The Topic of the Lesson “Septic Arthritis.”

The topic of the lesson “Septic arthritis.”

According to the evidence-based data from UpToDate extracted March of 19, 2020 Provide a conspectus in a format of .ppt (.pptx) presentation of not less than 50 slides containing information on:

1. Classification 2. Etiology 3. Pathogenesis 4. Diagnostic 5. Differential diagnostic 6. Treatment With 10 (ten) multiple answer questions.

Septic arthritis in adults - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Septic arthritis in adults Contributor Disclosures Authors: Don L Goldenberg, MD, Daniel J Sexton, MD Section Editor: Denis Spelman, MBBS, FRACP, FRCPA, MPH Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Feb 27, 2020.

INTRODUCTION

Septic arthritis is synonymous with an infection in a joint. Septic arthritis is usually caused by bacteria but can also be caused by other microorganisms. Septic arthritis due to bacterial infection is often a destructive form of acute arthritis [1].

The epidemiology, microbiology, clinical manifestations, diagnosis, differential diagnosis, and treatment of septic arthritis of native joints due to typical bacteria are reviewed here. An overview of monoarthritis in adults is presented separately. (See "Monoarthritis in adults: Etiology and evaluation".)

Issues related to prosthetic joint infection are discussed separately. (See "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Prosthetic joint infection: Treatment".)

Issues related to septic arthritis in children are discussed separately. (See "Bacterial arthritis: Clinical features and diagnosis in infants and children" and "Bacterial arthritis: Treatment and outcome in infants and children".)

Issues related to gonococcal arthritis, lyme arthritis, and viral causes of arthritis are discussed separately. (See "Disseminated gonococcal infection" and "Musculoskeletal manifestations of Lyme disease" and "Viruses that cause arthritis".)

EPIDEMIOLOGY

In the United States in 2012, septic arthritis was responsible for 16,000 emergency department visits [2].

Predisposing factors include [3-7]:

● Advance age ● https://www.uptodate.com/...rch=Bacterial%20arthritis&source=search_result&selectedTitle=3~129&usage_type=default&display_rank=3[19.03.2020 15:39:14] Septic arthritis in adults - UpToDate

Pre-existing joint disease ● Recent joint surgery or injection ● Skin or soft tissue infection ● Intravenous drug use ● Indwelling catheters ● Immunosuppression (including diabetes)

Most commonly, septic arthritis arises via hematogenous seeding. Bacteremia is more likely to localize in a joint with pre-existing arthritis (such as rheumatoid arthritis, osteoarthritis, gout, pseudogout, Charcot arthropathy), particularly if associated with synovitis [8-10]. Patients with rheumatoid arthritis, may have additional predisposing factors, such as intra-articular steroid injections and use of immunosuppressive medications [11-14].

In one series including more than 500 adult cases of native joint septic arthritis in New Zealand between 2009 and 2014, large joint septic arthritis (involving the knee, shoulder, hip, ankle, wrist, or elbow) occurred more frequently than small joint septic arthritis (involving the finger, toe, acromioclavicular, or sternoclavicular joints; incidence 13 vs 8 per 100,000 person-years) [15].

MECHANISM OF INFECTION

Septic arthritis develops as a result of hematogenous seeding or direct inoculation of bacteria into the joint [9,10,16].

Most commonly, septic arthritis arises via hematogenous seeding of the synovial membrane (which has no limiting basement membrane, thus allowing organisms to enter the joint space). Septic arthritis due to hematogenous seeding is most commonly caused by organisms with propensity to adhere to the synovial tissues (such as S. aureus) [17]. Hematogenous seeding most commonly involves large joints [15].

Bacterial arthritis can also occur via direct inoculation of bacteria into the joint; mechanisms include bite wounds, trauma, arthroscopy or other surgery, and intra-articular injection [18,19]. Septic arthritis following an intra-articular injection is uncommon; rarely it occurs in clusters due to unsafe injection practices [18,20].

Rarely, septic arthritis develops via extension of infection into the joint space from adjacent tissues. In the setting of long-bone osteomyelitis, infection within the metaphysis can break through the bone cortex, leading to discharge of pus into the joint. This occurs in joints in which the metaphysis is within the capsular reflection (eg, knees, hip, shoulder, and elbows). (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Hematogenous osteomyelitis'.).

Other examples include complications of subclavian vein and femoral catheterization (resulting in septic arthritis of the sternoclavicular and hip joints, respectively), and ruptured diverticulitis, resulting in dissection of infection via the retroperitoneal space into the posterior thigh and hip joint [21-23].

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MICROBIOLOGY

Numerous pathogens are capable of causing septic arthritis (table 1). The microbiology of septic arthritis depends in part on the mechanism of infection and relevant epidemiologic exposures. (See 'Epidemiology' above.)

Septic arthritis is usually monomicrobial. S. aureus (including methicillin-resistant S. aureus) is the most common cause of septic arthritis in adults [4,10,24]. Other gram-positive organisms such as streptococci are also important potential causes of septic arthritis [25]. Streptococcus pneumoniae is responsible for a small percentage of cases of septic arthritis in adults [26].

Septic arthritis due to gram-negative bacilli generally occurs in older adults, in patients with underlying immunosuppression, or intravenous drug users; it may also occur as a complication of trauma. Patients with underlying immunosuppression and intravenous drug users are at risk for infection due to Pseudomonas [27].

Polymicrobial septic arthritis is uncommon; it may occur in the setting of penetrating trauma involving the joint space or via hematogenous seeding in patients with polymicrobial bacteremia. Small joint septic arthritis is more likely to be polymicrobial and caused by streptococci, Eikenella, or anaerobic bacteria [15].

CLINICAL MANIFESTATIONS

Signs and symptoms — Septic arthritis may develop as a result of hematogenous seeding, direct inoculation of bacteria into the joint, or extension of bony infection into the joint space. (See 'Mechanism of infection' above.)

Patients with septic arthritis usually present acutely with a single swollen and painful joint (ie, monoarticular arthritis) [28]. Joint pain, swelling, warmth, and restricted movement occur in 80 percent of patients with septic arthritis [3]. Most patients with septic arthritis are febrile; however, older patients with septic arthritis may be afebrile [3].

The knee is involved in more than 50 percent of cases; wrists, ankles, and hips are also affected commonly [9]. Infection of the symphysis pubis is uncommon [29]. Involvement of axial joints (such as the sternoclavicular or sternomanubrial joint) may occur in injection drug users [30]. (See "Pelvic osteomyelitis and other infections of the bony pelvis in adults".)

Oligoarticular or polyarticular infection (usually two or three joints) occurs in approximately 20 percent of patients with septic arthritis. Polyarticular septic arthritis is most likely to occur in patients with rheumatoid arthritis or other systemic connective tissue disease and in patients with sepsis [31].

Septic arthritis may be a presenting manifestation of infective endocarditis; this occurs most commonly

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among injection drug users [32]. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

In septic arthritis that occurs as a result of hematogenous seeding, blood cultures are positive in approximately 50 percent of cases [10]. Laboratory findings such as elevated white blood cell count, erythrocyte sedimentation rate, and C-reactive protein are common but nonspecific [33].

Physical examination — The physical examination should include thorough evaluation of all joints for erythema, swelling, warmth, and tenderness [3]. Infected joints are characteristically painful and usually demonstrate an effusion, both of which are associated with limited active and passive range of motion. External findings such as swelling, erythema, and warmth may be less prominent in the setting of septic arthritis involving the hip, shoulder or spine joints. In addition, physical exam findings may be less prominent in patients who are older adults and/or immunocompromised.

DIAGNOSIS

General approach — The diagnosis of septic arthritis should be suspected in patients with acute onset of at least one swollen, painful joint, with or without relevant risk factors (including bacteremia, pre- existing joint disease, and immunosuppression).

The diagnosis of septic arthritis is made based on synovial fluid analysis and culture (algorithm 1 and table 2). Septic arthritis may be definitively established in the setting of positive synovial fluid Gram stain and/or culture [3]. In patients with purulent synovial fluid (leukocyte count of 50,000 to 150,000 cells/microL, mostly neutrophils) but negative synovial fluid cultures, a presumptive diagnosis of septic arthritis may be made. (See 'Interpreting synovial fluid test results' below and 'Differential diagnosis' below.)

In addition, blood cultures (two sets) and, when indicated, radiographs, ultrasound, or imaging studies of the involved joint should be obtained.

In the setting of septic arthritis due to organisms that commonly cause endocarditis (such as S. aureus, streptococci, or enterococci) with no clear predisposing cause, evaluation for endocarditis should be pursued. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

Obtaining clinical specimens — Collection of synovial fluid and blood cultures should be performed prior to administration of antibiotics. If synovial fluid cannot be obtained with closed needle aspiration, the joint should be aspirated under radiographic guidance. Certain joints (such as the hip or sacroiliac joint) may require surgical arthrotomy for aspiration. The only definitive way to diagnose a septic joint is via synovial fluid culture.

Synovial fluid should be sent for Gram stain, bacterial culture, white blood cell count with differential, and assessment for crystals (monosodium urate and calcium pyrophosphate crystal deposition crystals) with https://www.uptodate.com/...rch=Bacterial%20arthritis&source=search_result&selectedTitle=3~129&usage_type=default&display_rank=3[19.03.2020 15:39:14] Septic arthritis in adults - UpToDate

a polarizing microscope.

Synovial fluid may be sent for culture in a sterile tube (ideally with an anticoagulant such as ethylenediaminetetraacetic acid [EDTA] to guard against clotting) and/or in blood culture bottles (aerobic and anaerobic) [34-37]. If blood culture bottles are used, synovial fluid also should also be sent in a sterile container to allow Gram stain microscopy. 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. The use of blood culture bottles has no significant advantage when common causes of septic arthritis such as S. aureus is suspected [38] but may have advantages in detecting unusual organisms such as Kingella and Brucella [39]. Kingella kingae occurs more commonly in children than adults. (See "Bacterial arthritis: Clinical features and diagnosis in infants and children".)

Nucleic acid amplification tests such as polymerase chain reaction and other advanced diagnostic methods such as MALDI-TOF mass spectometry may be useful when routine cultures are negative and the suspicion for infection remains high; in infections due to N. gonorrhoeae cases (see "Disseminated gonococcal infection"); or cases in which prior treatment with antibiotics is suspected as having led to a spuriously negative routine culture. When positive, such test results need to be interpreted carefully and correlated with Gram stains and clinical and epidemiologic findings, because extremely small amounts of contaminating bacterial material can lead to a false-positive result [40].

Other synovial fluid assays (such as synovial fluid lactate, glucose, C-reactive protein (CRP), or immunoassays) are not useful for diagnosis of septic arthritis [41,42]. Measurement of procalcitonin levels (in the serum and/or synovial fluid) has been proposed as tools for diagnosis of septic arthritis, particularly when synovial fluid is difficult to obtain or in patients with coexisting inflammatory arthritis. However, the serum procalcitonin level has a relatively low sensitivity (pooled sensitivity in 10 studies 0.54 [95% CI 0.41-0.66] and a pooled negative likelihood ratio of 0.49 [95% CI 0.38-0.62]); thus, such a test cannot be used to rule out septic arthritis. The specificity of serum procalcitonin levels is higher (pooled sensitivity in one meta-analysis 0.95 [95% CI 0.87-0.96]); thus a positive test may be occasionally useful in deciding if a difficult-to-access joint such as the hip or sacroiliac joint should be aspirated [43,44]. Synovial fluid procalcitonin levels may be more predictive of septic arthritis than blood levels; however, such testing is not needed if a culture is obtained at the time of joint aspiration.

Synovial biopsy is rarely necessary, but may be indicated if there is evidence of concurrent contiguous osteomyelitis, in rare cases in which joint aspiration fails to provide a satisfactory sample for diagnostic testing, or when infection or coinfection with M. tuberculosis or other slow growing pathogens is a possibility.

Interpreting synovial fluid test results — In the setting of septic arthritis, synovial fluid analysis typically demonstrates the following (table 2 and algorithm 1 and algorithm 2) [10]:

● Leukocyte count of 50,000 to 150,000 cells/microL (mostly neutrophils) [34]. The likelihood of septic arthritis increases as the synovial fluid leukocyte count increases [4,15]. High synovial fluid white

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blood cell counts can also occur in other conditions, so it is important to interpret the results of synovial fluid testing in the overall clinical context. (See 'Differential diagnosis' below.)

● Gram stain is positive in some cases; the sensitivity is 30 to 50 percent [3]. False-positive results may reflect precipitated crystal violet and mucin in the synovial fluid, which can mimic the appearance of gram-positive cocci. False-negative results may occur if crystals are present or if clotting occurs [35,45].

● Synovial fluid culture is positive in the more than 60 percent of patients with nongonococcal bacterial arthritis [46]. Negative synovial fluid cultures may occur in the setting of recent antimicrobial therapy or infection with a fastidious organism.

Radiographic imaging — Radiographs of the involved joint should be obtained for evaluation of concurrent bone and joint disease; in addition, baseline radiography is often useful to guide subsequent management decisions. For joints that are difficult to examine (such as the hip or sacroiliac joint), computed tomography or magnetic resonance imaging are useful for detection of effusion. Nuclear imaging is not warranted for suspected septic arthritis. (See "Imaging techniques for evaluation of the painful joint".)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of septic arthritis includes infectious as well as noninfectious illnesses (table 3 and table 4). (See "Monoarthritis in adults: Etiology and evaluation".)

Other causes of infection include septic bursitis and alternate infectious causes of arthritis:

● Septic bursitis – Septic bursitis refers to inflammation of the bursa due to infection; the mechanisms for development of septic bursitis are the same as the mechanisms for development of septic arthritis. The diagnosis of septic bursitis is confirmed by culture of fluid from the affected bursa. (See "Septic bursitis".)

● Gonococcal arthritis – Gonococcal arthritis typically presents acutely in sexually active individuals with fever, chills, skin lesions, polyarthralgias, and tenosynovitis, evolving into a persistent monoarthritis or oligoarthritis. The diagnosis of disseminated gonococcal infection is made by identification of Neisseria gonorrhoeae (either through molecular testing or culture) via nucleic acid amplification testing or culture of a specimen of blood, synovial fluid or tissue, skin lesion, or other nonmucosal site. Culture requires processing on chocolate agar plates, Thayer-Martin medium, or other selective gonococcal medium; the organism cannot be cultured on routine culture media. (See "Disseminated gonococcal infection".)

● Lyme disease – Lyme disease should be suspected in patients with an acute monoarthritis in the setting of epidemiologic exposure in an endemic area; erythema migrans rash, fever, and migratory arthralgias may occur weeks or months prior. The diagnosis is established via serologic testing. (See https://www.uptodate.com/...rch=Bacterial%20arthritis&source=search_result&selectedTitle=3~129&usage_type=default&display_rank=3[19.03.2020 15:39:14] Septic arthritis in adults - UpToDate

"Musculoskeletal manifestations of Lyme disease", section on 'Laboratory testing'.)

● Tuberculous arthritis – Tuberculous arthritis should be suspected in patients with indolent presentation of persistent culture-negative oligoarthritis or monoarthritis, in the setting of relevant epidemiologic exposure. The sensitivity of synovial fluid Ziehl-Neelsen stain for detection of acid-fast bacilli is low; the diagnosis is established via synovial membrane histopathology and culture. (See "Skeletal tuberculosis", section on 'Arthritis'.)

● Viral causes of arthritis – Viral causes of arthritis typically present with polyarthritis; they include chikungunya, dengue fever, Zika virus, parvovirus, Ross River virus, Barmah Forest virus, and rubella. A number of other viruses including enterovirus, adenovirus, and alphaviruses may also cause arthritis. (See "Viruses that cause arthritis".)

● Fungal arthritis – Fungal arthritis should be suspected in patients with indolent presentation of persistent culture-negative oligoarthritis or monoarthritis, in the setting of relevant epidemiologic exposure; it is most common in the setting of immunosuppression. Fungal causes of arthritis include sporotrichosis, coccidioidomycosis, candidiasis, and others. The diagnosis is established via fungal stain and culture of synovial fluid or via synovial membrane histopathology and culture. (See related topics.)

Noninfectious causes of arthritis include trauma and inflammatory arthritis:

● Acute traumatic arthritis – Acute traumatic arthritis usually causes bloody synovial fluid and is generally associated with a history of significant trauma to the joint. (See "Overview of hemarthrosis", section on 'Traumatic'.)

