Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis

INTRODUCTION — Prosthetic joint infection (PJI) is a serious complication of prosthetic joint implantation [1-8]. The epidemiology, microbiology, clinical manifestations, and diagnosis of PJI will be reviewed here. Infections associated with other implanted orthopedic devices, such as pins and rods, will not be specifically discussed, but similar principles may apply.

Issues related to treatment and prevention of PJIs are discussed separately. (See "Prosthetic joint infection: Treatment" and "Prevention of prosthetic joint and other types of orthopedic hardware infection".)

EPIDEMIOLOGY — Nearly one million total hip arthroplasties (THAs) and total knee arthroplasties (TKAs) are each performed annually in the United States, with the number doubling by 2030 [9].

The risk of PJI is greater for knee arthroplasty than for hip arthroplasty [1,10]. The rate of PJI in most centers ranges between 0.5 to 2 percent for knee replacements, 0.5 to 1.0 percent for hip replacements, and <1 percent for shoulder replacements [11,12]. The higher rate of PJI in knee arthroplasties may be attributable to greater mobility in the joint and soft tissue and less protective soft tissue coverage.

Trends in PJI rates have varied. In a retrospective study including more than 10,700 patients in Taiwan who underwent primary TKA between 2002 and 2014, the rate of PJI declined from 1.9 percent (2002 to 2006) to 0.76 percent (2011 to 2014) [13]. Similarly, in a review including more than 11,800 patients in the United States who underwent primary THA or TKA, the incidence of PJI between 2008 and 2016 fell from 1.4 to 0.6 percent [14]. A population-based cohort study that included 129,613 patients ≥50 years of age in Canada from 2006 to 2016 also reported a decline in PJI following primary TKA [15]. In contrast, these investigators saw no change in PJI rate in patients with primary THA in the same Canadian population [16]. In another cohort that included more than 679,000 patients in England and Wales who underwent primary TKA between 2003 and 2013, the PJI rate increased [17].

In general, the rate of PJI is highest during the first two years following surgery [1]. In one study involving more than 69,000 patients undergoing elective TKA followed longitudinally from 1997 to 2006, the rate of PJI during the first two years following surgery was 1.5 percent; the rate of PJI 2 to 10 years after joint replacement was 0.5 percent [18].

Risk factors — Risk factors for PJI include [1,19-26]:

●Presence of comorbidities such as rheumatoid arthritis, diabetes mellitus, malignancy, chronic kidney disease, obesity, lymphedema, immunosuppression

●Use of prednisone, tumor necrosis factor inhibitors, and other biologic disease-modifying antirheumatic drugs

●Prior arthroplasty or prior infection at the surgical site

●American Society of Anesthesiologists score ≥3 (table 1)

●Prolonged duration of surgery

●Postoperative complications such hematoma, wound dehiscence

●Staphylococcus aureus bacteremia [27]

PJI involving multiple prosthetic joints is a unique complication. In one report including 197 patients with ≥2 joint prostheses who presented with PJI, 37 patients developed PJI in another joint; 11 had a synchronous PJI and 26 had a metachronous PJI [28]. Risk factors associated with PJI of another joint included female sex, rheumatoid arthritis, bacteremia at presentation, and infection due to methicillin-resistant S. aureus.

DEFINITIONS — PJIs are often categorized as early onset (<3 months after surgery), delayed onset (3 to 12 months after surgery), and late onset (>12 months after surgery). However, these definitions are controversial and not always clear-cut, particularly in patients for whom the diagnosis is delayed [29]. There is considerable overlap between early- and delayed-onset PJIs, and late onset PJI can present with acute symptoms (less than seven days), in which case it is defined as acute hematogenous PJI [30]. Hip PJIs tend to occur sooner than knee PJIs.

The timing of infection onset has implications for surgical management (eg, implant retention versus removal). These issues are discussed further separately. (See "Prosthetic joint infection: Treatment".)

MICROBIOLOGY

Pathogens — The timing of infection can be a clue as to the identity of the infecting organism. Early-onset infections are often due to S. aureus, gram-negative bacilli, anaerobes, or polymicrobial infection [1]. Delayed-onset infections are often due to coagulase-negative staphylococci, Cutibacterium (Propionibacterium) species, or enterococci. Late-onset infections are often due to S. aureus, gram-negative bacilli, or beta-hemolytic streptococci. (See 'Clinical manifestations' below.)

