spread of a superficial wound infection to the periprosthetic space.
• Type 2 infection the hallmark is a gradual reduction in function of the hip with increasing pain. The patient will often give a history of the hip never feeling “right” from the time of the original surgery, or they may have had a prolonged period of wound discharge postoperatively. Usually systemic symptoms are absent. Clinical examination is often unrewarding.
• Fitzgerald et al.,⁴while still dividing infection related to arthroplasty into three categories altered the timing slightly between groups 1 and 2:

• Acute postoperative infections occurring within 3 months of the surgery.
• Deep late infections that appear between 3 months and 2 years after the surgery. 
• Late haematogenic infections that occur more than 2 years after the surgery. The aetiological agents are of community origin.

• Tsukayama et al.⁵ proposed a four-stage system consisting of:

• Early postoperative.
• Late chronic.
• Acute haematogenous infections.
• Positive intraoperative cultures of specimens obtained during revision of a presumed aseptically loose total hip prosthesis.

• Current guidelines of the AAOS and the International Consensus on PJI make a clear distinction between early and late PJIs: an early infection is considered to occur within 3 weeks of the procedure, or in the case of a late haematogenous infection, within 3 weeks of the development of symptoms. Any PJI, which develops thereafter, is considered to be late. The distinction between early and late PJI is based on the assumption that within 3 weeks organisms can form a biofilm on the surface of the components, necessitating their removal.

• PJI has prompted implementation of enhanced prevention measures preoperatively (glycaemic control, skin decontamination, decolonisation, etc.), intraoperatively (ultraclean operative environment, blood conservation, etc.), and postoperatively (refined anticoagulation, improved wound dressing).

• No tests are 100% sensitive and specific and a diagnosis can often be difficult to make. No single test is considered the gold standard A careful history is mandatory and may provide crucial clues. A high index of clinical suspicion is required. Tests include:
• Bloods.
• Radiographs (likely to be normal but may show septic loosening in the late stages).
• Nuclear imaging: bone scan (will be “hot” for 2 years post-surgery) or labeled white cell scan.
• Microbiology:

• Aspiration (70% sensitive).
• PCR (high false positive rates).
• Intraoperative samples.

Serology

• White cell count (WCC) is of limited value as it is frequently normal (~85% of cases).
• Both serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) have been shown to provide good sensitivity >90%, but results for specificity are mixed, ranging from 20% to 80%.
• Ghanem et al.⁶defined cut-off values for ESR 30 mm/hour and CRP 10 mg/L for a diagnosis of PJI. This gives a sensitivity of 94.3% and 91.1%, respectively, and combining the two values increased the sensitivity to 97.6%.
• Newer inflammatory serum markers, such as interleukin (IL)-6, tumour necrosis factor (TNF)-α and procalcitonin, have not shown distinct advantages over CRP and ESR.

Radiographs

• Chronic infection can cause radiographic changes including periostitis, osteopenia, endosteal reaction and rapidly progressing loosening or osteolysis.
• Plain radiographs have low diagnostic sensitivity and speci?city for di?erentiating between septic and aseptic osteolysis.

Tissue swab cultures

• Inexpensive and easy to use but have inherent disadvantages that lead to inaccuracies. 
• In general avoid as low sensitivity, specificity and negative and positive predictive values.

Synovial fluid inoculated into blood culture vials

• Reports suggest this may be more sensitive than intraoperative swabs and tissue cultures.
• More accurate in acute rather than chronic infections.

Hip joint aspirate 

• Sensitivity 50–93%.
• Specificity 82–97%.
• This suggests aspiration is better for confirming infection than for excluding it.
• It allows identification of the infecting organism and therefore allows better preoperative planning and choice of antibiotics.
• It is important for the surgeon to have a protocol to reduce the possibility of false positives and introducing infection.
• Use of image intensification.
• Use of local anaesthetic only in the skin, as it is bacteriostatic.

Polymerase chain reaction (PCR)

• PCR works by amplifying the strains of bacterial DNA to allow detections of infectious bacteria.
• PCR-based methods provide a theoretically more sensitive means of detecting and identifying infectious bacteria.
• Advantages include faster availability of results, positive results in the presence of only a few copies of bacterial DNA, and the ability to identify non-viable bacteria, for instance, in those patients already on antibiotic treatment.
• There is a concern with reported high false positive rates.

Synovial fluid white cell count and differential count⁷

• Measurement of inflammatory markers in synovial fluid has shown promising initial results. In one study, synovial fluid CRP level showed a sensitivity of 85% at a threshold of 9.5 mg/L while specificity and accuracy of the test were 95% and 92%, respectively.
• Further studies are required to confirm diagnostic value of synovial fluid CRP and other synovial inflammatory markers for diagnosis of PJI.