● Crystal-induced arthritis (gout or pseudogout) – Manifestations of crystal-induced arthritis include monoarthritis and leukocytosis. Clues suggestive of gout include involvement of the first metatarsophalangeal joint, prior self-limited attacks of arthritis, and presence of tophi. The diagnosis of crystal-induced arthritis can be established by synovial fluid analysis demonstrating monosodium urate crystals of gout or calcium pyrophosphate dihydrate crystals of pseudogout. Concurrent crystal-induced and septic arthritis can occur [47]. In patients with concurrent gout and septic arthritis, the synovial fluid Gram stain may be negative; thus, cultures should be performed if concurrent infection is suspected [45]. (See "Clinical manifestations and diagnosis of gout" and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

● Reactive arthritis or spondyloarthritis – Chronic inflammatory joint disease can present with a new swollen joint, simulating septic arthritis; this is especially common in the seronegative spondyloarthropathies such as reactive arthritis. Most patients with reactive arthritis have recent genitourinary or gastrointestinal signs or symptoms, conjunctivitis, or skin or mucus membrane lesions. Occasionally, patients with ankylosing spondylitis present with acute-onset hip arthritis that mimics septic arthritis. (See "Reactive arthritis" and "Diagnosis and differential diagnosis of axial

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spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)

● Rheumatoid arthritis – Rheumatoid arthritis (RA) is typically a symmetric, chronic polyarthritis; however, acute or subacute exacerbation of one or a few joints can occur. The diagnosis may be difficult to establish because the clinical findings may be atypical; many patients with RA and superimposed septic arthritis present indolently (rather than acutely), often with little fever or leukocytosis. Conversely, RA itself may present with a "pseudoseptic arthritis" picture, including an explosive acute synovitis with a marked synovial fluid leukocytosis. The diagnosis of RA is established via clinical criteria summarized separately. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

TREATMENT

Management of acute bacterial arthritis consists of joint drainage and antibiotic therapy (algorithm 2) [48].

Joint drainage — In general, patients with septic arthritis warrant joint drainage, since this condition represents a closed abscess. Approaches to joint drainage for management of septic arthritis in adults include needle aspiration, arthroscopic drainage, or arthrotomy (open surgical drainage). The choice of approach depends on clinical factors including the joint affected and the duration of infection.

For septic arthritis of the knee, elbow, ankle, or wrist, the joint may be drained via needle aspiration or arthroscopy. For septic arthritis of the hip, shoulder, or difficult-to-access joint (such as the sternoclavicular joint), the joint should be drained by arthroscopy. In any joint, arthroscopy may facilitate more thorough irrigation [49-52].

Surgical drainage is warranted in the following circumstances [9,10,53-55]:

● Adequate drainage cannot be achieved by needle aspiration or arthroscopy ● Suspicion for penetrating trauma with a residual foreign body ● Joint effusion persists after seven days of serial aspiration

Patients with severe infection may require repeated aspirations or arthroscopic irrigations. Serial synovial fluid analyses should be performed; as infection is treated, these findings should demonstrate sterilization of the fluid and decreasing total white blood cell count. Adequacy of drainage may also be assessed clinically (based on improvement in fever curve, white blood cell count, joint swelling, and pain).

Antibiotic therapy

Initial approach — The initial choice of empiric antimicrobial therapy should cover the most likely pathogens. The approach below is supported by case series [4]; there are no randomized trials.

● If the initial Gram stain of synovial fluid demonstrates gram-positive cocci, empiric treatment with vancomycin (15 to 20 mg/kg/dose intravenously [IV] every 8 to 12 hours) should be administered [56]. Most patients with normal renal function can be started on 15 mg/kg/dose (usual maximum 2 g https://www.uptodate.com/...rch=Bacterial%20arthritis&source=search_result&selectedTitle=3~129&usage_type=default&display_rank=3[19.03.2020 15:39:14] Septic arthritis in adults - UpToDate

per dose initially) every 12 hours.

• Patients with septic arthritis due to methicillin-susceptible S. aureus should be treated with a beta-lactam agent such as cefazolin (2 g IV every eight hours), nafcillin or oxacillin (2 g IV every four hours), or flucloxacillin (2 g IV every six hours). Patients who are allergic to penicillin can be treated with vancomycin.

• Patients with septic arthritis due to methicillin-resistant S. aureus should be treated with vancomycin; if this is not feasible due to allergy or drug intolerance, reasonable alternative agents include daptomycin (6 mg/kg/day IV), linezolid (600 mg orally or IV twice daily), or clindamycin (600 mg orally or IV three times daily) [56].

● If the initial Gram stain of synovial fluid demonstrates gram-negative bacilli, treatment with a cephalosporin should be administered. Options include:

• Ceftriaxone (2 g IV once daily) • Cefotaxime (2 g IV every eight hours) • Ceftazidime (2 g IV every eight hours) • Cefepime (2 g IV every 8 to 12 hours)

In the setting of clinical suspicion for Pseudomonas aeruginosa (eg, in the setting of injection drug use), initial empiric therapy with two antipseudomonal agents is reasonable. Possible combination regimens include either a cephalosporin (such as ceftazidime or cefepime) in combination with ciprofloxacin (400 mg IV every 12 hours or 500 to 750 mg orally twice daily) or an aminoglycoside such as gentamicin (3 to 5 mg/kg IV per day in two or three divided doses). Aztreonam (2 g IV every eight hours) is an acceptable alternative empiric agent in patients allergic to cephalosporins. Empiric antimicrobial therapy should be streamlined to a single agent after antimicrobial susceptibility data are available. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)

● If the initial Gram stain of synovial fluid is negative but synovial fluid cell count is consistent with septic arthritis, the approach depends on individual clinical circumstances [27]:

• For immunocompetent patients without confounding factors (such as trauma), we suggest treatment with vancomycin.

• For patients with traumatic bacterial arthritis, we suggest treatment with vancomycin plus a third- generation cephalosporin.

• For immunocompromised patients and injection drug users, we suggest treatment with vancomycin plus a cephalosporin with activity against Pseudomonas (ceftazidime or cefepime).

For patients with septic arthritis associated with an animal bite, the approach to antibiotic selection is discussed separately. (See "Animal bites (dogs, cats, and other animals): Evaluation and management", section on 'Spectrum of therapy'.)

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The initial antibiotic regimen should be tailored to culture and susceptibility results when available. As an example, vancomycin should be discontinued in patients with staphylococcal or streptococcal infections that are susceptible to beta-lactam therapy.

There is no role for intra-articular antibiotics, since systemic antibiotic therapy produces adequate drug levels in joint fluid. Furthermore, direct instillation of antibiotics into a joint may induce an inflammatory response and carries a risk of iatrogenic complications such as secondary infection [10].

Duration — The optimal duration of antimicrobial therapy for treatment of septic arthritis is uncertain. The approach below is supported by case series [4]; there are no randomized trials.

For patients with septic arthritis due to S. aureus in the setting of concomitant bacteremia (but no evidence of endocarditis), we administer parenteral therapy for four weeks.

For patients with septic arthritis due to S. aureus in the absence of concomitant bacteremia or signs of endocarditis, we administer parenteral antibiotics for at least 14 days, followed by oral therapy for an additional 7 to 14 days. The choice of oral antibiotic regimen for completion of therapy depends on the pathogen:

● For septic arthritis due to methicillin-sensitive S. aureus, suitable choices include dicloxacillin (500 mg orally every six hours), flucloxacillin (500 mg orally every six hours), or cephalexin (500 mg orally every six hours). Patients who are allergic to penicillin can be treated with clindamycin (600 mg orally every eight hours).

● For septic arthritis due to methicillin-resistant S. aureus, suitable choices include clindamycin, trimethoprim-sulfamethoxazole, doxycycline (or minocycline), linezolid (or tedizolid), and rifampin in combination with either ciprofloxacin or fusidic acid (table 5).

For patients with septic arthritis due to organisms that are susceptible to oral agents with high bioavailability (such as a fluoroquinolone), we favor treatment with a short course (four to seven days) of parenteral therapy, followed by 14 to 21 days of oral therapy. Compliance and response to therapy should be monitored carefully in such cases.

For patients with septic arthritis due to difficult-to-treat pathogens (such as P. aeruginosa or Enterobacter spp), longer courses of outpatient parenteral antibiotic therapy (eg, three to four weeks) may be necessary.

For patients with septic arthritis and contiguous osteomyelitis, a long (four to six week) course of antibiotics may be indicated. (See "Osteomyelitis in adults: Treatment".)

For patients with septic arthritis in the setting of endocarditis, the duration of therapy is guided by the duration required for treatment of endocarditis. (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis".)

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OUTCOME

In the United States, these were 13,700 hospital admissions for septic arthritis in 2012 [2]. Average length of stay was seven days and only 40 percent of patients were discharged home. Discharge to a rehabilitation or nursing facility, longer hospital stay, and worse outcome correlated with age >50 years, Medicaid and self-pay as primary payer, teaching hospital status, heart failure, and diabetes. There was a 3 percent mortality rate during the primary hospitalization.

Unfortunately, there are few studies on the long-term joint outcome in patients with septic arthritis. In most, the functional outcome has depended on host factors (such as pre-existing joint disease), the virulence of the infecting organism, and duration of infection prior to initiation of therapy.

In one study including 121 adults with septic arthritis, a poor joint outcome (as defined by the need for amputation, arthrodesis, prosthetic surgery, or severe functional deterioration) occurred in one-third of the patients; adverse prognostic factors included older age and pre-existing joint disease [8].

The pathogen may also influence the outcome of treatment. In studies of septic arthritis due to S. aureus, poor joint outcomes have been observed in up to half of patients following completion of therapy [10,57]. In a three-year period, 93 patients with S. aureus arthritis were identified and 40 percent were methicillin- resistant S. aureus [58]. More than 90 percent of the cases were community acquired and 44 percent of the patients had diabetes mellitus. The in-hospital mortality rate was 5.4 percent. In contrast, a study of patients with pneumococcal septic arthritis noted a return to baseline joint function (or only mild limitation of joint motion) following therapy in 95 percent of cases [26].

Mortality due to septic arthritis depends on comorbid conditions such as advanced age, renal or cardiac disease, and immunosuppression. The mortality rates in most series range from 10 to 15 percent [8]. Polyarticular septic arthritis, particularly when it is due to S. aureus or occurs in the presence of rheumatoid arthritis, has an extremely poor prognosis, with mortality rates as high as 50 percent [31]. Mortality due to septic pneumococcal arthritis was reported as 19 percent in one series [26].

In a series of 55 patients treated with arthroscopic lavage and antibiotics for septic arthritis of the knee, medical comorbidities, increased age, and multiple medication use had worse outcomes [59].

The outcome of septic arthritis in people who inject drugs (PWID) is worse than in most other patient groups. In a nation-wide series of septic knees, the proportion of patients with injection drug user-related septic arthritis increased from 5 percent in 2000 to 11 percent in 2013 [60]. PWID-related cases were more likely to require repeat surgical procedures, longer hospital stays, and had higher mortality rates.

In one series including more than 500 adult cases of native joint septic arthritis in New Zealand between 2009 and 2014, large joint septic arthritis was associated with a higher rate of treatment failure than small joint septic arthritis (23 versus 12 percent) [15]. Adverse outcomes included death (5 percent), relapse (5 percent), reinfection (6 percent), and amputation (3 percent).

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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: Septic arthritis in adults".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

● Basics topic (see "Patient education: Septic arthritis (The Basics)")

● Beyond the Basics topics (see "Patient education: Arthritis (Beyond the Basics)" and "Patient education: Joint infection (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Septic arthritis refers to infection in a joint. Septic arthritis is usually caused by bacteria but can also be caused by other microorganisms. Most commonly, septic arthritis arises via hematogenous seeding. It may also develop as a result of direct inoculation of bacteria into the joint. Rarely, septic arthritis develops via extension of infection into the joint space from adjacent tissues. (See 'Introduction' above and 'Mechanism of infection' above.)

● Septic arthritis is usually monomicrobial. Staphylococcus aureus (including methicillin-resistant S. aureus) is the most common cause of septic arthritis in adults (table 1). Other gram-positive organisms such as streptococci are also important potential causes. Septic arthritis due to gram- negative bacilli generally occurs in older adults, in patients with underlying immunosuppression, or intravenous drug users; it may also occur as a complication of trauma. (See 'Microbiology' above.)

● Patients with septic arthritis usually present acutely with a single swollen and painful joint (ie, monoarticular arthritis); oligoarticular or polyarticular infection occurs in approximately 20 percent of patients. Joint pain, swelling, warmth, and restricted movement occur in most cases. Patients with

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septic arthritis are usually febrile; older patients may be afebrile. The knee is involved in more than half of cases; wrists, ankles, and hips are also affected commonly. (See 'Clinical manifestations' above.)

● The diagnosis of septic arthritis should be suspected in patients with acute onset of at least one swollen, painful joint. The diagnosis of septic arthritis is established based on synovial fluid analysis and culture (algorithm 1 and table 2). Septic arthritis may be definitively established in the setting of positive synovial fluid gram stain and/or culture. In patients with purulent synovial fluid (leukocyte count of 50,000 to 150,000 cells/microL, mostly neutrophils) but negative synovial fluid cultures, a presumptive diagnosis septic arthritis may be made. (See 'Diagnosis' above.)

● Prior to administration of antibiotics, synovial fluid should be sent for Gram stain, bacterial culture, white blood cell count with differential, and assessment for crystals. In addition, blood cultures (two sets) and radiographs of the involved joint should be obtained. (See 'Diagnosis' above.)

● Management of acute bacterial arthritis consists of joint drainage and antibiotic therapy. (See 'Treatment' above.)

• Approaches to joint drainage for management of septic arthritis include needle aspiration, arthroscopy, or arthrotomy (open surgical drainage). (See 'Joint drainage' above.)

• The initial choice of empiric antimicrobial therapy should cover the most likely pathogens; the approach is summarized in the algorithm (algorithm 2).

- If the initial Gram stain of the synovial fluid shows gram-positive cocci, treatment consists of vancomycin. If the initial Gram stain of the synovial fluid shows gram-negative bacilli, treatment consists of a third-generation cephalosporin.

- If the initial Gram stain of synovial fluid is negative but synovial fluid cell count is consistent with septic arthritis, the approach depends on individual clinical circumstances. For immunocompetent patients without confounding factors (such as trauma), we suggest treatment with vancomycin (Grade 2C). For patients with traumatic bacterial arthritis, we suggest treatment with vancomycin plus a third-generation cephalosporin (Grade 2C). For immunocompromised patients and injection drug users, we suggest treatment with vancomycin plus a cephalosporin with activity against Pseudomonas (ceftazidime or cefepime) (Grade 2C).

• Subsequently, antibiotic therapy should be tailored to microbiology and susceptibility data when available. The duration of therapy is tailored to individual clinical circumstances as described above. (See 'Antibiotic therapy' above.)

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15. McBride S, Mowbray J, Caughey W, et al. Epidemiology, Management, and Outcomes of Large and Small Native Joint Septic Arthritis in Adults. Clin Infect Dis 2020; 70:271. https://www.uptodate.com/...rch=Bacterial%20arthritis&source=search_result&selectedTitle=3~129&usage_type=default&display_rank=3[19.03.2020 15:39:14] Septic arthritis in adults - UpToDate

16. Morgan DS, Fisher D, Merianos A, Currie BJ. An 18 year clinical review of septic arthritis from tropical Australia. Epidemiol Infect 1996; 117:423.

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21. Aglas F, Gretler J, Rainer F, Krejs GJ. Sternoclavicular septic arthritis: a rare but serious complication of subclavian venous catheterization. Clin Rheumatol 1994; 13:507.

22. Fromm SE, Toohey JS. Septic arthritis of the hip in an adult following repeated femoral venipuncture. Orthopedics 1996; 19:1047.

23. Messieh M, Turner R, Bunch F, Camer S. Hip sepsis from retroperitoneal rupture of diverticular disease. Orthop Rev 1993; 22:597.

24. Frazee BW, Fee C, Lambert L. How common is MRSA in adult septic arthritis? Ann Emerg Med 2009; 54:695.

25. Nelson GE, Pondo T, Toews KA, et al. Epidemiology of Invasive Group A Streptococcal Infections in the United States, 2005-2012. Clin Infect Dis 2016; 63:478.

26. Ross JJ, Saltzman CL, Carling P, Shapiro DS. Pneumococcal septic arthritis: review of 190 cases. Clin Infect Dis 2003; 36:319.

27. Allison DC, Holtom PD, Patzakis MJ, Zalavras CG. Microbiology of bone and joint infections in injecting drug abusers. Clin Orthop Relat Res 2010; 468:2107.

28. Mikhail IS, Alarcón GS. Nongonococcal bacterial arthritis. Rheum Dis Clin North Am 1993; 19:311.

29. Ross JJ, Hu LT. Septic arthritis of the pubic symphysis: review of 100 cases. Medicine (Baltimore) 2003; 82:340.

30. Ross JJ, Shamsuddin H. Sternoclavicular septic arthritis: review of 180 cases. Medicine (Baltimore)

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2004; 83:139.

31. Dubost JJ, Fis I, Denis P, et al. Polyarticular septic arthritis. Medicine (Baltimore) 1993; 72:296.

32. Sapico FL, Liquete JA, Sarma RJ. Bone and joint infections in patients with infective endocarditis: review of a 4-year experience. Clin Infect Dis 1996; 22:783.

33. Hariharan P, Kabrhel C. Sensitivity of erythrocyte sedimentation rate and C-reactive protein for the exclusion of septic arthritis in emergency department patients. J Emerg Med 2011; 40:428.