In the setting of PJI due to coagulase-negative staphylococci, species identification may be useful in some circumstances. For example, Staphylococcus lugdunensis is a coagulase-negative Staphylococcus that shares some aspects of virulence with S. aureus but is often susceptible to beta-lactam antibiotics, including oxacillin [31]. (See "Staphylococcus lugdunensis".)

Cutibacterium acnes is a relatively common cause of PJI following shoulder arthroplasty (16 percent in one study) but is a rare cause of infection following hip or knee arthroplasty [32-34]. Cutibacterium avidum has been observed as a cause of hip PJI, and colonization of the groin in patients with obesity may be a risk factor for hip PJI [35,36]. (See "Invasive Cutibacterium (formerly Propionibacterium) infections", section on 'Orthopedic infection'.)

Rare causes of PJI include fungal infection (most often Candida spp) and mycobacterial infection (Mycobacterium tuberculosis and rapidly growing mycobacteria). (See "Bone and joint tuberculosis", section on 'Prosthetic joint infection' and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum", section on 'Prosthetic device infection'.)

Cultures are negative in 7 to 39 percent of patients with suspected PJI [37]. In general, cultures are commonly positive in the setting of early-onset PJI, but frequently negative in patients who present indolently. In some cases, "culture-negative" PJI may be attributable to small colony variants of staphylococci, due to slow growth of these variants [38]. Fastidious pathogens associated with culture-negative PJI include Coxiella burnetii, brucellosis, bartonellosis, mycoplasma, mycobacteria, and fungi [39].

Biofilm — Presence of orthopedic hardware enhances susceptibility to infection due to formation of a biofilm [40,41]. The process of biofilm formation consists of bacterial adherence to hardware, followed by multiplication and elaboration of exopolysaccharides ("glycocalyx"); over time, microcolonies of bacteria encased in glycocalyx coalesce to form biofilm [42,43].

Bacteria near the surface of the biofilm are usually metabolically active and have access to nutrients that diffuse through the upper surface. Bacteria deep within the biofilm are metabolically inactive or in various stages of dormancy and are protected from host defenses [42].

The microenvironment within a biofilm may adversely affect antimicrobial mechanisms, and diffusion of antimicrobial agents through biofilm may be limited or slow [43]. Soon after a biofilm is established, the susceptibility of bacteria to antimicrobial agents often demonstrates a logarithmic decline [44]. In the presence of biofilm, antibiotic administration may be associated with an initial clinical response, followed by relapse within days or months of stopping antibiotic therapy, unless the hardware is removed.

Presence of organisms in biofilm may explain the propensity of PJI to manifest weeks or months after surgery. It may also explain the difficulty associated with pathogen identification in patients with indolent, late-onset PJIs.

Given the slow metabolic rate of organisms in biofilm, suppressive antibiotic therapy may be successful in some cases; however, such therapy may ultimately fail in the absence of hardware removal.

CLINICAL MANIFESTATIONS

Signs and symptoms — The clinical manifestations of PJI depend on the timing of symptom onset: early onset (<3 months after surgery), delayed onset (3 to 12 months after surgery), or late onset (>12 months after surgery). (See 'Definitions' above.)

Early-onset infection is usually acquired during implantation. Less commonly, it can arise in the setting of postoperative wound dehiscence with contiguous spread of organisms from the superficial wound to the deeper structures. These infections are frequently associated with hematoma formation or superficial necrosis of the incision. Most early-onset infections present with the acute onset of one or more of the following findings: joint pain, warmth, erythema, induration or edema at the incision site, wound drainage or dehiscence, joint effusion, or fever.

Delayed-onset infection is often acquired during implantation; it typically presents with an indolent course characterized by persistent joint pain, with or without early implant loosening. Fever is present in less than half of cases [1]. Sinus tract associated with intermittent drainage may be observed; this finding on its own may be considered diagnostic of PJI [2]. In the absence of a sinus tract, physical exam findings are often minimal; if swelling is present, it is usually slight. Delayed-onset infections may be difficult to distinguish from aseptic failure of the prosthetic joint. PJI is often associated with persistent joint pain, while mechanical loosening commonly causes pain with joint motion and weight bearing (which abates with rest) [45,46]. (See 'Differential diagnosis' below.)