Intra-operative Gram stain

• Gram staining is a common method for bacterial detection used to differentiate two large groups of bacteria based on their cell wall characteristics.
• Fast and inexpensive.
• AAOS clinical guidelines on diagnosis of PJI recommend against the use of Gram stain to rule out PJI.

Intra-operative frozen section

• Considered a valuable part of the diagnostic work-up for patients undergoing revision arthroplasty, especially when the potential for infection remains after a thorough preoperative evaluation.
• A meta-analysis by Tsaras et al.⁸found that there was no significant difference between the diagnostic accuracy of frozen section histopathology utilising the most common thresholds of 5 or 10 PMNs per high-power field.
• According to the proposed criteria by the Musculoskeletal Infection Society (MSIS), PJI exists when:

1. There is a sinus tract communicating with the prosthesis.
2. A pathogen is isolated by culture from at least two separate tissue or fluid samples obtained from the affected prosthetic joint.
3. Four of the following six criteria exist:

• Elevated serum ESR and serum CRP concentration.
• Elevated synovial white blood cell (WBC) count.
• Elevated synovial neutrophil percentage (PMN%).
• Presence of purulence in the affected joint.
• Isolation of a microorganism in one culture of periprosthetic tissue or fluid.
• Greater than five neutrophils per high-power field in five high-power fields observed from histological analysis of periprosthetic tissue at ´400 magnification.

PJI may also be present if fewer than four of these criteria are met and clinical suspicion is high.

• See Appendage for full summary recommendations.
• Based on guidelines by the AAOS, work-up for the diagnosis of PIJ starts with ordering ESR/CRP due to their high sensitivity and acceptable specificity. In the presence of normal levels of these tests, infection is unlikely; however, abnormal levels of either test should prompt further investigation in the form of joint aspiration.
• The combination of serology and joint aspiration should help the surgeon confirm or exclude the diagnosis of PJI in the majority of cases.
• In a very few special cases, in whom PJI is suspected but cannot be confirmed, additional tests such as nuclear imaging may be ordered.

Implant retention

• Chronic antibiotic suppression:

• Considered in patients who have contraindications to revision surgery usually due to severe or multiple medical comorbidities or those with a limited life expectancy.
• When surgery is not appropriate (in those unfit or unwilling to undergo revision procedures) long-term antibiotic suppression is an option. The prosthesis should not be loose and better results are achieved when the organism and its sensitivities are known.
• The goal of suppressive treatment is an asymptomatic functioning prosthesis, but not necessarily infection eradication.

• Debridement:

• Extensive and meticulous debridement with retention of the prosthesis (DAIR).
• For infections occurring acutely within 6 weeks of implantation and infections occurring in a previously well-functioning joint replacement (haematogenous).
• Needs to be done as early as possible before biofilm formation.Thresholds of <3 weeks for acute haematogenous PJI and <30 days following the initial procedure are recommended.
• An open approach with thorough debridement, lavage and exchange of modular parts.
• Variably reported success rates from 26% to 71% with highest success rates for early treatment with low virulence organisms and healthy patients.

• Treatment with highly virulent organisms has a lower success rate.

One-stage revision

• This requires:

• Low virulence organisms.
• Good soft tissues.
• No bone loss.
• An identified microorganism and antibiotic sensitivity.

• One-stage exchange arthroplasty was originally described by Buchholz et al.⁹in the 1970s and is still widely used in several centres. The ability of the procedure to control infection is believed to rely on strict surgical indications, preoperative identification of the infecting organism, aggressive surgical debridement, and implantation of components with antibiotic-laden bone cement.
• In a systematic review of 12 studies that included 1299 infected THA, Jackson and Schmalzried¹⁰identified factors associated with a successful outcome.
• These included:

• Absence of wound complications after the initial THA.
• Good general health.
• Sensitive Staphylococcus or Streptococcus species.
• Organism sensitive to the antibiotic in the cement.

• The authors also identified factors associated with poor outcome that included:

• Polymicrobial infection.
• Gram-negative organisms, especially pseudomonas.
• MRSA and group D Streptococcus.

• They suggested that using cementless implants or bone graft may be a contraindication to the technique.
• Only a relatively small number of patients are suitable for a single stage procedure (approximately 10%).

Two-stage revision

• Two-stage revision is generally regarded as the gold standard for the treatment of infected THA.
• Consists of excision of any sinuses, abscess drainage, meticulous removal of all foreign material (membrane, cement, plugs and any potentially infected soft tissue).

• Success rates are quoted around 85–90%.
• The first stage involves removal of all implants including cement, radical debridement of all possible infected tissue and bone and insertion of a temporary “spacer.” 
• This is followed by antibiotic treatment, often for 6 weeks or longer. 
• The definitive (second stage) prosthesis is inserted when clinical signs of infection have been eliminated (lack of pain/redness), normalisation of CRP and ESR and negative repeat aspiration.
• The presence of ongoing infection requires repeat use of a spacer with ongoing antibiotics or consideration of excision arthroplasty.