34. Miller JM, Binnicker MJ, Campbell S, et al. A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for Microbiology. Clin Infect Dis 2018; 67:e1.

35. Stirling P, Faroug R, Amanat S, et al. False-negative rate of gram-stain microscopy for diagnosis of septic arthritis: suggestions for improvement. Int J Microbiol 2014; 2014:830857.

36. Kortekangas P, Aro HT, Lehtonen OP. Synovial fluid culture and blood culture in acute arthritis. A multi-case report of 90 patients. Scand J Rheumatol 1995; 24:44.

37. Ike RW. Bacterial arthritis. Curr Opin Rheumatol 1998; 10:330.

38. She RC, Romney MG, Jang W, et al. Performance of the BacT/Alert Virtuo Microbial Detection System for the culture of sterile body fluids: prospective multicentre study. Clin Microbiol Infect 2018; 24:992.

39. Hughes JG, Vetter EA, Patel R, et al. Culture with BACTEC Peds Plus/F bottle compared with conventional methods for detection of bacteria in synovial fluid. J Clin Microbiol 2001; 39:4468.

40. Carter K, Doern C, Jo CH, Copley LA. The Clinical Usefulness of Polymerase Chain Reaction as a Supplemental Diagnostic Tool in the Evaluation and the Treatment of Children With Septic Arthritis. J Pediatr Orthop 2016; 36:167.

41. Tetreault MW, Wetters NG, Moric M, et al. Is synovial C-reactive protein a useful marker for periprosthetic joint infection? Clin Orthop Relat Res 2014; 472:3997.

42. Shu E, Farshidpour L, Young M, et al. Utility of point-of-care synovial lactate to identify septic arthritis in the emergency department. Am J Emerg Med 2019; 37:502.

43. Zhao J, Zhang S, Zhang L, et al. Serum procalcitonin levels as a diagnostic marker for septic arthritis: A meta-analysis. Am J Emerg Med 2017; 35:1166.

44. Imagama T, Tokushige A, Seki K, et al. Early diagnosis of septic arthritis using synovial fluid presepsin: A preliminary study. J Infect Chemother 2019; 25:170.

45. Stirling P, Tahir M, Atkinson HD. The Limitations of Gram-stain Microscopy of Synovial Fluid in https://www.uptodate.com/...rch=Bacterial%20arthritis&source=search_result&selectedTitle=3~129&usage_type=default&display_rank=3[19.03.2020 15:39:14] Septic arthritis in adults - UpToDate

Concomitant Septic and Crystal Arthritis. Curr Rheumatol Rev 2018; 14:255.

46. Goldenberg DL. Septic arthritis. Lancet 1998; 351:197.

47. Papanicolas LE, Hakendorf P, Gordon DL. Concomitant septic arthritis in crystal monoarthritis. J Rheumatol 2012; 39:157.

48. Sharff KA, Richards EP, Townes JM. Clinical management of septic arthritis. Curr Rheumatol Rep 2013; 15:332.

49. Thiery JA. Arthroscopic drainage in septic arthritides of the knee: a multicenter study. Arthroscopy 1989; 5:65.

50. Stutz G, Kuster MS, Kleinstück F, Gächter A. Arthroscopic management of septic arthritis: stages of infection and results. Knee Surg Sports Traumatol Arthrosc 2000; 8:270.

51. Sammer DM, Shin AY. Comparison of arthroscopic and open treatment of septic arthritis of the wrist. J Bone Joint Surg Am 2009; 91:1387.

52. Johns BP, Loewenthal MR, Dewar DC. Open Compared with Arthroscopic Treatment of Acute Septic Arthritis of the Native Knee. J Bone Joint Surg Am 2017; 99:499.

53. Hunter JG, Gross JM, Dahl JD, et al. Risk factors for failure of a single surgical debridement in adults with acute septic arthritis. J Bone Joint Surg Am 2015; 97:558.

54. Ho G Jr. How best to drain an infected joint. Will we ever know for certain? J Rheumatol 1993; 20:2001.

55. García-Arias M, Balsa A, Mola EM. Septic arthritis. Best Pract Res Clin Rheumatol 2011; 25:407.

56. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18.

57. Weston VC, Jones AC, Bradbury N, et al. Clinical features and outcome of septic arthritis in a single UK Health District 1982-1991. Ann Rheum Dis 1999; 58:214.

58. Lin WT, Wu CD, Cheng SC, et al. High Prevalence of Methicillin-Resistant Staphylococcus aureus among Patients with Septic Arthritis Caused by Staphylococcus aureus. PLoS One 2015; 10:e0127150.

59. Kang T, Lee JK. Host Factors Affect the Outcome of Arthroscopic Lavage Treatment of Septic Arthritis of the Knee. Orthopedics 2018; 41:e184.

60. Oh DHW, Wurcel AG, Tybor DJ, et al. Increased Mortality and Reoperation Rates After Treatment

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for Septic Arthritis of the Knee in People Who Inject Drugs: Nationwide Inpatient Sample, 2000- 2013. Clin Orthop Relat Res 2018; 476:1557.

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GRAPHICS

Causes of infectious arthritis

Organism Clinical clues

Staphylococcus aureus Healthy adults, skin breakdown, previously damaged joint (eg, rheumatoid arthritis), prosthetic joint

Streptococcal species Healthy adults, splenic dysfunction

Neisseria gonorrhoeae Healthy adults (particularly young, sexually active), associated tenosynovitis, vesicular pustules, late complement deficiency, negative synovial fluid culture and Gram stain

Aerobic gram-negative bacteria Immunocompromised hosts, gastrointestinal infection

Anaerobic gram-negative bacteria Immunocompromised hosts, gastrointestinal infection

Brucellosis Zoonosis

Mycobacterial species Immunocompromised hosts, travel to or residence in an endemic area

Fungal species (Candida species, Immunocompromised hosts sporotrichosis, Cryptococcus, blastomycosis, coccidioidomycosis)

Spirochete (Borellia burgdorferi) Exposure to ticks, antecedent rash, knee joint involvement

Mycoplasma hominis Immunocompromised hosts with prior urinary tract manipulation

Refer to separate UpToDate topic for discussion of viral causes of arthritis.

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Guide to interpretation of synovial fluid analysis

WBC: white blood cell; MSU: monosodium urate; CPPD: calcium pyrophosphate crystal deposition. * Septic arthritis is typically associated with synovial fluid white blood cell counts >20,000 cells/microL, but lower counts may be observed, especially for arthritis due to disseminated gonococcal infection. With most bacterial organisms, particularly Staphylococcus aureus, the synovial fluid white blood cell count is typically >50,000 cells/microL (and often >100,000 cells/microL). ¶ Crystal-induced arthritis may still be considered despite the absence of identified crystals; false-negative results occur, especially with CPPD. Δ If treatment of crystal-induced arthritis does not result in clinical improvement, consider other inflammatory or infectious arthridites.

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Categories of synovial fluid based upon clinical and laboratory findings

Measure Normal Noninflammatory Inflammatory Septic Hemorrhagic

Volume, mL <3.5 Often >3.5 Often >3.5 Often >3.5 Usually >3.5 (knee)

Clarity Transparent Transparent Translucent- Opaque Bloody opaque

Color Clear Yellow Yellow Yellow Red

Viscosity High High Low Variable Variable

White blood cell, <200 0 to 2000 >2000* >20,000¶ Variable per microL

Polymorphonuclear <25 <25 ≥50 ≥75 50 to 75 leukocytes, percent

Culture Negative Negative Negative Often positive Negative

* Inflammatory arthritis may include septic arthritis. ¶ Septic arthritis is typically associated with synovial fluid white blood cell counts >20,000 cells/microL, but lower counts may be observed, especially for arthritis due to disseminated gonococcal infection. With most bacterial organisms, particularly Staphylococcus aureus, the synovial fluid white blood cell count is typically >50,000 cells/microL (and often >100,000 cells/microL).

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Approach to evaluation and management of patients with suspected septic arthritis

This algorithm summarizes an approach to evaluation and management of patients with suspected septic arthritis. Issues r bites are discussed separately (refer to the UpToDate topic on animal bites), as are issues related to septic bursitis (refer t

* Include empiric double gram-negative coverage if Pseudomonas is suspected (refer to the UpToDate topic on septic arthritis for furt ¶ Refer to the UpToDate topic on disseminated gonococcal infection for details on treatment regimens. Δ If crystal analysis is positive, refer to the UpToDate topic on treatment of gout or pseudogout. ◊ In the context of clinical suspicion for lyme arthritis (including relevant epidemiologic exposure), serologic testing for Lyme disease diagnosis and musculoskeletal manifestations of Lyme disease). § The clinical approach in the setting of a positive Gram stain and negative culture depends on individual circumstances. It is advisabl specialist if possible, repeat cultures if applicable, and assess the evidence for the presence of an alternate diagnosis (such as crystal- ¥ If there is high suspicion for disseminated gonococcal infection (eg, tenosynovitis or dermatitis, evidence of urogenital, rectal, or ph treatment for gonococcal infection is reasonable. ‡ The duration of therapy for septic arthritis is tailored to individual clinical circumstances (refer to the UpToDate topic on septic arthr † Administration of antibiotics prior to synovial fluid aspiration may be associated with false-negative culture results; in such cases, ev individual circumstances.

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Differential diagnosis of acute monoarthritis

Infection Tumor

Bacterial Tenosynovial giant cell tumor (formerly pigmented villonodular synovitis)

Fungal Chondrosarcoma

Mycobacterial Osteoid osteoma

Viral Metastatic disease

Spirochete Systemic rheumatic disease

Crystal induced Rheumatoid arthritis

Monosodium urate Spondyloarthritis

Calcium pyrophosphate dihydrate Systemic lupus erythematosus

Hydroxyapatite Sarcoidosis

Calcium oxalate Osteoarthritis

Lipid Erosive variant

Hemarthrosis Intraarticular derangement

Trauma Meniscal tear

Anticoagulation Osteonecrosis

Clotting disorders Fracture Fracture Other Pigmented villonodular synovitis Plant thorn synovitis

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Major causes of inflammatory polyarthritis

Infectious arthritis Bacterial Lyme disease Bacterial endocarditis Viral Other infections

Postinfectious (reactive) arthritis Rheumatic fever Reactive arthritis Enteric infection

Other seronegative spondyloarthritides Ankylosing spondylitis Psoriatic arthritis Inflammatory bowel disease

Rheumatoid arthritis

Inflammatory osteoarthritis

Crystal-induced arthritis

Juvenile idiopathic arthritis

Systemic rheumatic illnesses Systemic lupus erythematosus Systemic vasculitis Systemic sclerosis Polymyositis/dermatomyositis Still's disease Behçet syndrome Relapsing polychondritis Autoinflammatory disorders

Other systemic illnesses Sarcoidosis Palindromic rheumatism Familial Mediterranean fever Malignancy Hyperlipoproteinemias

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Δ ◊

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Oral antimicrobial agents for completing treatment of septic arthritis due to methicillin- resistant Staphylococcus aureus (MRSA) in adults*

Treatment Adult dose

Clindamycin 600 mg orally three times daily

Trimethoprim-sulfamethoxazole (cotrimoxazole) 2 DS tablets orally twice daily (alternatively: 4 mg/kg per dose [trimethoprim component] orally twice daily [maximum 2 DS tablets twice daily])

Doxycycline 100 mg orally twice daily

Minocycline 200 mg orally once, then 100 mg orally twice daily

Linezolid¶ 600 mg orally twice daily

RifampinΔ 300 to 450 mg orally twice daily◊

PLUS

One of the following agents:

Ciprofloxacin 500 to 750 mg twice daily

Fusidic acid (where available)§ 500 mg orally 3 times daily

The doses above are intended for patients with normal renal function; dosing may require adjustment in patients with renal insufficiency.

DS: double strength (ie, 160 mg trimethoprim with 800 mg sulfamethoxazole per tablet). * Following joint drainage, the typical duration of antibiotic therapy for treatment of septic arthritis is three to four weeks; we typically administer parenteral antibiotics for at least 14 days followed by oral therapy for an additional 14 days. If linezolid is used as initial therapy, it may be administered orally for the entire duration given its high oral bioavailability. ¶ The mechanism of action for tedizolid is comparable with that of linezolid; however, thus far there are no data/experience regarding use of tedizolid for treatment of septic arthritis. Δ Patients who cannot take rifampin because of drug resistance, allergy, toxicity, intolerance, or drug-drug interactions should remain on intravenous antistaphylococcal therapy for 4 to 6 weeks (before transitioning to antibiotic suppression with an oral regimen, if warranted). ◊ We favor administration of rifampin 450 orally twice daily; the dose may be reduced to 300 mg orally twice daily in the setting of nausea. § Not available in the United States. Fusidic acid should not be used alone; it must be combined with a second active agent to reduce the likelihood of selection for drug resistance. When rifampin is combined with fusidic acid, fusidic levels may be reduced.

Data from: 1. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014; 59:e10. 2. Liu C, Bayer A, Cosgrove SE, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children. Clin Infect Dis 2011; 52:e18.

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Contributor Disclosures

Don L Goldenberg, MD Nothing to disclose Daniel J Sexton, MD Grant/Research/Clinical Trial Support: Centers for Disease Control and Prevention; National Institutes of Health [Healthcare epidemiology]. Consultant/Advisory Boards: Magnolia Medical Technologies [Medical diagnostics]; National Football League [Infection prevention]; Johnson & Johnson [Mesh-related infections]. Equity Ownership/Stock Options: Magnolia Medical Technologies [Medical diagnostics]. Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

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Contributor Disclosures

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Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Monoarthritis in adults: Etiology and evaluation Contributor Disclosures Author: Simon M Helfgott, MD Section Editor: Robert H Shmerling, MD Deputy Editor: Monica Ramirez Curtis, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Jul 01, 2019.

INTRODUCTION

The symptom of joint pain is associated with a variety of disorders. The initial step in evaluating the patient with monarticular pain is confirming that the source of the pain is the joint, rather than the nearby soft tissues. Arthritis is likely when the pain is aggravated by movement, is associated with loss of motion, and is accompanied by swelling and/or erythema. However, deep-seated articulations, such as the shoulder, hip, and sacroiliac joints, may not exhibit the latter two findings. If joint motion is preserved but tenderness can be elicited by palpation over one of the regional bursae, tendons, or ligaments, it is unlikely that the joint pain is due to arthritis. (See "Bursitis: An overview of clinical manifestations, diagnosis, and management" and "Overview of soft tissue rheumatic disorders".)

In addition to a careful history and physical examination, arthrocentesis and synovial fluid analysis is often required in making a definitive diagnosis. The initial evaluation and differential diagnosis of an adult presenting with a single sore joint is presented here (table 1). The approach to a patient with pain in specific joints is addressed elsewhere (see "Approach to the adult with unspecified knee pain" and "Evaluation of the adult with shoulder complaints" and "Evaluation of elbow pain in adults" and "History and examination of the adult with hand pain" and "Approach to the adult with unspecified hip pain"). The evaluation of a child with joint pain is also presented separately. (See "Evaluation of the child with joint pain and/or swelling".)

ETIOLOGY

The major causes of acute monoarticular symptoms include trauma, infection, crystal-induced arthritis, osteoarthritis, systemic rheumatic diseases, and mechanical derangement (table 1) [1-3]. The differential diagnosis of an acute monoarthritis can also overlap with that of polyarthritis since virtually any polyarthritis disorder can initially present as a monoarthritis (table 2). (See "Evaluation of the adult with polyarticular pain".)

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Trauma — Trauma sufficient to cause joint pain and swelling is typically recollected by the patient. However, if a loss of consciousness (eg, due to a drug overdose, motor vehicle accident, alcohol ingestion, or concussion) has occurred, the patient may not remember injuring the joint. Thus, if there is a history of joint injury or loss of consciousness, initial immobilization and imaging studies to rule out a fracture or dislocation are appropriately obtained before proceeding with a thorough physical examination of the joint.

Intraarticular fractures, dislocations, ligamentous sprains and complete tears (eg, of the anterior or posterior cruciate ligaments of the knee), and meniscal damage are often associated with hemarthrosis. Intraarticular bleeding may also be related to coagulopathies, anticoagulation therapy, intraarticular tumors, and crystal disease, among other causes. (See "Overview of hemarthrosis".)

Infection

Gonococcal infection — Patients with disseminated gonococcal infection (DGI) typically present with one of two syndromes (table 3):

● A triad of tenosynovitis, vesiculopustular skin lesions (picture 1), and polyarthralgias without purulent arthritis ● Purulent arthritis without associated skin lesions

Diagnosis of this disorder is based upon the history, physical examination, synovial fluid culture, blood cultures, and cultures of any skin lesions, the pharynx, urethra, cervix, or rectum. (See "Disseminated gonococcal infection".)

Nongonococcal bacterial infections — Nongonococcal bacterial arthritis is the most potentially dangerous and destructive form of acute monoarthritis. These infections typically affect large joints such as the hip and knee, although the wrists and ankles are also commonly involved [1]. Staphylococcus aureus is the most common bacterium infecting adult joints, followed by Streptococcus pneumoniae and, less often, Gram-negative organisms (table 4). Patients who are immunocompromised, inject drugs intravenously, have a prosthetic joint, or have underlying conditions such as neoplasia, chronic renal failure, or rheumatoid arthritis are more susceptible to these infections. (See "Septic arthritis in adults".)