Late-onset PJI often occurs in the setting of hematogenous seeding from infection at another site (such as vascular catheter, urinary tract, or soft tissue infection) [47]. Patients with late-onset PJI typically present with acute onset of systemic symptoms associated with bacteremia (similar to early-onset infection), including joint pain in a previously well-functioning joint, warmth, erythema, induration or edema at the incision site, joint effusion, and fever. Dislocation may occur [48]. It is not always possible to determine whether a PJI arose hematogenously; in one study including 50 cases of hematogenous PJI, the median time of onset was nearly five years after surgery and a distant source for the infection was identified in only approximately half of the cases [49].

The timing of infection may be an important clue as to the identity of the infecting organism. (See 'Microbiology' above.)

Asymptomatic infection — Asymptomatic PJI may be detected incidentally in the setting of revision surgery for other indications [50]. In one study including more than 600 hip or knee arthroplasty revision surgeries, PJI (defined as two or more positive cultures with the same organism) was diagnosed in 10 percent of cases [51].

DIAGNOSIS

Clinical approach — PJI should be suspected patients with a joint prosthesis and relevant signs and symptoms of infection (including joint pain, warmth, erythema, induration, or edema at the incision site, sinus tract or persistent wound drainage, wound dehiscence, joint effusion, or fever) [4].

The diagnosis of PJI can be challenging because the definition is not standardized; a number of diagnostic criteria have been proposed, including the 2021 European Bone and Joint Infection Society (EBJIS) criteria, the 2018 International Consensus Meeting (ICM) criteria, the 2013 ICM criteria, the 2013 Infectious Disease Society of America guidelines, and the 2011 Infection Society (MSIS) criteria (table 2) [3-7,52]. The MSIS 2011 diagnostic criteria are relatively straightforward and remain widely used; the EBJIS criteria are adopted more widely in Europe [53]. (See 'Synovial fluid analysis' below.)

In general, the diagnosis rests on a combination of factors including history and physical examination, synovial fluid analysis, serum inflammatory markers, culture data, and intraoperative findings [54]. Discriminating between chronic PJI and aseptic joint failure can be challenging. (See 'Differential diagnosis' below.)

The diagnosis of PJI may be established in any of the following circumstances [3,4] (see 'Interpreting test results' below):

●Presence of a sinus tract that communicates with the prosthesis

●Two or more periprosthetic cultures with phenotypically identical organisms (≥2 intraoperative cultures or a combination of preoperative synovial fluid aspiration culture and intraoperative tissue culture)

•A single positive culture with a virulent organism (such as S. aureus) may also represent PJI.

•A single positive culture due to an organism of relatively low virulence (such as many of the coagulase-negative staphylococcal species, Corynebacterium species, Cutibacterium species, or Bacillus species) is generally considered a contaminant. Such organisms may be presumed to represent a true pathogen if the same organism is observed in multiple cultures; these cases should be evaluated in the context of other available evidence (such as intraoperative tissue biopsy).

Findings suggestive of PJI include prosthesis with surrounding purulence and histopathologic examination of periprosthetic tissue demonstrating acute inflammation [4]. However, these findings are nonspecific and may be observed with alternative etiologies including metallosis and inflammatory arthritis. (See 'Differential diagnosis' below.)

For cases in which a definitive diagnosis of PJI cannot be made, additional data (including serum inflammatory markers and synovial fluid examination) may provide supportive evidence regarding the likelihood of infection (table 2):

●Routine serum inflammatory markers include erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) [1,2,54]. Less commonly used serum markers that may warrant further study include D-dimer [55,56], fibrinogen, procalcitonin, and interleukin-6 [57]. (See 'Serum inflammatory markers' below.)

●Routine synovial fluid analysis consists of cell count with differential, aerobic and anaerobic culture, and crystal analysis [3,4,45]. The value of Gram stain is debatable, and some experts obtain Gram stain whereas others do not. Less commonly used synovial fluid markers that may warrant further study include alpha-defensin, leukocyte esterase, absolute neutrophil count [58], absolute synovial polymorphonuclear cell count [59], and CRP [60]. (See 'Synovial fluid analysis' below.)