• Beswick et al.¹¹ in a systematic review for comparing one and with two-stage procedures in unselected patients reported re-infection rates of 8.6% (95% confidence interval (CI) 4.5 to 13.9) and 10.2% (95% CI 7.7 to 12.9).

Arthrodesis 

• Largely historical unless the soft tissue envelope is severely compromised.
• Technically demanding, rarely performed.

Excision arthroplasty 

• This is a fairly disabling procedure and often reserved for the moribund or when the joint is unreconstructable.

Amputation/disarticulation

• For recurrent infections with poor bone and soft tissues and when all other strategies have failed.
• Occasionally indicated for severe life-threatening or limb-threatening infection.

Antibiotics

• Are required in all cases of revision surgery. The type, mode of delivery and duration depend on the individual patient and close liaison with the microbiology department is essential. 
• When surgery is not appropriate (in those unfit or unwilling to undergo revision procedures) long-term antibiotic suppression is an option. The prosthesis should not be loose and better results are achieved when the organism and its sensitivities are known.

Prevention

Preoperatively:

• Medical optimisation:

• Control of blood glucose.
• Cessation of smoking.
• Avoiding surgery with concomitant infection.
• Reducing obesity and vascular insufficiency.

• Antiseptic agents and proper bathing.
• MRSA decolonisation.

Peri-operatively:

• Antimicrobial prophylaxis.
• Theatre positive pressure ventilation and laminar flow.
• Appropriate surgical attire and drapes.
• Antibiotic impregnated cement.
• Bleeding control.

Surgical technique: gentle handling of tissues, avoid cremation of local tissues/necrosis, length of surgery, wound lavage.

Postoperatively:

• Sterile dressing.
• Avoiding disturbing the incision site.
• Appropriate hand washing.
• Antibiotic cover for urinary catheterisation.

• In the early 1980s, laminar airflow was introduced to reduce airborne contamination and initially showed a significant reduction in PJI. Recent studies, however, have revealed inconsistencies and that laminar flow has no clear benefit, and may potentially increase the risk of PJI.^13,14
• Hooper et al.¹⁴investigated whether laminar flow theatres and space suits reduced the rate of revision for early deep infection after THA and total knee arthroplasty (TKA) by reviewed 10-year results of the New Zealand Joint Registry.

For THA there was a significant increase in early infection in those procedures performed with the use of a space suit compared with those without (P<0.0001), in those carried out in a laminar flow theatre compared with a conventional theatre (P<0.003) and in those undertaken in a laminar flow theatre with a space suit (P<0.001) when compared with conventional theatres without such a suit. The results were similar for TKR with the use of a space suit (P<0.001), in laminar flow theatres (P<0.019) and when space suits were used in those theatres (P<0.001).

Use of ultraviolet light

• Ultraviolet light disrupts bacterial DNA, preventing replication and contamination. Ritter et al.¹⁵ demonstrated a rate of infection of 1.77% with laminar airflow, but only 0.57% with ultraviolet light (P<0.001) during primary arthroplasty. In addition, ultraviolet light eliminates bacterial contamination on solid surfaces. However, its use is not currently recommended due to the potential harm it may cause theatre staff, which is at an increased risk of eye damage and skin cancer if exposed.
• There may be other applications of ultraviolet light such as sterilising the operating room between patients or overnight, as the handles, lights, keyboards, floors and walls are additional sources of pathogens.¹²

Prosthesis modification

• Many new strategies have focused on modifying the composition of the prosthesis, in particular the use of metal ions.
• The use of silver, iron, zinc, titanium, and carbon can reduce microbial adhesion, proliferation and biofilm growth.

Antibiotic prosthetic coatings

• Antibiotic-bonded prostheses prevent bacterial adhesion to the prosthesis, thus reducing biofilm formation and preventing its ability to harbour bacteria.

Antibiofilm prosthetic coating

• Targeted therapy has been developed to interrupt the physical integrity of the matrix, such as deoxyribonuclease (DNase) I and dispersin B. DNase I degrades extracellular DNA, known to cause firmness and stability of the biofilm and inhibit biofilm formation in vitro, making it more susceptible to various antibiotics.
• Dispersin B, a soluble beta-N-acetylglucosaminidase, targets intercellular adhesin produced by the biofilm.

Use of spacers

• Broadly classified as static or articulating.
• Static spacers consist of a block or beads of antibiotic impregnated cement, left within the dead space after implant removal. Articulating spacers include the PROSTALAC spacer.
• Spacers allow a local delivery of antibiotics in high concentration, help to maintain proper limb length and soft tissue tension between stages, which improves patient function, preserves bone stock, prevents soft tissue contraction and helps with re-implantation.
• Concerns with spacers include re-infection with resistant organisms or infection persistence. This may occur with low release of antibiotics late in the life of the spacer. Other complications include dislocation, spacer fractures, femoral fractures and migration.
• Increased complications can be expected with single-size spacers, especially without endoskeleton reinforcement (Figure 2).