Mycobacterial and fungal infection — Mycobacterial species and fungi can produce an indolent, progressive monoarthritis [4]. A high index of suspicion is required to establish these diagnoses; immunocompromised status and travel to endemic areas are the primary risk factors. The diagnosis should also be considered if a patient fails to respond to courses of antibiotic therapy or if synovial fluid cultures fail to identify a causative organism. (See "Skeletal tuberculosis" and "Candida osteoarticular infections" and "Clinical features and diagnosis of sporotrichosis".)

Arthritis may represent either an articular infection or a sterile extrapulmonary manifestation of either histoplasmosis or coccidioidomycosis (see "Pathogenesis and clinical features of pulmonary histoplasmosis", section on 'Rheumatologic manifestations'). Arthralgia, usually polyarticular, may accompany the panniculitis of erythema nodosum that can occur with pulmonary infection with these https://www.uptodate.com/...hritis-in-adults-etiology-and-evaluation/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:27] Monoarthritis in adults: Etiology and evaluation - UpToDate

fungal organisms and others. (See "Erythema nodosum".)

Lyme disease — Later stages of Lyme disease include the development of a prominent monoarticular synovitis in approximately 10 percent of patients; the knee is most commonly involved. Clinical difficulties that may arise include the lack of history of a tick bite or an antecedent skin rash. Culture of the synovial fluid or tissue is routinely negative; confirmation of the diagnosis requires serologic testing. (See "Diagnosis of Lyme disease".)

Crystal-induced arthritis — At least 80 percent of initial attacks of acute gout involve a single joint, typically in the lower extremity, most often at the base of the great toe (first metatarsophalangeal joint, known as podagra), at the midfoot, in the ankle, or in the knee. However, the fingers, elbows, and wrists may become inflamed and cause diagnostic confusion.

The typical attack is intensely inflammatory, and is characterized by severe pain, redness, swelling, and disability. The maximal severity of the attack is usually reached over several hours. Complete resolution of the earliest attacks almost inevitably occurs within a few days to weeks, even in untreated individuals. The signs of inflammation associated with acute gout often extend beyond the confines of the joint that is primarily involved and, in the foot or ankles, may give the impression of arthritis in several contiguous joints, of tenosynovitis, or cellulitis. Involvement in an ankle or instep or in a wrist, finger, or olecranon bursa more commonly occurs in a recurrent episode of a gout flare. (See "Clinical manifestations and diagnosis of gout".)

The knee is the most common joint involved in patients with calcium pyrophosphate dihydrate (CPPD) crystals (pseudogout). The wrist, shoulder, ankle, and occasionally smaller joints may also be targets, and bilateral wrist involvement is common in older patients [1]. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

Systemic disorders — Several systemic disorders may present with an acute monoarthritis:

● Seronegative spondyloarthritis (eg, reactive arthritis, psoriatic arthritis, inflammatory bowel disease- associated arthritis) can present as a monoarthritis, typically involving the lower-extremity joints. The effusion may be quite large when the knee is affected, while toe joint involvement can appear as a "sausage" swelling due to the periosteal bone involvement; the latter finding can distinguish these disorders from rheumatoid arthritis (picture 2). (See "Reactive arthritis" and "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults" and "Clinical manifestations and diagnosis of psoriatic arthritis".)

● Sarcoid periarthritis typically presents with pain and swelling around the ankle joints; erythema nodosum over the distal tibial region may be a helpful clue. (See "Sarcoid arthropathy".)

● Rheumatoid arthritis can occasionally present as a monoarthritis in its earliest stages. (See "Clinical manifestations of rheumatoid arthritis".)

● Myelodysplastic and leukemic disorders may cause arthralgia or an acute arthritis. (See "Malignancy https://www.uptodate.com/...hritis-in-adults-etiology-and-evaluation/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:27] Monoarthritis in adults: Etiology and evaluation - UpToDate

and rheumatic disorders", section on 'Leukemia' and "Clinical manifestations and diagnosis of the myelodysplastic syndromes", section on 'Autoimmune abnormalities'.)

Osteoarthritis — Osteoarthritis of a single joint, although usually associated with mild symptoms and a relatively noninflammatory synovial fluid (white blood cell [WBC] <2,000 cells/mm3), can present as an acutely painful synovitis which may mimic infection [5]. (See "Clinical manifestations and diagnosis of osteoarthritis".)

Neoplasms — Juxtaarticular benign and malignant neoplasms or, less often, tumors in the synovium or other soft tissues of the joint may cause monoarticular pain. (See "Radiologic evaluation of knee tumors in adults", section on 'Intraarticular tumors and tumor-like lesions' and "Radiologic evaluation of knee tumors in adults", section on 'Juxtaarticular bone or soft tissue tumor' and "Bone tumors: Diagnosis and biopsy techniques" and "Treatment for tenosynovial giant cell tumor and other benign neoplasms affecting soft tissue and bone", section on 'Desmoplastic fibroma of bone' and "Treatment for tenosynovial giant cell tumor and other benign neoplasms affecting soft tissue and bone", section on 'Tenosynovial giant cell tumor'.)

Plant thorn synovitis — Plant thorn synovitis is a foreign-body granulomatous inflammation that is caused by direct subcutaneous inoculation of plant material. The most common plants reported include rose thorn, black thorn, and date palms. Following initial penetration of the thorn, there may be a mild synovitis that may subside. Over time, the symptoms of pain, stiffness, and joint warmth may bring the patient to medical attention. A high degree of suspicion is required since imaging studies fail to identify the plant thorn [6].

EVALUATION

The history and physical examination often provide sufficient information to eliminate many disorders in the differential diagnosis (table 1).

History — Specific symptoms and/or patient characteristics help narrow the underlying possible causes of monoarticular pain (table 1).

Symptoms suggestive of a musculoskeletal emergency — The evaluation of monoarticular pain begins by ruling out potential musculoskeletal emergencies. These conditions generally have an acute presentation and are important to identify since failure to make the correct diagnosis could lead to permanent harm to the patient. Important historical points include the following [7]:

● Hot or swollen joints may suggest infection. (See "Septic arthritis in adults".)

● Constitutional symptoms (high-grade fever, weight loss, malaise) also raise the suspicion of infection or sepsis.

● Weakness may be a symptom of a compartment syndrome or an acute myelopathy. However, lack

of strength can also be due to pain in the joint or periarticular tissues or myopathy.

● Burning pain, numbness, or paresthesia may suggest an acute myelopathy, radiculopathy, or neuropathy.

Joint symptoms — It is important to obtain a detailed history of the character of the joint pain, including pain quality, time of onset, exacerbating or remitting factors, severity, and duration.

● In most forms of systemic inflammatory arthritis, symptoms may worsen with immobility ("morning stiffness"). However, morning stiffness lasting more than one hour reflects a severity of joint inflammation which rarely occurs in diseases other than rheumatoid arthritis or polymyalgia rheumatica.

● By contrast, the pain of osteoarthritis is usually aggravated by motion and weightbearing and is lessened by rest.

● A history of prior joint pain or swelling (single or multiple, symmetric or asymmetric, migratory or additive, small or large joints) should be ascertained.

● Pain that has been present for weeks is less likely to be acute gout or bacterial arthritis but could be chronic tophaceous gout, a mycobacterial or fungal arthritis, or a spondyloarthritis.

● Antecedent trauma may point towards a fracture, meniscal tear, or hemarthrosis.

Systemic symptoms — The presence of extraarticular symptoms may help to limit the differential diagnosis:

● Signs and symptoms of multisystem involvement (fatigue, rash, adenopathy, alopecia, oral and nasal ulcers, pleuritic chest pain, Raynaud phenomenon, or dry eyes and mouth) are often observed in patients with systemic rheumatic diseases.

● High-grade fever suggests infection, although low-grade elevation in body temperature may accompany crystal-induced arthritis as well as many systemic rheumatic diseases.

● Gastrointestinal or genitourinary complaints and recent sexual exposures suggest possible infectious portals of entry or may be associated with a seronegative spondyloarthritis (eg, reactive arthritis, psoriasis, or inflammatory bowel disease).

Patient characteristics — Specific patient characteristics should also be considered when narrowing the differential diagnosis.

● A family history of some systemic rheumatic diseases (eg, psoriatic arthritis) may predispose the patient to the same conditions.

● A history of immunosuppression, either due to underlying disease or medical therapy, may predispose the patient to unusual infectious agents. (See "Septic arthritis in adults".)

● Recent travel to endemic regions (eg, the Northeastern United States for Lyme disease, developing countries for mycobacterial and parasitic infections) may suggest a specific pathogen.

Physical examination — The most important objective of the physical examination in a patient with monoarticular pain is to establish the presence or absence of an effusion or synovitis [7]. Detecting an effusion or synovitis limits the differential to the inflammatory arthritides (including infection) and systemic rheumatic diseases. The hallmarks of synovitis include:

● Soft tissue swelling ● Warmth over a joint ● Joint effusion

Assessing range of motion of the joint is also important. Reduced active range of motion with preserved passive range of motion suggests soft tissue disorders such as bursitis, tendinitis, or muscle injury (see "Overview of soft tissue rheumatic disorders"). If, on the other hand, both active and passive ranges of motion are decreased, then soft tissue contracture, synovitis, and a structural abnormality of the joint are more likely [7].

Some extraarticular findings may suggest a specific disease process:

● A search for subcutaneous nodules may reveal rheumatoid nodules (picture 3) or tophi (picture 4) suggestive of rheumatoid arthritis or gout, respectively. Erythema nodosum (picture 5), particularly over the shins, may herald an ankle periarthritis that can be seen in some patients with sarcoidosis.

● Particular attention should be given to the skin since some disorders are associated with characteristic rashes (eg, psoriasis, systemic lupus erythematosus, viral exanthems, and adult Still's disease).

● Eye involvement is a feature of some rheumatic illnesses (eg, keratoconjunctivitis sicca, uveitis, conjunctivitis, and episcleritis).

Imaging studies

Radiographs — Patients with a history of significant trauma or focal bone pain should have radiographs to rule out a fracture, tumor, or osteonecrosis [5]. Radiographs may also confirm the presence of a joint effusion, particularly in joints such as the elbow, ankle, and hip, where they may be difficult to ascertain on physical examination. Chondrocalcinosis, tophaceous erosions, or joint space narrowing may also be visible. Soft tissue calcification (or calcific tendonitis) may be noted adjacent to affected joints. (See "Imaging techniques for evaluation of the painful joint", section on 'Radiography' and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

Ultrasonography — Musculoskeletal ultrasound provides a simple technique for the detection of joint effusions, and is more sensitive than physical examination in the detection of synovitis [8,9]. It can also be used to guide joint aspirations and injections. (See "Musculoskeletal ultrasonography: Clinical

applications" and "Musculoskeletal ultrasonography: Guided injection and aspiration of joints and related structures".)

Computed tomography — Computed tomography (CT) should be reserved for the evaluation and proper needle placement for joint aspiration of difficult-to-access areas such as the hip, sacroiliac, or sternoclavicular joints. (See "Imaging techniques for evaluation of the painful joint", section on 'Computed tomography'.)

Magnetic resonance imaging — Magnetic resonance imaging (MRI) is useful for diagnosing effusions in deep-seated joints such as the hips and shoulders, which may be difficult to detect on physical examination. MRI can also be used to distinguish synovitis from ligamentous or other soft tissue injuries or abnormalities. (See "Imaging techniques for evaluation of the painful joint", section on 'Magnetic resonance imaging'.)

Joint aspiration — Arthrocentesis with synovial fluid analysis should be attempted in all patients with joint pain of unknown cause who have an effusion or have signs suggestive of inflammation within the joint [10]. (See "Joint aspiration or injection in adults: Technique and indications".)

The main purpose of synovial fluid analysis is to narrow the differential diagnosis by categorizing the effusion as noninflammatory, inflammatory, hemorrhagic, or septic (table 5). Analysis of the joint fluid should include the following (see "Synovial fluid analysis", section on 'Routine components of synovial fluid analysis'):

● Gross appearance – The volume, clarity, color and viscosity of the joint fluid should be noted. As examples, xanthochromia is suggestive of a recent hemorrhage due to a fracture or other trauma, or a coagulopathy; clear fluid may be normal or relatively noninflammatory; cloudy fluid may be suggestive of inflammatory or septic fluid. (See "Synovial fluid analysis", section on 'Gross appearance'.)

● Crystal analysis – Examination of synovial fluid for monosodium urate crystals (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals with a polarizing microscope should be done to evaluate for gout and pseudogout, respectively. (See "Synovial fluid analysis", section on 'Routine components of synovial fluid analysis'.)

● Nucleated (white) cell count and differential – In normal synovial fluid or in noninflammatory joint effusions, polymorphonuclear (PMN) leukocytes represent a small proportion of the nucleated cells present. Noninflammatory fluids generally have fewer than 2,000 white blood cells/mm3, with fewer than 75 percent PMN leukocytes [11]. Inflammatory and septic fluids have increasing proportions of PMNs present. (See "Synovial fluid analysis", section on 'Nucleated (white) cell count and differential'.)

● Gram stain and culture – If there is a clinical suspicion of joint infection, gram stain and culture of synovial fluid should be requested. Unless there are clinical features that suggest gonococcal, mycobacterial, or fungal infection, routine bacterial culture for aerobic and anaerobic bacteria are https://www.uptodate.com/...hritis-in-adults-etiology-and-evaluation/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:27] Monoarthritis in adults: Etiology and evaluation - UpToDate

generally appropriate. If gonococcal infection is suspected, the microbiology laboratory should be informed so that the appropriate media can be used to improve the yield. (See "Synovial fluid analysis", section on 'Gram stain' and "Microbiology specimen collection and transport" and "Synovial fluid analysis", section on 'Routine components of synovial fluid analysis'.)

Chemistry studies of synovial fluid such as the concentrations of glucose, lactate dehydrogenase, or protein have only limited value; a reduction in glucose concentration and elevation in lactate dehydrogenase (LDH) level are consistent with bacterial infection but are not sufficiently sensitive (table 5). Complement levels and immune complex analysis of synovial fluid are also of limited use and are not generally recommended for diagnostic purposes [11]. (See "Synovial fluid analysis".)

Interpretation of synovial fluid analysis — After a careful history and physical examination of the patient with monoarthritis, the results of the synovial fluid analysis can be interpreted as follows (algorithm 1):

● For hemorrhagic effusions, the clinician should consider trauma, mechanical derangement, or a coagulopathy as possible etiologies.

● Non-hemorrhagic effusions should be classified as either inflammatory or noninflammatory (table 6).

• Synovial fluid with a nucleated (white) cell count <2,000 white blood cells/mm3 is noninflammatory. Examples of conditions associated with noninflammatory synovial fluid include osteoarthritis, avascular necrosis, or a meniscal tear.

• Synovial fluid with a nucleated cell count ≥2,000 white blood cells/mm3 is considered inflammatory. A wide range of conditions are associated with inflammatory synovial fluid such as septic arthritis, crystal-induced arthritis, or a spondyloarthritis. The range of nucleated (white) cell counts that can be observed with each of these conditions overlap considerably [12]. However, the higher the leukocyte count (eg, >10,000/mm3) and the greater the proportion of PMN leukocytes (eg, >90 percent) in the differential, the higher is the likelihood of septic arthritis. (See "Synovial fluid analysis", section on 'Nucleated (white) cell count and differential'.)

● Inflammatory synovial fluid should also be evaluated for crystals (monosodium urate crystals and CPPD crystals) with a polarizing microscope. In cases of suspected septic arthritis, the fluid should also be sent for gram stain and culture as the presence of crystals does not exclude infection.

Laboratory studies — Laboratory studies in addition to imaging studies and synovial fluid analysis should be considered in certain circumstances [7]. The patient with bloody synovial fluid and no evidence of trauma, for example, should have a prothrombin (PT), partial tissue thromboplastin time (PTT), platelet count, and bleeding time. The patient with inflammatory joint fluid should have blood cultures and, in the sexually active patient, cultures of any skin lesions, the pharynx, urethra, cervix, or rectum as appropriate to assess for gonococcal infection. (See "Disseminated gonococcal infection".)

In addition, more extensive laboratory studies should be considered in those with sterile but inflammatory https://www.uptodate.com/...hritis-in-adults-etiology-and-evaluation/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:27] Monoarthritis in adults: Etiology and evaluation - UpToDate

joint fluid (without crystals), including the following:

● The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration are nonspecific indicators of inflammation; they tend to be elevated in the presence of infection, inflammatory states, and malignancy. These tests may be most useful in patients with an equivocal joint examination; in this setting, an elevated ESR or CRP makes an inflammatory arthritis more likely. (See "Acute phase reactants".)