Obtaining diagnostic studies

Initial evaluation — In the setting of suspected PJI, initial diagnostic evaluation consists of plain radiography (to evaluate for alternative causes of pain and instability) and measurement of serum inflammatory markers (ESR and CRP) [57]. (See 'Radiographic imaging' below and 'Serum inflammatory markers' below.)

Thereafter, diagnostic arthrocentesis should be performed, unless the diagnosis of PJI is evident clinically (eg, in the setting of a sinus tract) and definitive surgical debridement is planned [3,4,45]. If feasible, antimicrobial therapy should be withheld for at least two weeks prior to collecting specimens for culture [61].

Knee and shoulder joint aspiration often can be performed at the bedside; hip joint aspiration requires guidance by ultrasound or fluoroscopy. If difficulty is encountered in obtaining synovial fluid, irrigation with sterile saline may be performed to obtain fluid for culture, although this may reduce the culture specificity [62,63].

Synovial fluid should be sent for cell count with differential, aerobic and anaerobic culture, and crystal analysis [3,4,45]. The value of Gram stain is debatable. Mycobacterial and fungal cultures should be submitted for patients with chronic, indolent, or refractory infection; previously culture-negative infection; or immunosuppression [54,64,65].

Synovial fluid may be sent for culture in a sterile tube (ideally a red-top tube with no additives and a tube with an anticoagulant such as ethylenediaminetetraacetic acid to guard against clotting) or in blood culture bottles. If blood culture bottles are used, synovial fluid also should also be sent in a sterile container for Gram stain. Use of blood culture bottles may increase the likelihood of recovering nonpathogenic skin contaminants; in such cases, culture results should be interpreted in the context of the Gram stain result. (See 'Microbiology studies' below and 'Synovial fluid analysis' below and "Septic arthritis in adults", section on 'Obtaining clinical specimens'.)

In patients with a sinus tract, drainage (collected by aspiration) can be sent for culture; swabs from the sinus tract should not be sent given discordance with deep cultures [45,66]. In patients with fever or other systemic manifestations of infection, blood cultures (two sets) should be obtained.

Intraoperative evaluation — Purulence noted during surgery may be attributable to PJI in the absence of other causes. Alternative etiologies include crystal-associated arthritis and metallosis. (See 'Differential diagnosis' below.)

Intraoperative specimens should consist of at least three periprosthetic tissue samples (ideally five, to minimize sampling error and optimize specificity) obtained with different instruments and put into separate sterile containers, to ensure that there is no cross-contamination between specimens. Cultures may be falsely negative if insufficient tissue is sent or if only swabs are obtained. The samples should be sent for culture (aerobic and anaerobic) and frozen section histology; some experts send tissue for Gram stain whereas others do not (it has high specificity but low sensitivity for diagnosis of PJI) [67-69]. Inoculation of periprosthetic tissues into blood culture bottles has been associated with higher sensitivity compared with cultures using conventional plates and broth media [70-72]. (See 'Microbiology studies' below and 'Histopathology' below.)

If pus is encountered, it should be aspirated in a sterile tube and sent for culture. Swab cultures should be avoided given low sensitivity [45].

Mycobacterial and fungal cultures should be submitted for patients with chronic, indolent, or refractory infection; previously culture-negative infection; or immunosuppression [54,64].

If the prosthesis is explanted, sonication (eg, to dislodge biofilm) may be performed, followed by culture of sonication fluid (which is included in the 2021 EBJIS PJI diagnostic criteria) (table 2) [73,74]. (See 'Culture-negative infection' below.)

Interpreting test results

Microbiology studies — The microbiology of PJI is discussed above. (See 'Microbiology' above.)

The diagnosis of PJI may be established in the setting of two or more periprosthetic cultures with phenotypically identical organisms (a combination of preoperative synovial fluid aspiration culture and intraoperative tissue culture or ≥2 intraoperative tissue cultures) [3,4]. (See 'Clinical approach' above.)