Figure 2. AP radiograph showing right PROSTALAC spacer in place

Figure 3. AP radiograph showing antibiotic loaded cement beads used as spacer in right hip

Figure 4. AP radiograph showing an antibiotic loaded cement static spacer in right knee joint

Antibiotic use in spacers

• To maintain the mechanical integrity of the cement, the amount of antibiotics to cement should not exceed 10% of the total cement used. The most commonly added antibiotics include tobramycin, gentamicin, and vancomycin. Combining antibiotics results in a synergistic elution effect (Figure 5).

Figure 5. Picture of an articulating knee spacer made of antibiotic loaded cement

Duration of antibiotic therapy between stages

• There is no consensus regarding duration of antibiotic therapy prior to second-stage reimplantation. The literature demonstrates a variety of protocols ranging from no antibiotics postoperatively to prolonged intravenous antibiotics.
• Most units consider 4–6 weeks of intravenous antibiotics with or without a course of oral antibiotics.
• Reducing unnecessary antibiotic use slows the development of bacterial resistance, decreases the risk of complications, and lowers cost considerably.

• In June 2010 the American Academy of Orthopaedic Surgeons released its clinical practice guidelines to diagnose periprosthetic joint infection (PJI). These guidelines are based on a systematic review of the published literature. They have been developed to improve clinical practice. These guidelines are not designed to replace clinical judgement and each patient should be treated according to the individual situation.

1. In the absence of reliable evidence about risk strati?cation of patients with a potential periprosthetic joint infection, it is the opinion of the work group that testing strategies be planned according to whether there is a higher or lower probability that a patient has a hip or knee periprosthetic infection.

Strength of recommendation: Consensus

2. We recommend erythrocyte sedimentation rate and C-reactive protein testing for patients assessed for periprosthetic joint infection.

Strength of recommendation: Strong

3. We recommend joint aspiration of patients being assessed for periprosthetic knee infections who have abnormal erythrocyte sedimentation rate and/or C-reactive protein results. We recommend that the aspirated ?uid be sent for microbiological culture, synovial ?uid white blood cell count and differential.

Strength of recommendation: Strong

4. We recommend a selective approach to aspiration of the hip based on the patient’s probability of periprosthetic joint infection and the results of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). We recommend that the aspirated ?uid be sent for microbiological culture, synovial ?uid white blood cell count and differential.

Strength of recommendation: Strong

Table 1.

Strength of recommendation: Moderate

6. In the absence of reliable evidence, it is the opinion of the work group that patients judged to be at lower probability for periprosthetic hip infection and without planned reoperation who have abnormal erythrocyte sedimentation rates or abnormal C-reactive protein levels be re-evaluated within 3 months. We are unable to recommend speci?c diagnostic tests at the time of this follow-up.

Strength of recommendation: Consensus

7. In the absence of reliable evidence, it is the opinion of the work group that a repeat knee aspiration be performed when there is a discrepancy between the probability of periprosthetic joint infection and the initial aspiration culture result.

Strength of recommendation: Consensus

8. We suggest patients be off antibiotics for a minimum of 2 weeks prior to obtaining intra-articular culture.

Strength of recommendation: Moderate

9. Nuclear imaging (labeled leukocyte imaging combined with bone or bone marrow imaging, FDG-PET imaging, gallium imaging, or labeled leukocyte imaging) is an option in patients in whom a diagnosis of periprosthetic joint infection has not been established and are not scheduled for reoperation.

Strength of recommendation: Weak

10. We are unable to recommend for or against computed tomography (CT) or magnetic resonance imaging (MRI) as a diagnostic test for periprosthetic joint infection.

Strength of recommendation: Inconclusive

11. We recommend against the use of intraoperative Gram stain to rule out periprosthetic joint infection.

Strength of recommendation: Strong

12. We recommend the use of frozen sections of peri-implant tissues in patients who are undergoing reoperation for whom the diagnosis of periprosthetic joint infection has not been established or excluded.

Strength of recommendation: Strong

13. We recommend that multiple cultures be obtained at the time of reoperation in patients being assessed for periprosthetic joint infection.

Strength of recommendation: Strong

14. We recommend against initiating antibiotic treatment in patients with suspected periprosthetic joint infection until after cultures from the joint have been obtained.

Strength of recommendation: Strong

15. We suggest that prophylactic preoperative antibiotics not be withheld in patients at lower probability for periprosthetic joint infection and those with an established diagnosis of periprosthetic joint infection who are undergoing reoperation.