● The antinuclear antibody (ANA) test has high sensitivity but low specificity for systemic lupus erythematosus (SLE). Thus, it may be appropriate to order an ANA, since a negative test essentially rules out a diagnosis of SLE. On the other hand, a positive ANA may occur in the absence of disease and may occur in many rheumatic and non-rheumatic illnesses; therefore, a patient with few or no clinical features of SLE is unlikely to have the disease, even in the presence of a positive ANA. (See "Measurement and clinical significance of antinuclear antibodies".)

● A serum rheumatoid factor (RF) and anticyclic citrullinated peptide (CCP) antibodies should be ordered when there is at least a moderate suspicion of rheumatoid arthritis; however, these tests must be interpreted in clinical context, particularly in the setting of a monoarthritis. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Serology'.)

● Routine tests such as a complete blood count and liver function tests should be considered if a multisystem disease is suspected based upon the history and physical examination.

● Other tests such as human leukocyte antigen (HLA)-B27 and Lyme serologies should be ordered only when the clinical suspicion is high for a spondyloarthritis or Lyme infection, respectively.

Synovial biopsy — In rare instances, the correct diagnosis in a patient with monoarticular arthritis will depend upon a tissue biopsy. Indications for synovial biopsy include refractory monoarthritis, a high degree of suspicion for atypical infectious agents, or evaluation for intraarticular tumors. As an example, synovial biopsy may be useful in the diagnosis of a mycobacterial or fungal infection, or sarcoidosis.

INFORMATION FOR PATIENTS

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by https://www.uptodate.com/...hritis-in-adults-etiology-and-evaluation/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:27] Monoarthritis in adults: Etiology and evaluation - UpToDate

searching on "patient info" and the keyword(s) of interest.)

● Beyond the Basics topics (see "Patient education: Arthritis (Beyond the Basics)")

SUMMARY

● Major causes of monoarthritis include osteoarthritis, Lyme disease, some systemic rheumatic diseases, infection, trauma, and internal derangement (table 1). The differential diagnosis of an acute monoarthritis can also overlap with that of polyarthritis since virtually any polyarthritis disorder can initially present as a monoarthritis (table 2). (See 'Etiology' above.)

● The evaluation of the patient should begin with a detailed history and physical examination to help narrow the underlying possible causes of monoarticular pain. The most important objective of the physical examination is to establish the presence or absence of an effusion or synovitis . (See 'History' above and 'Physical examination' above.)

● Patients with a history of significant trauma or focal bone pain should have plain radiographs of the affected joint to evaluate for fracture or tumor. (See 'Radiographs' above.)

● When an effusion or synovitis is present on physical examination and the cause is uncertain, an arthrocentesis with synovial fluid analysis (algorithm 1) should be strongly considered. The main purpose of the synovial fluid analysis is to narrow the differential diagnosis by categorizing the effusion as noninflammatory, inflammatory, hemorrhagic, or septic. (See 'Joint aspiration' above.)

● For hemorrhagic effusions, the clinician should consider trauma, mechanical derangement, or a coagulopathy as possible etiologies. The patient with hemorrhagic synovial fluid and no evidence of trauma should have a prothrombin (PT), partial tissue thromboplastin time (PTT), platelet count, and bleeding time. (See 'Interpretation of synovial fluid analysis' above.)

● Non-hemorrhagic effusions should be classified as either inflammatory or noninflammatory. Inflammatory synovial fluid (eg, >2,000 white cells/mm3) should also be evaluated for crystals (monosodium urate crystals and calcium pyrophosphate dihydrate [CPPD] crystals) with a polarizing microscope to rule out crystal-induced arthritis. In cases of suspected septic arthritis, the fluid should also be sent for gram stain and culture, as the presence of crystals does not exclude infection. (See 'Interpretation of synovial fluid analysis' above.)

● A sterile inflammatory joint fluid that is also without crystals raises the suspicion of systemic rheumatic diseases; such patients should have further evaluation that may include a complete blood count, liver function tests, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), rheumatoid factor (RF), anticyclic citrullinated peptide (CCP), human leukocyte antigen (HLA)-B27 antibodies, antinuclear antibodies (ANA), or Lyme serologies. (See 'Laboratory studies' above.)

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REFERENCES

1. Sack K. Monarthritis: differential diagnosis. Am J Med 1997; 102:30S.

2. Ma L, Cranney A, Holroyd-Leduc JM. Acute monoarthritis: what is the cause of my patient's painful swollen joint? CMAJ 2009; 180:59.

3. Siva C, Velazquez C, Mody A, Brasington R. Diagnosing acute monoarthritis in adults: a practical approach for the family physician. Am Fam Physician 2003; 68:83.

4. Louie JS, Bocanegra TS. Mycobacterial, Brucella, fungal and parasitic arthritides. In: Rheumatology , Hochberg MC, Silman AJ, Smolen JS, et al (Eds), Mosby, St. Louis 2003. p.1077.

5. Mohana-Borges AV, Chung CB, Resnick D. Monoarticular arthritis. Radiol Clin North Am 2004; 42:135.

6. Tung CH, Chen YH, Lan HH, et al. Diagnosis of plant-thorn synovitis by high-resolution ultrasonography: a case report and literature review. Clin Rheumatol 2007; 26:849.

7. Guidelines for the initial evaluation of the adult patient with acute musculoskeletal symptoms. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996; 39:1.

8. Wakefield RJ, Green MJ, Marzo-Ortega H, et al. Should oligoarthritis be reclassified? Ultrasound reveals a high prevalence of subclinical disease. Ann Rheum Dis 2004; 63:382.

9. Szkudlarek M, Narvestad E, Klarlund M, et al. Ultrasonography of the metatarsophalangeal joints in rheumatoid arthritis: comparison with magnetic resonance imaging, conventional radiography, and clinical examination. Arthritis Rheum 2004; 50:2103.

10. Gatter RA, Schumacher HR Jr. Joint aspiration: Indications and technique. In: A Practical Handboo k of Synovial Fluid Analysis, Gatter RA, Schumacher HR Jr (Eds), Lea and Febiger, Philadelphia 19 91. p.14.

11. Shmerling RH, Delbanco TL, Tosteson AN, Trentham DE. Synovial fluid tests. What should be ordered? JAMA 1990; 264:1009.

12. McCutchan HJ, Fisher RC. Synovial leukocytosis in infectious arthritis. Clin Orthop Relat Res 1990; :226.

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GRAPHICS

Differential diagnosis of acute monoarthritis

Infection Tumor

Bacterial Tenosynovial giant cell tumor (formerly pigmented villonodular synovitis)

Fungal Chondrosarcoma

Mycobacterial Osteoid osteoma

Viral Metastatic disease

Spirochete Systemic rheumatic disease

Crystal induced Rheumatoid arthritis

Monosodium urate Spondyloarthritis

Calcium pyrophosphate dihydrate Systemic lupus erythematosus

Hydroxyapatite Sarcoidosis

Calcium oxalate Osteoarthritis

Lipid Erosive variant

Hemarthrosis Intraarticular derangement

Trauma Meniscal tear

Anticoagulation Osteonecrosis

Clotting disorders Fracture Fracture Other Pigmented villonodular synovitis Plant thorn synovitis

Graphic 62597 Version 5.0

Major causes of inflammatory polyarthritis

Infectious arthritis Bacterial Lyme disease Bacterial endocarditis Viral Other infections

Postinfectious (reactive) arthritis Rheumatic fever Reactive arthritis Enteric infection

Other seronegative spondyloarthritides Ankylosing spondylitis Psoriatic arthritis Inflammatory bowel disease

Rheumatoid arthritis

Inflammatory osteoarthritis

Crystal-induced arthritis

Juvenile idiopathic arthritis

Other systemic illnesses Sarcoidosis Palindromic rheumatism Familial Mediterranean fever Malignancy Hyperlipoproteinemias

Graphic 74266 Version 7.0

Major symptoms and signs of disseminated gonococcal infection

Symptom or sign Percentage of patients

Migratory polyarthralgia 70

Tenosynovitis 67

Dermatitis 67

Fever 63

Purulent arthritis 42

One joint 32 More than one joint 10 Genitourinary symptoms 25

Adapted from: O'Brien, JP, Goldenberg, DL, Rice, PA, Medicine 1983; 62:395.

Graphic 56577 Version 1.0

Skin lesions in disseminated gonococcal infection

Typical small pustular skin lesion in a patient with disseminated gonococcal infection.

Courtesy of Don L Goldenberg, MD.

Graphic 71303 Version 3.0

Causes of infectious arthritis

Organism Clinical clues

Staphylococcus aureus Healthy adults, skin breakdown, previously damaged joint (eg, rheumatoid arthritis), prosthetic joint

Streptococcal species Healthy adults, splenic dysfunction

Neisseria gonorrhoeae Healthy adults (particularly young, sexually active), associated tenosynovitis, vesicular pustules, late complement deficiency, negative synovial fluid culture and Gram stain

Aerobic gram-negative bacteria Immunocompromised hosts, gastrointestinal infection

Anaerobic gram-negative bacteria Immunocompromised hosts, gastrointestinal infection

Brucellosis Zoonosis

Mycobacterial species Immunocompromised hosts, travel to or residence in an endemic area

Fungal species (Candida species, Immunocompromised hosts sporotrichosis, Cryptococcus, blastomycosis, coccidioidomycosis)

Spirochete (Borellia burgdorferi) Exposure to ticks, antecedent rash, knee joint involvement

Mycoplasma hominis Immunocompromised hosts with prior urinary tract manipulation

Refer to separate UpToDate topic for discussion of viral causes of arthritis.

Graphic 57688 Version 10.0

Sausage toe in reactive arthritis

Sausage toe (with diffuse swelling) of the second digit and mild keratoderma blenorrhagica on the dorsum of the foot in a man with reactive arthritis (formerly Reiter's syndrome).

Courtesy of Craig Wiesenhutter, MD and David Yu, MD.

Graphic 61696 Version 1.0

Rheumatoid nodules

Rheumatoid nodules are firm, nontender lesions that typically occur in areas of trauma in individuals with rheumatoid arthritis. Nodules are present near the elbows in this patient.

Graphic 74194 Version 4.0

Inflamed gouty tophi

Gout is a disorder of urate metabolism that leads to high levels of uric acid and the formation of urate crystals. Urate crystals can be deposited under the skin, in joints, and within tendon sheaths as gouty tophi, which can cause an intense inflammatory process. Panel A demonstrates the clinical appearance of gouty tophi. Panel B illustrates the radiographic appearance of gouty tophi. Note the multiple juxta-articular, punched-out lytic erosions (red circles) and a lack of osteoporosis, which is characteristic of gout.

Graphic 74050 Version 4.0

Erythema nodosum

Erythematous nodules on the lower leg.

Graphic 108926 Version 2.0

Categories of synovial fluid based upon clinical and laboratory findings

Measure Normal Noninflammatory Inflammatory Septic Hemorrhagic

Volume, mL <3.5 Often >3.5 Often >3.5 Often >3.5 Usually >3.5 (knee)

Clarity Transparent Transparent Translucent- Opaque Bloody opaque

Color Clear Yellow Yellow Yellow Red

Viscosity High High Low Variable Variable

White blood cell, <200 0 to 2000 >2000* >20,000¶ Variable per microL

Polymorphonuclear <25 <25 ≥50 ≥75 50 to 75 leukocytes, percent

Culture Negative Negative Negative Often positive Negative

Graphic 76506 Version 11.0

Guide to interpretation of synovial fluid analysis

Graphic 111452 Version 2.0

3 3 9

Contributor Disclosures

Simon M Helfgott, MD Nothing to disclose Robert H Shmerling, MD Consultant/Advisory Board: Knowyourmeds [Advise on matters relating to the Company’s business, technology and products]. Monica Ramirez Curtis, MD, MPH Nothing to disclose

Conflict of interest policy

Examples of inflammatory versus noninflammatory arthritis

Noninflammatory: <2000 WBC per mm3 (2 x Inflammatory: >2000 WBC per mm3 109 per L)

Osteoarthritis Septic arthritis*

Trauma Crystal-induced monoarthritis (eg, gout, pseudogout)

Avascular necrosis Rheumatoid arthritis and juvenile idiopathic arthritis

Charcot's arthropathy Spondyloarthritis

Hemochromatosis Systemic lupus erythematosus

Pigmented villonodular synovitis Lyme disease

WBC: white blood cell. * Synovial fluid analysis in patients with septic arthritis often shows more than 90% polymorphonuclear neutrophilic leukocytes.

Reprinted with permission from Diagnosing Acute Monoarthritis in Adults: A Practical Approach for the Family Physician, July 1, 2003, Vol 68, No 1, American Family Physician. Copyright © 2003 American Academy of Family Physicians. All Rights Reserved.

Graphic 101008 Version 4.0

Contributor Disclosures

Conflict of interest policy

Contributor Disclosures

Conflict of interest policy

https://www.uptodate.com/...hritis-in-adults-etiology-and-evaluation/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:27] Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis - UpToDate

Authors: Elie Berbari, MD, FIDSA, Larry M Baddour, MD, FIDSA, FAHA, Antonia F Chen, MD, MBA Section Editor: Denis Spelman, MBBS, FRACP, FRCPA, MPH Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Sep 16, 2019.

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) or total knee arthroplasties (TKAs) are performed in the United States each year. It is estimated that, by 2030, nearly two million THAs or TKAs will be performed in the United States annually [9].

The risk of PJI is greater for knee arthroplasty than 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.

PJI rates appear to be declining. 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]. In another cohort including more than 679,000 patients in the United https://www.uptodate.com/...y-clinical-manifestations-and-diagnosis/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:43] Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis - UpToDate

Kingdom who underwent primary TKA between 2003 and 2013, the infection rate was 0.5 percent [15].

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 [16].

Risk factors — Risk factors for PJI include [1,17-24]:

● 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 [25]

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 [26]. There is considerable overlap between early- and delayed-onset PJIs, and 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 [27]. (See "Staphylococcus lugdunensis".)

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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 [28-30]. Cutibacterium avidum has been observed as a cause of hip PJI, and colonization of the groin in obese patients may be a risk factor for hip PJI [31,32]. (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 "Skeletal 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 [33]. In general, cultures are commonly positive in the setting of early-onset PJI, but frequently negative in patients who present indolently with a loose, painful prosthesis. Cultures may be negative if insufficient tissue is sent for culture or if only swabs are obtained. In addition, antibiotic administration prior to culture collection diminishes culture yield [1,34]. In some cases, "culture-negative" PJI may be attributable to small colony variants of staphylococci, due to slow growth of these variants [35]. Fastidious pathogens associated with culture- negative PJI include Coxiella burnetii, brucellosis, bartonellosis, mycoplasma, mycobacteria, and fungi [36].

Biofilm — Presence of orthopedic hardware enhances susceptibility to infection due to formation of a biofilm [37,38]. 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 [39,40].

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 [39].

The microenvironment within a biofilm may adversely affect antimicrobial mechanisms, and diffusion of antimicrobial agents through biofilm may be limited or slow [40]. Soon after a biofilm is established, the susceptibility of bacteria to antimicrobial agents often demonstrates a logarithmic decline [41]. 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).

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, and 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 [3]. 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) [42,43]. (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) [44]. 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 [45]. 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 [46].

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 [47]. 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 [48].

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) [5].

The diagnosis of PJI can be challenging because the definition is not standardized; a number of diagnostic criteria have been proposed, including the 2018 International Consensus Meeting (ICM) criteria, the 2013 ICM criteria, the 2013 Infectious Disease Society of America guidelines, and the 2011 Musculoskeletal Infection Society (MSIS) criteria (table 2) [4-8]. We favor the MSIS 2011 diagnostic criteria, which are used most widely. (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 [2]. 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 [4,5] (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 culture due to an organism of relatively low virulence (such as Staphylococcus epidermidis, 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 Gram stain or tissue biopsy).

Findings suggestive of PJI include prosthesis with surrounding purulence and histopathologic examination of periprosthetic tissue demonstrating acute inflammation [5]. 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) [1-3]. Less commonly used serum markers that may warrant further study include D- dimer, procalcitonin, and interleukin-6 [49]. (See 'Serum inflammatory markers' below.)

● Routine synovial fluid analysis consists of cell count with differential, Gram stain, aerobic and

anaerobic culture, and crystal analysis [4,5,42]. Less commonly used synovial fluid markers that may warrant further study include alpha-defensin, leukocyte esterase, and CRP [50]. (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) [49]. (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 [4,5,42]. If feasible, antimicrobial therapy should be withheld for at least two weeks prior to collecting specimens for culture [34].

Knee and shoulder joint aspiration often can be performed at the bedside; hip joint aspiration frequently 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 [51].

Synovial fluid should be sent for cell count with differential, Gram stain, aerobic and anaerobic culture, and crystal analysis [4,5,42]. Mycobacterial and fungal cultures should be submitted for patients with chronic, indolent, or refractory infection; previously culture-negative infection; or immunosuppression [2,52].

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) should be sent for culture; swabs from the sinus tract should be not be sent given discordance with deep cultures [42,53]. In patients with fever or other systemic manifestations of infection, blood cultures (two sets) should be obtained.