A single positive culture with a virulent organism (such as S. aureus) may also represent PJI [75]. A single culture due to an organism of relatively low virulence (such as S. epidermidis, Corynebacterium spp, Cutibacterium spp, or Bacillus spp) is generally considered a contaminant. If the same organism is observed in multiple cultures, it may be presumed to represent a true pathogen; such cases should be evaluated in the context of other available evidence [1].

Synovial fluid culture has a sensitivity and specificity for diagnosis of PJI (72 and 95 percent, respectively, based on findings from a systematic review) [76]. The sensitivity of periprosthetic tissue culture is variable (65 to 94 percent) [45,77].

Sinus tract culture findings must be correlated with other data, since results may reflect skin flora contamination.

Synovial fluid analysis — Synovial fluid should be sent for cell count with differential, aerobic and anaerobic culture, and crystal analysis [3,4,45]. The value of Gram stain is debatable, and some experts send it whereas others do not. Less commonly used synovial fluid markers that may warrant further study include synovial fluid alpha-defensin, leukocyte esterase, absolute neutrophil count [58], absolute synovial polymorphonuclear cell count [59], and CRP [60].

In cases without a definitive diagnosis of PJI, synovial fluid analysis may be used (in conjunction with serum inflammatory markers) as supportive evidence regarding the likelihood of infection. (See 'Clinical approach' above.)

The approach to interpretation of synovial fluid analysis depends in part on the timing of clinical presentation. For total knee [78] replacement PJI within six weeks of the index surgery, the synovial fluid cell count can be >27,800 cells/microL (>89 percent neutrophils). For total hip [79] replacement PJI within six weeks of the index surgery, the synovial fluid cell count can be >12,800 cells/microL (>89 percent neutrophils). In the setting of delayed- and late-onset PJI, the synovial fluid cell count is often >3000 cells/microL (80 percent neutrophils). For acute hematogenous PJI (hip or knee), the synovial fluid count is >10,000 cells/microL.

The interpretation of synovial fluid markers in the context of other clinical factors has not been standardized; a number of criteria have been proposed (table 2) [3-7]. We favor the MSIS 2011 diagnostic criteria given the simplicity and wide use. The ICM 2018 diagnostic criteria proposed a score-based definition for PJI with inclusion of synovial fluid parameters as minor criteria; however, these criteria include a scoring system that include the use of alpha-defensin and synovial fluid leukocyte esterase, which are not widely available. The EBJIS 2021 criteria incorporated addition of sonication fluid culture results to the criteria.

Cell count and polymorphonuclear leukocytes (PMN) thresholds have been observed to differ slightly between chronic total knee arthroplasty infection (1100 to 3000 cells/microL, 64 to 75 percent PMNs) and chronic total hip arthroplasty (THA) infection (745 to 3000 cells/microL, 74 to 80 percent PMNs) [46,63,80-84]. In a retrospective study including 337 patients with suspected PJI, the most accurate cell count threshold for patients with knee PJI was 1630 cells/microL (sensitivity and specificity 84 and 82 percent, respectively) with 60 percent neutrophils (sensitivity and specificity 80 and 77 percent, respectively) [85]. The most accurate cell count threshold for patients with hip PJI was 2582 cells/microL (sensitivity and specificity 80 and 85 percent, respectively) with 66 percent neutrophils (sensitivity and specificity 82 percent). Use of saline irrigation to obtain synovial fluid may confound the cell count.

Synovial fluid alpha-defensin may be useful for diagnosis of PJI. In one prospective study including 156 patients with suspected PJI, the sensitivity, specificity, positive predictive value, and negative predictive value were 97, 97, 88, and 99 percent, respectively [86] (based on the 2014 International Consensus Group definition) [5]. A lateral flow assay for measurement of synovial fluid alpha-defensin (Synovasure lateral flow test) was approved by the United States Food and Drug Administration in 2019; however, it uncertain whether this test is more useful for prediction of PJI than cell count with differential. In a meta-analysis including 10 studies and more than 750 patients with suspected PJI, the sensitivity and specificity of the test for diagnosis of PJI were 78 and 91 percent, respectively [87].

Serum inflammatory markers — Routine serum inflammatory markers include ESR and CRP [1,2,54]; less commonly used serum markers that may warrant further study include D-dimer, fibrinogen, procalcitonin, and interleukin-6 [57].