Intraoperative evaluation — Intraoperative purulence 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. The

samples should be sent for culture (aerobic and anaerobic) and frozen section histology; tissue Gram stain need not be sent routinely (it has high specificity but low sensitivity for diagnosis of PJI) [54-56]. Inoculation of periprosthetic tissues into blood culture bottles has been associated with higher sensitivity compared with cultures using conventional plates and broth media [57-59]. (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 [42].

Mycobacterial and fungal cultures should be submitted for patients with chronic, indolent, or refractory infection; previously culture-negative infection; or immunosuppression [2,52].

If the prosthesis is explanted, sonication (eg, to dislodge biofilm) may be performed, followed by culture of sonication fluid. (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) [4,5]. (See 'Clinical approach' above.)

A single positive culture with a virulent organism (such as S. aureus) may also represent PJI [60]. 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 high sensitivity and specificity for diagnosis of PJI (72 and 95 percent, respectively, in one systematic review) [61]. The sensitivity of periprosthetic tissue culture is variable (65 to 94 percent) [42,62]. Use of saline irrigation to obtain cultures may reduce the culture specificity [63].

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, Gram stain, aerobic and anaerobic culture, and crystal analysis [4,5,42]. Less commonly used synovial fluid markers that may warrant further study include synovial fluid alpha-defensin, leukocyte esterase, and CRP [50].

For cases in which a definitive diagnosis of PJI cannot be made, 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. In the setting of early-onset PJI, the synovial fluid cell count is often >10,000 cells/microL (>90 percent neutrophils). In the setting of delayed- and late-onset PJI, the synovial fluid cell count is often >3000 cells/microL (80 percent neutrophils).

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) [4-8]. We favor the MSIS 2011 diagnostic criteria, which are used most widely. 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 use of alpha-defensin and synovial fluid leukocyte esterase, which are not routinely available.

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) [43,63- 68]. 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) [69]. 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 [70] (based on the 2014 International Consensus Group definition) [6]. An 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 [71].

Serum inflammatory markers — Routine serum inflammatory markers include ESR and CRP [1-3]; less commonly used serum markers that may warrant further study include D-dimer, procalcitonin, and interleukin-6 [49].

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 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) [4-8]. 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 [72]. 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, sensitivity and specificity of ESR and CRP for diagnosis of PJI were 75 and 88 percent and 70 and 74 percent, respectively [49]. Combined use of ESR and CRP has been associated with sensitivity of 96 percent [66,73]; 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 infection due to pathogens of low virulence, prior antibiotic use, and immunosuppression [3].

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 diagnosis of PJI [2].

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 [74]. 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 studies 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 [5].

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 [75]. 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 [76]. 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 [77]. 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 https://www.uptodate.com/...y-clinical-manifestations-and-diagnosis/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:43] Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis - UpToDate

only with implants that are safe for this modality, such as those composed of titanium or tantalum [42]. 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 [76].

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) [1-3]. In one meta-analysis, histopathology had a pooled diagnostic odds ratio of 54.7 (95% CI 31.2-95.7) for diagnosis of PJI [55]; however, sensitivity of the test is limited (18 to 67 percent) [78-83].

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. In addition to aerobic and anaerobic cultures, mycobacterial and fungal cultures should be submitted [2,52]. 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) [84,85].

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

Sonication of an explanted prosthesis can improve the yield of microbiologic diagnosis compared with tissue culture, especially in the setting of perioperative antibiotics [86,87]. In one meta-analysis including 12 studies, pooled sensitivity and specificity were 80 and 95 percent, respectively [87]. Sonication is not routinely available in many microbiology laboratories; vortexing an explanted prosthesis is a reasonable alternative [88].

Nucleic acid amplification tests may be useful when routine cultures are negative and clinical suspicion for PJI is high [89-94]. Many of these assays are based on detection of 16S rRNA gene(s) using a variety of polymerase chain reaction (PCR) techniques to evaluate sonicate fluid, synovial fluid, and joint tissue [95]. The results must be interpreted carefully and correlated with Gram stains and clinical and epidemiologic findings, since small amounts of contaminating bacterial material can lead to a false- positive result [92]. Metagenomic shotgun sequencing is a novel method under development for extracting, sequencing, and identifying nucleic acid as an alternative to PCR [96].

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 "Clinical manifestations and diagnosis of Q fever" and "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".)

INFORMATION FOR PATIENTS

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.)

● Beyond the Basics topic (see "Patient education: Joint infection (Beyond the Basics)")

SUMMARY

● 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. 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. (See 'Epidemiology' above.)

● 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.)

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

• Patients with early-onset infection 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.

• Patients with delayed-onset infection 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.

• Patients with late-onset infection typically present with acute onset of systemic symptoms associated with bacteremia, together with joint pain in a previously well-functioning joint. https://www.uptodate.com/...y-clinical-manifestations-and-diagnosis/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:43] Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis - UpToDate

● 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 of PJI can be challenging because the definition is not standardized; a number of diagnostic criteria have been proposed (table 2). (See 'Clinical approach' above.)

● The diagnosis of PJI may be established in any of the following circumstances (see 'Clinical approach' above):

• 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)

● 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). Thereafter, 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, Gram stain, aerobic and anaerobic culture, and crystal analysis. 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.)

● 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. The approach to interpretation of synovial fluid analysis depends in part on the timing of clinical presentation. The interpretation of synovial fluid parameters in the context of other clinical factors has not been standardized; we favor the Musculoskeletal Infection Society 2011 diagnostic criteria, which are used most widely (table 2). (See 'Clinical approach' above and 'Synovial fluid analysis' above.)

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REFERENCES

1. Beam E, Osmon D. Prosthetic Joint Infection Update. Infect Dis Clin North Am 2018; 32:843.

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51. Li R, Lu Q, Chai W, et al. Saline Solution Lavage and Reaspiration for Culture with a Blood Culture System Is a Feasible Method for Diagnosing Periprosthetic Joint Infection in Patients with Insufficient Synovial Fluid. J Bone Joint Surg Am 2019; 101:1004.

52. Wadey VM, Huddleston JI, Goodman SB, et al. Use and cost-effectiveness of intraoperative acid- fast bacilli and fungal cultures in assessing infection of joint arthroplasties. J Arthroplasty 2010; 25:1231.

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57. Bémer P, Léger J, Tandé D, et al. How Many Samples and How Many Culture Media To Diagnose a Prosthetic Joint Infection: a Clinical and Microbiological Prospective Multicenter Study. J Clin Microbiol 2016; 54:385.

58. Minassian AM, Newnham R, Kalimeris E, et al. Use of an automated blood culture system (BD BACTEC™) for diagnosis of prosthetic joint infections: easy and fast. BMC Infect Dis 2014; 14:233.

59. Peel TN, Dylla BL, Hughes JG, et al. Improved Diagnosis of Prosthetic Joint Infection by Culturing Periprosthetic Tissue Specimens in Blood Culture Bottles. mBio 2016; 7:e01776.

60. Saleh A, Guirguis A, Klika AK, et al. Unexpected positive intraoperative cultures in aseptic revision arthroplasty. J Arthroplasty 2014; 29:2181.

61. Qu X, Zhai Z, Wu C, et al. Preoperative aspiration culture for preoperative diagnosis of infection in total hip or knee arthroplasty. J Clin Microbiol 2013; 51:3830.

62. Pandey R, Berendt AR, Athanasou NA. Histological and microbiological findings in non-infected and infected revision arthroplasty tissues. The OSIRIS Collaborative Study Group. Oxford Skeletal Infection Research and Intervention Service. Arch Orthop Trauma Surg 2000; 120:570.

63. Ali F, Wilkinson JM, Cooper JR, et al. Accuracy of joint aspiration for the preoperative diagnosis of infection in total hip arthroplasty. J Arthroplasty 2006; 21:221.

64. Schinsky MF, Della Valle CJ, Sporer SM, Paprosky WG. Perioperative testing for joint infection in patients undergoing revision total hip arthroplasty. J Bone Joint Surg Am 2008; 90:1869.

65. Ghanem E, Parvizi J, Burnett RS, et al. Cell count and differential of aspirated fluid in the diagnosis of infection at the site of total knee arthroplasty. J Bone Joint Surg Am 2008; 90:1637.

66. Parvizi J, Ghanem E, Sharkey P, et al. Diagnosis of infected total knee: findings of a multicenter database. Clin Orthop Relat Res 2008; 466:2628.

67. Zmistowski B, Restrepo C, Huang R, et al. Periprosthetic joint infection diagnosis: a complete understanding of white blood cell count and differential. J Arthroplasty 2012; 27:1589.

68. Chalmers PN, Sporer SM, Levine BR. Correlation of aspiration results with periprosthetic sepsis in revision total hip arthroplasty. J Arthroplasty 2014; 29:438.

69. Zahar A, Lausmann C, Cavalheiro C, et al. How Reliable Is the Cell Count Analysis in the Diagnosis of Prosthetic Joint Infection? J Arthroplasty 2018; 33:3257.

70. Bonanzinga T, Zahar A, Dütsch M, et al. How Reliable Is the Alpha-defensin Immunoassay Test for Diagnosing Periprosthetic Joint Infection? A Prospective Study. Clin Orthop Relat Res 2017; 475:408.

71. Suen K, Keeka M, Ailabouni R, Tran P. Synovasure 'quick test' is not as accurate as the laboratory- based α-defensin immunoassay: a systematic review and meta-analysis. Bone Joint J 2018; 100- B:66.

72. Honsawek S, Deepaisarnsakul B, Tanavalee A, et al. Relationship of serum IL-6, C-reactive protein, erythrocyte sedimentation rate, and knee skin temperature after total knee arthroplasty: a prospective study. Int Orthop 2011; 35:31.

73. McArthur BA, Abdel MP, Taunton MJ, et al. Seronegative infections in hip and knee arthroplasty: periprosthetic infections with normal erythrocyte sedimentation rate and C-reactive protein level. Bone Joint J 2015; 97-B:939.

74. Tigges S, Stiles RG, Roberson JR. Appearance of septic hip prostheses on plain radiographs. AJR Am J Roentgenol 1994; 163:377.

75. Smith SL, Wastie ML, Forster I. Radionuclide bone scintigraphy in the detection of significant complications after total knee joint replacement. Clin Radiol 2001; 56:221.

76. Censullo A, Vijayan T. Using Nuclear Medicine Imaging Wisely in Diagnosing Infectious Diseases. Open Forum Infect Dis 2017; 4:ofx011.

77. Kwee TC, Kwee RM, Alavi A. FDG-PET for diagnosing prosthetic joint infection: systematic review and metaanalysis. Eur J Nucl Med Mol Imaging 2008; 35:2122.

78. Fehring TK, McAlister JA Jr. Frozen histologic section as a guide to sepsis in revision joint arthroplasty. Clin Orthop Relat Res 1994; :229.

79. Abdul-Karim FW, McGinnis MG, Kraay M, et al. Frozen section biopsy assessment for the presence of polymorphonuclear leukocytes in patients undergoing revision of arthroplasties. Mod Pathol 1998; 11:427.

80. Della Valle CJ, Bogner E, Desai P, et al. Analysis of frozen sections of intraoperative specimens obtained at the time of reoperation after hip or knee resection arthroplasty for the treatment of infection. J Bone Joint Surg Am 1999; 81:684.

81. Musso AD, Mohanty K, Spencer-Jones R. Role of frozen section histology in diagnosis of infection during revision arthroplasty. Postgrad Med J 2003; 79:590.

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Topic 7664 Version 36.0

GRAPHICS

American Society of Anesthesiologists (ASA) Physical Status Classification System

ASA PS Examples, including, but not limited Definition classification to:

ASA I A normal healthy patient. Healthy, non-smoking, no or minimal alcohol use.

ASA II A patient with mild systemic disease. Mild diseases only without substantive functional limitations. Current smoker, social alcohol drinker, pregnancy, obesity (30

ASA III A patient with severe systemic disease. Substantive functional limitations; one or more moderate to severe diseases. Poorly controlled DM or HTN, COPD, morbid obesity (BMI ≥40), active hepatitis, alcohol dependence or abuse, implanted pacemaker, moderate reduction of ejection fraction, ESRD undergoing regularly scheduled dialysis, premature infant PCA<60 weeks, history (>3 months) of MI, CVA, TIA, or CAD/stents.

ASA IV A patient with severe systemic disease that is a Recent (<3 months) MI, CVA, TIA, or constant threat to life. CAD/stents, ongoing cardiac ischemia or severe valve dysfunction, severe reduction of ejection fraction, sepsis, DIC, ARDS, or ESRD not undergoing regularly scheduled dialysis.

ASA V A moribund patient who is not expected to Ruptured abdominal/thoracic aneurysm, survive without the operation. massive trauma, intracranial bleed with mass effect, ischemic bowel in the face of significant cardiac pathology or multiple organ/system dysfunction.

ASA VI A declared brain-dead patient whose organs are being removed for donor purposes.

The addition of "E" to the numerical status (eg, IE, IIE, etc.) denotes Emergency surgery (an emergency is defined as existing when delay in treatment of the patient would lead to a significant increase in the threat to life or body part).

BMI: body mass index; DM: diabetes mellitus; HTN: hypertension; COPD: chronic obstructive pulmonary disease; ESRD: end- stage renal disease; PCA: post conceptual age; MI: myocardial infarction; CVA: cerebrovascular accident; TIA: transient ischemic attack; CAD: coronary artery disease; DIC: disseminated intravascular coagulation; ARDS: acute respiratory distress syndrome.

Graphic 87504 Version 8.0

[1]

Proposed definitions for prosthetic joint infection (PJI)

2011 Musculoskeletal Infection Society (MSIS) criteria[1]

PJI is present when one major criteria exist or four out of six minor criteria exist

Major criteria: Two positive periprosthetic cultures with phenotypically identical organisms A sinus tract communicating with the joint

Minor criteria: Elevated CRP and ESR Elevated synovial fluid WBC count or ++ change on leukocyte esterase test strip Elevated synovial fluid PMN% Presence of purulence in the affected joint Positive histologic analysis of periprosthetic tissue A single positive culture

2013 International Consensus Meeting criteria[2]

PJI is present when one major criteria exist or three out of five minor criteria exist

Major criteria: Two positive periposthetic cultures with phenotypically identical organisms A sinus tract communicating with the joint

Minor criteria: Elevated CRP and ESR Elevated synovial fluid WBC count or ++ changed on leukocyte esterase test strip Elevated synovial fluid PMN% Positive histologic analysis of periprosthetic tissue A single positive culture

2013 Infectious Disease Society of America guidelines[3]

PJI is present when one of the following criteria exist: Sinus tract communicating with prosthesis Presence of purulence Acute inflammation on histopathologic evaluation of periprosthetic tissue Two or more positive cultures with same organism (intraoperatively and/or preoperatively) Single positive cultue with virulent organism

2018 International Consensus Meeting criteria[4]

Major criteria (at least one of the following) Decision

Two positive cultures of the same organism Infected Sinus tract with evidence of communication to the joint or visualization of the prosthesis

Preoperative diagnosis

Minor criteria Score Decision

Serum ≥6 = Infected

Elevated CRP OR D-Dimer 2 2 to 5 = Possibly infected* 0 to 1 = Not infected Elevated ESR 1

Synovial fluid

Elevated synovial WBC count OR leukocyte esterase 3

Positive alpha-defensin 3

Elevated synovial PMN% 2

Elevated synovial CRP 1

Intraoperative diagnosis

Inconclusive preoperative score OR dry tap* Score Decision

Preoperative score – ≥6 = Infected ¶ Positive histology 3 4 to 5 = Inconclusive ≤3 = Not infected Purulence 3

Single positive culture 2

The most commonly used diagnostic criteria are the MSIS 2011 diagnostic criteria. The International Consensus Meeting 2018 diagnostic criteria proposed a score-based definition for PJI with inclusion of synovial fluid parameters as minor criteria; however, these criteria include use of alpha-defensin and synovial fluid leukocyte esterase, which are not routinely available.

CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; WBC: white blood cell; PMN%: polymorphonuclear neutrophils percentage. * For patients with inconclusive minor criteria, operative criteria can also be used to fulfill definition for PJI. ¶ Consider further molecular diagnostics such as next-generation sequencing.

References: 1. Parvizi J, Zmistowski B, Berbari EF, et al. New definition for periprosthetic joint infection: from the Workgroup of the Musculoskeletal Infection Society. Clin Orthop Relat Res 2011; 469:2992. 2. Parvizi J, Gehrke T, Chen AF. Proceedings of the International Consensus Meeting on Periprosthetic Joint Infection. Bone Joint J 2013; 95:1450. 3. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013; 56:e1. 4. Original figure modified for this publication. From: Parvizi J, Tan TL, Goswami K, et al. The 2018 Definition of Periprosthetic Hip and Knee Infection: An Evidence-Based and Validated Criteria. J Arthroplasty 2018; 33:1309. Table used with the permission of Elsevier Inc. All rights reserved.

Graphic 121743 Version 2.0

Contributor Disclosures

Elie Berbari, MD, FIDSA Grant/Research/Clinical Trial Support: Pfizer [Spine infection (Staphylococcus aureus vaccine to prevent SSI after spinal surgery)]. Larry M Baddour, MD, FIDSA, FAHA Consultant/Advisory Boards: Boston Scientific [Cardiovascular device infection (Subcutaneous implantable cardioverter-defibrillator)]. Antonia F Chen, MD, MBA Equity ownership/Stock Options: Joint Purification Systems; Sonoran; Irrimax; Graftworx [Total joint arthroplasty infection (Wound debridement and cleaning system)]. Grant/Research/Clinical Trial Support: Halyard [Knee osteoarthritis, hip osteoarthritis (Cooled radiofrequency treatment)]. Consultant/Advisory Boards: ACI; bOne; DJO; Stryker; Zimmer; American Medical Foundation; Halyard; Pfizer; 3M; Convatec; Recro; DePuy; Heraeus [Product development, periprosthetic joint infection (Total knee arthroplasty implants)]. Other Financial Interest: SLACK Incorporated [Royalty payments for books]. Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Conflict of interest policy

Contributor Disclosures

Conflict of interest policy

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Prosthetic joint infection: Treatment Contributor Disclosures Authors: Elie Berbari, MD, FIDSA, Larry M Baddour, MD, FIDSA, FAHA, Antonia F Chen, MD, MBA Section Editor: Denis Spelman, MBBS, FRACP, FRCPA, MPH Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Feb 28, 2020.

INTRODUCTION

Goals for management of prosthetic joint infection (PJI) include alleviation of symptoms and restoration of function [1-5].

Issues related to treatment of PJI will be reviewed here. Issues related to the epidemiology, clinical manifestations, diagnosis, and prevention of PJIs are discussed separately. (See "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Prevention of prosthetic joint and other types of orthopedic hardware infection".)

Issues related to osteomyelitis are discussed separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis" and "Osteomyelitis in adults: Treatment".)

CLINICAL APPROACH

Overview — In general, management of PJIs consists of surgery and antimicrobial therapy. The approach depends on the timing and microbiology of infection, condition of the joint and implant, quality of the soft tissue envelope, and individual patient circumstances.

Whenever possible, initiation of antibiotic therapy should be delayed until specimens for culture are obtained (via joint aspiration, joint debridement, and/or hardware removal).

Surgical options include debridement and retention of prosthesis, resection arthroplasty with reimplantation (in one or two stages), resection arthroplasty with no reimplantation, or amputation. The choice of surgical approach is based on data from cohort studies [1].

Patients with a well-fixed prosthesis with no sinus tract within approximately 30 days of prosthesis implantation or <3 weeks of symptom onset may be candidates for debridement and retention of prosthesis, followed by systemic antibiotic therapy guided by the microbiology of the infection [1]. (See

https://www.uptodate.com/...ents/prosthetic-joint-infection-treatment/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:52] Prosthetic joint infection: Treatment - UpToDate

'Debridement and retention of prosthesis' below.)

Patients who do not meet criteria for debridement and retention of prosthesis may be considered for resection arthroplasty with reimplantation (in one or two stages) (see 'Resection arthroplasty with reimplantation' below):

● One-stage exchange arthroplasty consists of prosthesis resection with debridement of the soft tissue and bone, patient redraping (as if performing a new surgical procedure, with different instruments), and implantation of a new prosthesis during the same surgery, followed by systemic antibiotic therapy guided by the microbiology of the infection [1]. This procedure has been advocated in patients with good soft tissue envelope, provided the microbiology is known preoperatively and the pathogen(s) are susceptible to antimicrobials with excellent oral bioavailability. One-stage exchange arthroplasty is less commonly performed in the United States compared with Europe. (See 'One- stage exchange arthoplasty' below.)

● Two-stage exchange arthroplasty consists of prosthesis resection with debridement of soft tissue and bone and placement of a joint spacer with antimicrobial-impregnated cement, followed by systemic antibiotic therapy for four to six weeks, and subsequent implantation of a new prosthesis once the infection is considered controlled [1,6,7]. Two-stage exchange arthroplasty is the most common approach for management of PJI in the United States. (See 'Two-stage exchange arthoplasty' below.)

Long-term antibiotic suppression may be warranted for patients with residual hardware following surgery (eg, patients who undergo debridement with retention of prosthesis or patients who undergo one-stage exchange arthroplasty).

Patients who do not meet criteria for reimplantation may warrant permanent resection arthroplasty [1]. Such patients may include nonambulatory patients, patients who are poor candidates for major surgery (including those with limited bone stock or soft tissue coverage), patients with infection due to a highly resistant organism, and patients who failed a previous exchange arthroplasty in whom the risk of recurrent infection after another implantation is deemed unacceptably high. Patients with total knee arthroplasty infection may undergo permanent resection arthroplasty with arthrodesis [2]. (See 'Permanent resection arthroplasty' below.)

Amputation should be the last option considered; it may be appropriate for patients who do not meet criteria for the above approaches. (See 'Amputation' below.)

Debridement and retention of prosthesis — Debridement and retention of prosthesis (also termed "debridement, antibiotics, and implant retention" [DAIR], or "irrigation and debridement with polyethylene liner exchange") may be an appropriate strategy in the following circumstances [1]:

● Diagnosis of PJI within approximately 30 days of prosthesis implantation, or within approximately three weeks of symptom onset, in patients with a well-fixed prosthesis with no sinus tract. In such cases, eradication of infection occurs in up to 70 percent of patients [8-11]. https://www.uptodate.com/...ents/prosthetic-joint-infection-treatment/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:52] Prosthetic joint infection: Treatment - UpToDate

● Patients who are poor surgical candidates for resection arthroplasty; in such cases, the likelihood of relapsed infection is greater than for patients who undergo resection arthroplasty [1,12].

Debridement and retention of prosthesis is not an effective strategy if the prosthesis is loose or if a sinus tract is present; in such cases, resection arthroplasty is required for definitive management.

Debridement should be performed via open arthrotomy to facilitate polyethylene liner exchange; this approach has been associated with better outcomes than arthroscopic lavage (which precludes liner exchange) [8,11]. Extensive soft tissue debridement should be performed, including debridement of the implant surface and behind polyethylene surfaces. In the setting of significant soft tissue infection, more than one debridement may be warranted.

Following debridement with polyethylene liner exchange and retention of prosthesis, the initial approach to antibiotic therapy depends on the microbiology of infection:

● For patients with Staphylococcus aureus PJI who undergo debridement and retention of prosthesis, antibiotic therapy consists of pathogen-specific intravenous therapy in combination with rifampin for the first two to six weeks (table 1) [1,9,10,13].

• For patients with S. aureus infection associated with hip, elbow, shoulder, or ankle PJI, subsequent therapy consists of pathogen-specific oral therapy in combination with rifampin to complete a total duration of three months [9,10,13-16].

• For patients with S. aureus infection associated with knee PJI, subsequent therapy consists of pathogen-specific oral therapy in combination with rifampin to complete a total duration of six months [1,17].

Options for oral therapy that may be combined with rifampin are summarized in the table (table 2); fluoroquinolones are preferred. Clindamycin should be avoided due to increased risk of Clostridioides (formerly Clostridium) difficile infection associated with clindamycin use [8,9,18]. (See 'Use of adjunctive rifampin' below.)

For patients with S. aureus PJI who cannot take rifampin because of drug resistance, allergy, toxicity, intolerance, or drug-drug interactions, antibiotic therapy consists of pathogen-specific intravenous therapy for four to six weeks (before transitioning to antibiotic suppression with an oral regimen, if warranted) [1].

In carefully selected cases of staphylococcal PJI managed with debridement, retention of prosthesis, and rifampin-based therapy, eradication of infection can occur in nearly 90 percent of cases; among patients with staphylococcal PJI managed with debridement and retention in the absence of rifampin, eradication of infection occurs in 50 to 60 percent of cases [19-23]. Risk factors associated with treatment failure include presence of a sinus tract, symptom duration ≥21 days prior to debridement, and lack of a rifampin-based antibiotic regimen [10].

● For patients with PJI due to other pathogens who undergo debridement and retention of prosthesis, antibiotic therapy consists of pathogen-specific intravenous therapy or highly bioavailable oral therapy for four to six weeks (table 1) [1].

In a retrospective study including more than 460 patients with streptococcal PJI managed with implant retention, this approach was associated with treatment failure in 42 percent of cases [24]. Factors associated with failure included rheumatoid arthritis, late postoperative infection, and bacteremia; factors associated with success included exchange of removable components and treatment for at least 21 days with a beta-lactam agent.

Following administration of antibiotic therapy as described above, indefinite antibiotic suppression with an oral regimen may be warranted (table 3) [1]. The approach to use of suppressive therapy must be made based on individual clinical circumstances, taking into consideration the nature of the organism and its antimicrobial susceptibility pattern, the potential for implant loosening and loss of bone stock, the nature of soft tissues, the hazards of prolonged antibiotic therapy, candidacy for further orthopedic surgery, and the age and immune status of the patient [1].

Resection arthroplasty with reimplantation — In general, patients with PJI presenting >30 days after prosthesis implantation require prosthesis removal for definitive management [25].

Options for surgical management include one-stage or two-stage arthroplasty; resection and reimplantation are performed in one or two procedures. The two-stage procedure is associated with the highest success rates to prevent PJI recurrence and is the preferred procedure in the United States; the one-stage procedure is more commonly performed outside the United States [1,2,14,26,27]. There are no randomized clinical trials comparing outcomes among patients who undergo one-stage or two-stage procedures [27]. Moreover, a relatively small number of patients have been included in case series and comparative investigations that have sought to define patients who are candidates for either procedure.

Candidates for one-stage exchange arthroplasty include patients with all of the following [1]:

● Total hip or knee arthroplasty ● Good soft tissue coverage (in the absence of a sinus tract) ● Good bone stock (no bone grafting anticipated) ● Microbiology known preoperatively ● Pathogen(s) are susceptible to antimicrobials with high oral bioavailability (to facilitate suppressive therapy) ● Immunocompetent

Candidates for two-stage exchange arthroplasty include patients with all of the following [1]:

● No prior two-stage exchange arthroplasty for infection (or prior two-stage exchange arthroplasty with other reason for failure); in selected circumstances, more than one two-stage exchange arthroplasty can be successful if the first one fails.

● Delayed reimplantation technically feasible. ● Good functional outcome anticipated. ● Patient able and willing to undergo two surgeries.

Patients with sinus tracts, poor soft tissue coverage, and/or difficult to treat pathogen(s) (such as methicillin-resistant S. aureus, enterococci, and Candida species) are typically managed with two-stage exchange arthroplasty.

One-stage exchange arthoplasty — One-stage exchange arthroplasty consists of prosthesis resection with debridement of the soft tissue and bone, patient redraping (as if performing a new surgical procedure, with different instruments), followed by implantation of a new prosthesis during the same surgery; many favor the use of antibiotic-impregnated cement to fix the new prosthesis [1,28]. One-stage exchange arthroplasty is less commonly performed in the United States compared with Europe.

In some circumstances, one-stage exchange arthroplasty is performed inadvertently, such as in the setting of revision for presumed aseptic loosening; in such cases, the diagnosis of PJI is made based on intraoperative cultures [29].

Following one-stage exchange arthroplasty, the initial approach to antibiotic therapy depends on the microbiology of infection:

● For patients with S. aureus PJI who undergo one-stage exchange arthroplasty, antibiotic therapy consists of pathogen-specific intravenous therapy in combination with rifampin for two to six weeks (table 1), followed by pathogen-specific oral therapy in combination with rifampin to complete a total duration of three months [1]. Options for oral therapy that may be combined with rifampin include fluoroquinolones, trimethoprim-sulfamethoxazole, doxycycline, minocycline, dicloxacillin, and first- generation cephalosporins (table 2). (See 'Use of adjunctive rifampin' below.)

For patients with S. aureus PJI who cannot take rifampin because of drug resistance, allergy, toxicity, or intolerance, antibiotic therapy consists of pathogen-specific intravenous therapy for four to six weeks [1].

● For patients with PJI due to other pathogens who undergo one-stage exchange arthroplasty, antibiotic therapy consists of pathogen-specific intravenous therapy or highly bioavailable oral therapy for four to six weeks (table 1) [1].

Thereafter, indefinite antibiotic suppression with an oral regimen may be warranted (table 3) [1]. Determination regarding use of suppressive therapy must be made based on individual clinical circumstances, taking into consideration the nature of the organism and its antimicrobial susceptibility pattern, whether cultures are positive at the time of the one-stage revision, the potential for implant loosening and loss of bone stock, the nature of soft tissues, the hazards of prolonged antibiotic therapy, candidacy for further orthopedic surgery, and the immune status of the patient.

In selected case series, eradication of infection occurs in approximately 80 percent of patients who

undergo one-stage exchange arthroplasty [23,30]. In one systematic review including 22 articles and more than 960 patients who underwent single-stage revision arthroplasty of an infected hip or knee joint, recurrent infection was observed in up to 18 percent of patients at ≤2 years follow-up [27].

Two-stage exchange arthoplasty — A two-stage exchange arthroplasty consists of:

● Stage 1: Prosthesis resection with debridement of soft tissue and bone and placement of an antibiotic-impregnated spacer, followed by systemic antibiotic therapy for four to six weeks.

● Stage 2: Implantation of new prosthesis; the need for additional antibiotic therapy is determined by cultures obtained at the time of reimplantation [1,6,7].

Eradication of infection occurs in more than 85 percent of patients who undergo two-stage exchange [23,31,32].

Stage one — Stage one consists of prosthesis resection with debridement of soft tissue and bone and placement of a spacer, followed by systemic antibiotic therapy for four to six weeks. We favor a two- week interval off of antibiotic therapy prior to hardware removal, to improve the diagnostic yield of operative cultures.

Antibiotic-impregnated cement spacers are commonly used in between stages; it is uncertain whether this practice confers additional benefit beyond the benefit associated with systemic antibiotic therapy [1,33-38]. Most commercially available antibiotic-impregnated cements are prepared with aminoglycosides, which have activity against gram-negative organisms. In the setting of infection due to gram-positive organisms, it may be appropriate to mix vancomycin with a commercial preparation containing an aminoglycoside [39].

A static or articulating spacer may be used; the choice does not appear to influence infection-related outcomes [40]. Use of an articulating spacer may permit earlier ambulation, increased range of motion, and may allow for a more extended antibiotic-free period prior to hardware reimplantation; use of a static spacer may limit range of motion and lead to muscle atrophy and arthrofibrosis [6,7].

Following removal of the infected prosthesis, antimicrobials with activity against the infecting organism(s) are typically administered for four to six weeks (table 1) [1].

It is can be difficult to know whether eradication of infection has been achieved following completion of systemic antimicrobial. The optimal approach to evaluating for signs of infection is uncertain [2]:

● We favor checking inflammatory markers (erythrocyte sedimentation rate or C-reactive protein) after completing antibiotics, prior to new prosthesis implantation [1]. Persistently elevated inflammatory markers without an alternative explanation should prompt workup for persistent infection (including repeat aspiration, frozen section, radiographic imaging, and/or open biopsy and culture) prior to reimplantation. However, the correlation between persistently elevated inflammatory markers and likelihood of residual infection at the time of new prosthesis implantation is not clear [5,41-43]. (See

'Treatment monitoring' below.)

● Some favor obtaining synovial fluid culture to assess sterilization of the joint space following an observation period (at least two weeks) off all antimicrobials prior to new prosthesis implantation; others favor proceeding with new prosthesis implantation immediately following completion of antimicrobials if there are no clinical signs of infection [1]. In general, we favor obtaining synovial fluid cultures in selected cases when there is clinical concern regarding the presence of persistent infection. Molecular methods are promising but thus far, data are insufficient to support routine use of this tool [44]. Patients with known or suspected residual infection should undergo further debridement with spacer exchange and further antimicrobial therapy [2].

In one retrospective study including more than 250 patients with PJI who underwent two-stage exchange arthroplasty, the risk of failure was increased among patients with a positive culture at reimplantation (45 vs 21 percent) [45]. In another retrospective study including more than 150 patients with PJI, the presence of positive cultures obtained at the time of new prosthesis implantation was not associated with a worse outcome [46].

Stage two — Stage two consists of new prosthesis implantation. Arthrotomy is performed with operative inspection, collection of cultures and frozen section histology [47]. If frozen section is negative, hardware reimplantation may be performed. If frozen section is positive, then a determination of whether or not to proceed with implantation of new hardware must be made; intraoperative findings are important in such decision-making.

If there are no apparent signs of infection, the new prosthesis may be implanted; many favor the use of antibiotic-impregnated cement to fix the new prosthesis [1]. Empiric antibiotic therapy (guided by culture data obtained at the time of the original resection and at the time of reimplantation) should be administered pending final operative culture results.

Patients with positive cultures at the time of reimplantation should be managed with reinstitution of antimicrobial therapy to complete another treatment course, followed by chronic suppressive antimicrobial therapy. Patients with negative cultures at the time of reimplantation do not require further antimicrobial therapy.