For cases in which a definitive diagnosis of PJI cannot be made, serum inflammatory markers may be used (in conjunction with synovial fluid analysis) as supportive evidence regarding the likelihood of infection. (See 'Clinical approach' above.)

The approach to interpretation of serum inflammatory markers depends in part on the timing of clinical presentation. In the setting of early-onset PJI, ESR is not useful; CRP is often >100 mg/L. In the setting of delayed and late onset PJI, ESR is often >30 mm/hour and CRP is often >10 mg/L.

The interpretation of serum inflammatory markers in the context of other clinical factors has not been standardized; a number of criteria have been proposed (table 2) [3-7]. We favor the MSIS 2011 diagnostic criteria, which are used most widely.

Following joint replacement surgery, the CRP may require two to three weeks to return to normal preoperative values, and the ESR may require up to a year to return to normal preoperative values [88]. Serum inflammatory markers must also be interpreted with caution in the setting of coexistent chronic inflammatory disease, which can also elevate serum inflammatory markers.

In a meta-analysis including 30 studies and more than 3900 revision arthroplasties, the sensitivity and specificity of ESR and CRP for diagnosis of PJI were 75 and 88 percent and 70 and 74 percent, respectively [57]. Combined use of ESR and CRP has been associated with a sensitivity of 96 percent [82,89]; if both tests are negative, the likelihood of PJI is low. However, PJI may be present in the setting of normal ESR and CRP; factors associated with such cases include late PJI, infection due to pathogens of low virulence, prior antibiotic use, and immunosuppression [2,90].

Radiographic imaging — Radiographic imaging may be of value but usually does not provide a definitive diagnosis of PJI. In general, plain radiographs should be performed in the setting of suspected PJI; these are useful to screen for prosthetic loosening and fracture but lack sensitivity and specificity for the diagnosis of PJI [54].

The following plain radiography findings may be observed in the setting of PJI: abnormal lucency larger than 2 mm in width at the bone-cement interface, changes in the position of prosthetic components, cement fractures, periosteal reaction, or motion of components on stress views [91]. These findings are correlated with the duration of infection; three to six months may be required before manifestation of such changes. In addition, these changes are not specific for infection; they are also seen frequently with aseptic processes.

Other imaging modalities such as leukocyte scans, positron emission tomography (PET) scans, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, or bone scans are not useful for routine diagnostic evaluation in most cases of suspected PJI [4].

Scintigraphy (such as technetium-colloid scans or gallium-67 labeled white blood cell scans) is rarely useful in early infection; scans may be falsely abnormal for up to 12 months following surgery due to periprosthetic bone remodeling [92]. In addition, technetium-colloid scans can be positive in the setting of aseptic loosening. A normal scintigraphy study can be considered evidence against the presence of infection (high sensitivity), but a positive study is not definitive for establishing the diagnosis of PJI (low specificity).

Fluorodeoxyglucose-positron emission tomography (FDG-PET) is not useful within the first year of arthroplasty due to false-positive results associated with postoperative inflammation [93]. In a systematic review including 11 studies evaluating the diagnostic utility of PET for imaging patients with suspected PJI, the pooled sensitivity and specificity of FDG-PET was 82 and 86 percent, respectively [94]. The accuracy of PET scan was higher in THA infection and when criteria for PJI were predetermined.

Use of CT scan is limited by imaging artifacts caused by metallic implants, and MRI can be performed only with implants that are safe for this modality, such as those composed of titanium or tantalum [45]. Some MRI scanners have metal suppression modalities (Metal Artifact Reduction Sequence) that permit greater resolution and an improved recognition of prosthesis failure, with or without infection [93].

Histopathology — Histopathologic examination of periprosthetic tissue may be performed to evaluate for infiltration of polymorphonuclear cells, indicative of an acute inflammatory reaction supporting a diagnosis of PJI. This is often done as a frozen section; it may also be done via standard histopathologic examination. The threshold number of PMNs per high-power field (HPF; 400x magnification) to distinguish PJI from aseptic failure is uncertain; a threshold of at least five PMNs per HPF has been used (sensitivity and specificity >80 percent and >90 percent, respectively) [1,2,54]. In one meta-analysis, histopathology had a pooled diagnostic odds ratio of 54.7 (95% CI 31.2-95.7) for diagnosis of PJI [68]; however, sensitivity of the test is limited (18 to 67 percent) [95-100].

Culture-negative infection — For patients with suspected PJI and negative cultures from synovial fluid and periprosthetic tissue, repeat joint aspiration should be attempted. If feasible, antimicrobial therapy should be withheld for at least two weeks prior to collecting specimens for culture because it diminishes culture sensitivity [1,61]. In addition to aerobic and anaerobic cultures, mycobacterial and fungal cultures should be submitted [54,64]. In the setting of suspected delayed-onset PJI, extended culture incubation (at least 14 days) may increase culture sensitivity (especially for recovery of Cutibacterium spp) [101,102].

Additional tools for diagnosis of culture-negative PJI include explant sonication, molecular diagnostic testing, and serologic testing.

●Explant sonication – Sonication of an explanted prosthesis can improve the yield of microbiologic diagnosis compared with tissue culture, especially in the setting of perioperative antibiotics [73,74]. In one meta-analysis including 12 studies, pooled sensitivity and specificity were 80 and 95 percent, respectively [74]. Sonication is not routinely available in many microbiology laboratories; vortexing an explanted prosthesis is a reasonable alternative [103].

●Molecular diagnostic testing – These tests may be useful when routine cultures are negative and clinical suspicion for PJI is high. They can identify not only bacteria but also fungi. The results must be correlated with Gram stains and clinical and epidemiologic findings since small amounts of contaminating genetic material can lead to false-positive results [104].

Nucleic acid amplification techniques, such as assays based on detection of 16S rRNA gene(s), use a variety of polymerase chain reaction (PCR) techniques to evaluate sonicate fluid, synovial fluid, and joint tissue [104-108].

Metagenomic shotgun sequencing is another novel molecular technique used for extracting, sequencing, and identifying nucleic acid in cases of culture-negative PJI [109-112]. Most of the published evaluations of this technique have used joint sonicate fluid, but periprosthetic tissue has also been used.

Current limitations of molecular diagnostic techniques are that these tools are not routinely available in many clinical microbiology laboratories and may not be covered by insurance. In addition, whether these different molecular diagnostic techniques will be addressed in future orthopedic-related societal guidelines and how they will be positioned in an algorithmic approach to PJI pathogen diagnosis are yet to be defined.

●Serologic tests – In the setting of relevant epidemiologic risk factors for infection due to C. burnetii or Brucella spp (eg, travel history, environmental or animal exposure), serologic tests to evaluate for infection due to these organisms should be performed. (See "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

DIFFERENTIAL DIAGNOSIS — PJI must be differentiated from mechanical and aseptic problems:

●Aseptic loosening – Hardware loosening occurs due to wear of the prosthetic components. Persistent joint pain is suggestive of infection, whereas pain with joint motion and weight bearing (which abates with rest) is suggestive of hardware loosening. (See "Complications of total hip arthroplasty", section on 'Aseptic loosening'.)

●Dislocation – Dislocation refers to an injury that forces the prosthesis out of position. Clinical manifestations include pain, difficulty moving the joint, and deformity of the joint area. Uncommonly, dislocation can occur in the setting of PJI, most frequently in the setting of late-onset infection. The presence of dislocation is established radiographically. (See "Complications of total hip arthroplasty", section on 'Dislocation'.)

●Gout and pseudogout – Gout (monosodium urate crystal deposition disease) and pseudogout (calcium pyrophosphate crystal deposition [CPPD] disease) are characterized by severe pain, erythema, edema, and warmth. The diagnosis of gout is established by visualization of uric acid crystals in synovial fluid; the diagnosis of pseudogout is established by visualization of CPPD crystals in synovial fluid. (See "Clinical manifestations and diagnosis of gout" and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

●Hemarthrosis – Hemarthrosis refers to bleeding into a joint due to traumatic or nontraumatic causes. It is characterized by pain, swelling, warmth, and impaired mobility; the diagnosis is established by joint aspiration. (See "Overview of hemarthrosis".)

●Osteolysis – Osteolysis refers to bone resorption as a biologic response to particulate debris due to wear of the prosthetic components. The diagnosis is established radiographically. (See "Complications of total hip arthroplasty", section on 'Osteolysis and wear'.)

●Metallosis – Metallosis refers to reactive synovitis to metallic debris. Synovial fluid cell counts may be elevated in this condition, but the neutrophil percentage is usually below the threshold for diagnosis of PJI. (See "Complications of total hip arthroplasty".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteomyelitis and prosthetic joint infection in adults".)

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SUMMARY AND RECOMMENDATIONS

●Epidemiology – Prosthetic joint infection (PJI) is a serious complication of prosthetic joint implantation. The rate of PJI is highest during the first two years following surgery. The rate of PJI ranges between 0.5 to 2 percent for knee replacements, 0.5 to 1.0 percent for hip replacements, and <1 percent for shoulder replacements. (See 'Epidemiology' above.)

●Definitions – PJIs may be categorized as early onset (<3 months after surgery), delayed onset (3 to 12 months after surgery), and late onset (>12 months after surgery). The timing of infection can be a clue as to the mechanism of infection and the identity of the infecting organism. However, these definitions are controversial and not always clear-cut, particularly in patients for whom the diagnosis is delayed. (See 'Definitions' above and 'Microbiology' above.)

●Clinical manifestations – The clinical features of PJI depend on the timing of symptom onset (see 'Clinical manifestations' above):

•Early-onset infection – Patients may present with hematoma formation or superficial necrosis of the incision. One or more of the following findings may be observed: joint pain, warmth, erythema, induration, or edema at the incision site, wound drainage or dehiscence, joint effusion, and fever.

•Delayed-onset infection – Patients typically present with an indolent course characterized by persistent joint pain, with or without early implant loosening. Fever is present in less than half of cases. Sinus tract associated with intermittent drainage may be observed; in the absence of a sinus tract, physical exam findings are often minimal.

•Late-onset infection – Patients typically present with acute onset of systemic symptoms associated with bacteremia, together with joint pain in a previously well-functioning joint.

●Diagnosis – PJI should be suspected patients with a joint prosthesis and relevant signs and symptoms of infection (including joint pain, warmth, erythema, induration, or edema at the incision site, sinus tract or persistent wound drainage, wound dehiscence, joint effusion, or fever).

The diagnosis can be challenging, and multiple sets of diagnostic criteria have been proposed (table 2). In general, the diagnosis of PJI is confirmed if one of the following is present (see 'Clinical approach' above):

•A sinus tract that communicates with the prosthesis

•Two or more periprosthetic cultures with phenotypically identical organisms (≥2 intraoperative cultures or a combination of preoperative synovial fluid aspiration culture and intraoperative tissue culture)

For cases in which a definitive diagnosis of PJI cannot be established, data such as serum inflammatory markers and synovial fluid examination may provide supportive evidence regarding the likelihood of infection.

●Diagnostic evaluation – In the setting of suspected PJI, initial diagnostic evaluation consists of plain radiography (to evaluate for alternative causes of pain and instability) and measurement of serum inflammatory markers (erythrocyte sedimentation rate and C-reactive protein).

Diagnostic arthrocentesis should be performed (unless a sinus tract is present and definitive debridement is planned). Synovial fluid should be sent for cell count with differential, aerobic and anaerobic culture, and crystal analysis; the value of Gram stain is debatable. In patients with a sinus tract, drainage (collected by aspiration) should be sent for culture. In patients with fever or other systemic manifestations of infection, blood cultures (two sets) should be obtained. Intraoperative specimens should consist of at least three periprosthetic tissue samples (ideally five); if pus is encountered, it should be aspirated in a sterile tube and sent for culture. (See 'Obtaining diagnostic studies' above.)

●Synovial fluid analysis – Interpretation of synovial fluid findings depends in part on the timing of clinical presentation and has not been standardized. We favor the Musculoskeletal Infection Society 2011 diagnostic criteria, which are the most widely used (table 2). (See 'Clinical approach' above and 'Synovial fluid analysis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Elie Berbari, MD, FIDSA, who contributed to earlier versions of this topic review.