Permanent resection arthroplasty — Permanent resection arthroplasty may be appropriate for patients who must undergo resection for management of infection, but who do not meet criteria for reimplantation or for whom reimplantation does not offer a significant functional improvement (such as patients who are nonambulatory for other reasons) [1]. Such patients may include nonambulatory patients, patients who are poor candidates for major surgery (including those with limited bone stock or soft tissue coverage), patients with infection due to highly resistant organisms, and patients who failed a previous exchange in whom the risk of recurrent infection after another implantation is deemed unacceptably high.

Patients with total hip arthroplasty infection may undergo permanent resection arthroplasty without arthrodesis (Girdlestone procedure); this is frequently associated with limb length discrepancy [48].

Retention of a prosthetic spacer may be associated with a reasonable outcome, based on limited data [49].

Patients with total knee arthroplasty infection may undergo permanent resection with arthrodesis; approaches include intramedullary nailing or external fixation (with or without placement of an antibiotic cement spacer) [2]. In such cases, adequate bone must be present to create a fusion, and the limb will be shorter than the contralateral limb. Patients will not have knee mobility, but the limb will be preserved.

Following permanent resection arthroplasty, a four- to six-week course of pathogen-directed parenteral antimicrobial therapy or highly oral bioavailable agent should be administered (table 1) [50].

Eradication of infection occurs in 60 to 100 percent of patients who undergo permanent resection arthroplasty, which is lower than the reported efficacy of two-stage exchange arthroplasty [1]. An increased risk of reinfection has been observed among patients with a preoperative sinus tract who undergo resection hip or knee arthroplasty with placement of a permanent joint spacer (either fully constructed of polymethylmethacrylate or with new prostheses); in one cohort study including 51 such patients, administration of antimicrobial suppression therapy did not prevent subsequent PJI [51].

Amputation — Amputation may be warranted in the following circumstances (any of the following) [1]:

● Necrotizing fasciitis ● Severe bone loss ● Inadequate soft tissue coverage ● Failed prior attempt of resection arthroplasty or arthrodesis to control infection ● Functional benefit to amputation over resection arthroplasty or arthrodesis

For patients in whom all infected bone and soft tissue was resected in the absence of bacteremia or sepsis, pathogen-specific antimicrobial therapy should administered for 24 to 48 hours following amputation (table 1).

For patients with bacteremia or sepsis, the duration of therapy should be guided by these conditions (see separate topics).

For patients with residual infected bone and/or soft tissue, a four- to six-week course of pathogen- directed parenteral antimicrobial therapy or highly oral bioavailable agent should be administered (table 1) [1]. (See "Osteomyelitis in adults: Treatment".)

Nonsurgical management — Antimicrobial therapy without accompanying surgery most often results in a delay in appropriate management and confusion regarding the microbiologic diagnosis. Therefore, this approach is warranted only for patients unable to undergo even a single surgical procedure [2].

In such cases, joint aspiration should be performed to determine the microbiology of infection, followed by four to six weeks of pathogen-directed intravenous or highly bioavailable oral antimicrobial therapy (table 1).

Thereafter, indefinite antibiotic suppression with an oral regimen is warranted (table 3). (See 'Suppressive therapy' below.)

TREATMENT MONITORING

Treatment monitoring includes clinical monitoring (including monitoring for wound healing and resolution of joint inflammation) and laboratory monitoring.

Laboratory monitoring — Laboratory monitoring is needed during prolonged administration of antimicrobial therapy to monitor for adverse drug effects and to assess control of infection.

For patients on parenteral antimicrobial therapy, we obtain weekly complete blood count and chemistries. We obtain serum inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) at the beginning and end of parenteral therapy and at the time of transition to oral suppressive therapy (if used).

During parenteral antimicrobial therapy, we do not routinely monitor weekly serum inflammatory markers. However, if there is clinical suspicion for treatment failure, we use inflammatory markers (in conjunction with clinical examination and radiographic studies such as magnetic resonance imaging or plain radiograph) to guide further management.

For patients on oral suppressive antimicrobial therapy, we obtain a complete blood count, creatinine, and alanine aminotransferase at 2, 4, 8, and 12 weeks and then every 6 to 12 months thereafter

Persistently elevated inflammatory markers — In the setting of persistently elevated inflammatory markers after completing a course of antibiotic therapy, the first priority should be to ensure that a thorough and complete debridement has been performed. In addition, the microbiologic diagnosis and susceptibility data should be reviewed.

Persistently elevated inflammatory markers without an alternative explanation two weeks following completion of antimicrobial therapy should prompt workup for persistent infection. Patients with associated symptoms warrant repeat debridement and additional antimicrobial therapy. In the absence of clinical signs consistent with persistent infection, clinical observation may be reasonable.

ANTIBIOTIC THERAPY

Whenever possible, initiation of antibiotic therapy should be delayed until the specimens for culture are obtained (via joint aspiration, joint debridement, and/or hardware removal).

In general, management of prosthetic joint infection usually includes a prolonged course of intravenous antibiotic therapy. Data regarding use of oral antibiotic therapy are emerging [52]. (See "Osteomyelitis in adults: Treatment", section on 'Systemic therapy'.)

Suggested antibiotic regimens are outlined in the table (table 1). Antibiotic therapy should be tailored to

culture and susceptibility data when available.

Empiric therapy — For patients with PJI who present with sepsis or are otherwise too unstable to wait for culture data to guide therapy, empiric antibiotic therapy may be justified.

In such cases, empiric treatment of PJI should include activity against staphylococci (including methicillin- resistant strains) and aerobic gram-negative bacilli. Reasonable regimens include vancomycin in combination with a third- or fourth-generation cephalosporin (table 1).

Antibiotic therapy should be tailored to culture and susceptibility data when available.

Definitive therapy — The approach to antimicrobial therapy (including duration of therapy) depends on the surgical approach, as discussed above. (See 'Clinical approach' above.)

Antimicrobial therapy should be tailored to culture data, as discussed in the following sections.

Staphylococci

Staphylococcus aureus — In general, definitive therapy for treatment of PJI due to S. aureus consists of parenteral antibiotic therapy; regimens are summarized in the table (table 1). In addition, use of adjunctive agents for treatment of S. aureus PJI may be warranted in some circumstances. (See 'Use of adjunctive rifampin' below.)

Parenteral agents with activity against methicillin-sensitive S. aureus (MSSA) include nafcillin, oxacillin, and cefazolin (table 1). Ceftriaxone may be as effective as other anti-staphylococcal beta-lactams for treatment of oxacillin-susceptible staphylococcal PJIs, based on retrospective data [46,53].

For outpatient antimicrobial therapy, treatment with nafcillin or oxacillin may be continued via infusion pump; alternatively, treatment with cefazolin may allow greater convenience. In one retrospective study, outpatient treatment of serious MSSA infections with cefazolin was associated with fewer drug emergent effects (12 versus 31 percent) and premature discontinuations (7 versus 34 percent) compared with nafcillin [54].

Patients with an MSSA infection and a history of type I hypersensitivity (anaphylaxis) to beta-lactams can be treated with either vancomycin or daptomycin [1]. Use of linezolid is limited by risks of myelosuppression, peripheral neuropathy, and optic neuritis.

The antibiotic of choice for treatment of PJI due to methicillin-resistant S. aureus (MRSA) is vancomycin; it is the antibiotic agent for which there is the greatest cumulative clinical experience, although there are no controlled trials. Acceptable alternative agents to vancomycin for treatment of PJI due to MRSA include daptomycin (and teicoplanin, where available).

Use of adjunctive agents for treatment staphylococcal PJI may be warranted in some circumstances. (See 'Use of adjunctive rifampin' below.)

Antibiotic agents that warrant further study for treatment of staphylococcal PJI include ceftaroline and

telavancin. We do not favor use of trimethoprim-sulfamethoxazole, linezolid, tedizolid, clindamycin, fluoroquinolones, quinupristin-dalfopristin, or tigecycline for definitive treatment of PJI due to S. aureus [1,13,55,56]. (See "Osteomyelitis in adults: Treatment" and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".)

Coagulase-negative staphylococci — Most coagulase-negative staphylococci are methicillin resistant (an exception is Staphylococcus lugdunensis, which is almost universally methicillin susceptible). (See "Staphylococcus lugdunensis".)

Empiric treatment for PJI due to coagulase-negative staphylococci should consist of an agent with activity against methicillin-resistant staphylococci. If susceptibility testing demonstrates methicillin susceptibility, a beta-lactam with activity against methicillin-susceptible staphylococci should be used (table 1).

Use of adjunctive rifampin — For patients with S. aureus PJI and residual hardware following surgery (eg, patients who undergo debridement with retention or patients who undergo one-stage exchange), we favor the use of rifampin (in combination with at least one other anti-staphylococcal agent) (table 2 and table 1). (See 'Debridement and retention of prosthesis' above and 'One-stage exchange arthoplasty' above.)

Rifampin has activity against microorganisms in biofilms, which are important in the pathophysiology of staphylococcal osteomyelitis (particularly in the setting of hardware) [9,13,57]. (See "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Biofilm'.)

Rapid emergence of resistance in the setting of rifampin monotherapy is common. Therefore, rifampin should be initiated several days after surgical debridement and initiation of anti-staphylococcal therapy (eg, once the burden of organisms has been reduced). Rifampin should be coadministered with another active antibacterial agent.

Rifampin has significant drug-drug interactions and a high risk of toxicity; careful consideration of an individual's medications and comorbidities (particularly history of liver disease) is warranted prior to initiation of rifampin.

Gram-negative bacilli — For treatment of PJI due to gram-negative organisms, we favor fluoroquinolones (if susceptibility testing confirms sensitivity) since they have high bone penetration with oral administration. Other antibiotics for treatment of PJI due to gram-negative organisms include parenteral beta-lactams and carbapenems. Antibiotic dosing is summarized in the table (table 1).

PJIs due to Pseudomonas aeruginosa are difficult to cure, even with debridement and hardware removal. Agents with activity against P. aeruginosa include ciprofloxacin, levofloxacin, ceftazidime, cefepime, and meropenem (table 1) [1].

Enterococci — Treatment for enterococcal PJI should be tailored to susceptibility results. It is unclear whether combination therapy is superior to monotherapy [58]. We favor combination therapy in the setting of retained hardware; the regimen of ampicillin and ceftriaxone is generally well tolerated [59].

However, if antibiotic-impregnated material containing gentamicin is implanted at the time of debridement, monotherapy is likely sufficient; in such cases, we favor treatment with intravenous ampicillin or penicillin.

The treatment of choice for penicillin-resistant enterococcal PJI is vancomycin; acceptable alternative agents to include daptomycin (and teicoplanin, where available) [1].

Streptococci — The treatment of choice for streptococcal PJI is penicillin or ampicillin (table 1) [60]. Ceftriaxone is an equally acceptable agent and is favored for dosing convenience in the outpatient setting. Patients allergic to beta-lactams may be treated with vancomycin.

Cutibacterium acnes — Shoulder infection is the most common presentation of PJI due to Cutibacterium (formerly Propionibacterium) acnes. Options for treatment of infection due to C. acnes include penicillin or ceftriaxone (table 1); patients allergic to beta-lactams may be treated with vancomycin [1]. (See "Invasive Cutibacterium (formerly Propionibacterium) infections".)

Fungi — Management of fungal PJI is discussed separately. (See "Candida osteoarticular infections".)

Culture negative — The most common cause of culture-negative PJI is administration of antibiotic therapy prior to collection of specimens for culture [61]. Other causes include infection with a pathogen that cannot be identified using available methods and noninfectious mimic of PJI [2].

Patients with culture-negative PJIs should receive antimicrobial agents with activity against gram-positive and gram-negative pathogens. (See 'Empiric therapy' above.)

Patients with culture-negative PJI have similar outcomes as patients with positive cultures following standard treatment regimens. In a retrospective study including 60 patients with PJI and negative cultures, five-year survival free of treatment failure was 94 percent in patients treated with two-stage exchange arthroplasties and 71 percent in patients who underwent debridement with retention of their prosthesis [61].

Suppressive therapy — Long-term antibiotic suppression with an oral regimen may be warranted for patients with PJI and residual hardware following surgery (eg, patients who undergo debridement with retention or patients who undergo one-stage exchange). (See 'Debridement and retention of prosthesis' above and 'One-stage exchange arthoplasty' above.)

Determination regarding the use and duration of suppressive therapy must be made based on individual clinical circumstances, taking into consideration the nature of the organism and its antimicrobial susceptibility pattern, the potential for implant loosening and loss of bone stock, the nature of soft tissues, the hazards of prolonged antibiotic therapy, candidacy for further orthopedic surgery, and the age and immune status of the patient [1].

Options for suppressive therapy are summarized in the table (table 3). The optimal duration of suppressive therapy is uncertain. Many favor at least three to six months of therapy; some favor indefinite

therapy [2]. Individual patient factors (such as clinical course, microbiology, patient preference) may impact the duration of suppressive therapy.

Suppressive oral antibiotic therapy typically postpones rather than prevents treatment failure [8,22,46]. Studies evaluating use of suppressive oral antibiotic therapy include:

● A randomized trial including more than 100 patients with PJI managed with two-stage exchange arthroplasty, followed by randomization to three months of oral antibiotic suppressive therapy or no further antibiotic treatment; repeat infection during 24-month follow-up occurred less frequently among patients treated with suppressive antibiotics (5 versus 19 percent) [62].

● A cohort study including more than 130 patients with retained PJI; oral antibiotic suppressive therapy was effective and well-tolerated during two years of follow-up in 61 percent of cases [63].

● A cohort study including more than 80 patients with orthopedic infection in the setting of retained hardware; oral antibiotic suppressive therapy was successful among those treated for three months but not among those treated for six months [64].

● A retrospective review including more than 90 patients with PJI; the infection-free rate at five years was greater among those who received oral antibiotic suppressive therapy for at least six months than among those who did not (68 versus 41 percent) [65].

Duration of therapy — The duration of antimicrobial therapy for treatment of PJI is tailored to the surgical management, as discussed above. (See 'Clinical approach' above.)

In general, management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic therapy; data regarding shortened antibiotic duration and use of oral antibiotic therapy are emerging [52,66]. In one meta-analysis including 10 studies (9 observational studies and 1 randomized trial) and more than 850 patients with PJI managed with debridement and retention or two- stage exchange arthroplasty, no significant difference between short-course and long-course antibiotics was observed (relative risk 0.87, 95% CI 0.62-1.22) [66]. The generalizability of these findings is limited; further study is needed.

OUTCOME

Outcomes depend on the type of surgical procedure, the microbiology of infection and individual patient circumstances. The definition of success after treatment for infection is variable:

● In 2019 the Musculoskeletal Infection Society published a definition of success including four tiers: (1) Control of infection (without continued antibiotic therapy), (2) Control of infection on suppressive antibiotic, (3) Need for reoperation, revision, and/or spacer retention, and (4) Death (less than one year, likely due to reinfection; greater than one year, unlikely due to reinfection) [67]

● In a 2013 consensus report of experts (including orthopedic surgeons, infectious disease specialists, https://www.uptodate.com/...ents/prosthetic-joint-infection-treatment/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:52] Prosthetic joint infection: Treatment - UpToDate

and clinical researchers), success after PJI treatment was defined by three factors: (1) Eradication of infection, (2) No further surgical intervention for infection, and (3) No mortality associated with PJ [68].

In one study including 200 patients with PJI, the rate of five-year survival (free of treatment failure) varied by the type of surgical procedure; rates for two-stage exchange, permanent resection arthroplasty, and debridement with retention of prosthesis were 79, 61, and 32 percent, respectively [21].

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topics (see "Patient education: Knee replacement (The Basics)" and "Patient education: Hip replacement (The Basics)")

● Beyond the Basics topics (see "Patient education: Joint infection (Beyond the Basics)" and "Patient education: Total hip replacement (arthroplasty) (Beyond the Basics)" and "Patient education: Total knee replacement (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● In general, management of prosthetic joint infection (PJI) consists of surgery and antimicrobial therapy. The approach depends on a number of factors including the timing and microbiology of infection, condition of the joint and implant, and individual patient circumstances. (See 'Overview'

above.)

● Surgical approaches for management of PJI include debridement and retention of prosthesis, resection arthroplasty with reimplantation (one- or two-stage exchange arthroplasty), permanent resection arthroplasty, or amputation. (See 'Clinical approach' above.)

• Patients presenting >30 days after prosthesis implantation should undergo prosthesis removal for definitive management. Options for replacement arthroplasty include one-stage or two-stage procedures. (See 'Resection arthroplasty with reimplantation' above.)

- The two-stage exchange arthroplasty is the most commonly used approach for management of PJI in the United States. Stage one consists of prosthesis resection, debridement of soft tissue and bone, and placement of a joint spacer, followed by systemic antibiotic therapy for four to six weeks; stage two consists of new prosthesis implantation and additional antibiotic therapy in some circumstances. (See 'Two-stage exchange arthoplasty' above.)

• Patients presenting within 30 days of prosthesis implantation or <3 weeks of symptom onset (in the setting of a well-fixed prosthesis and in the absence of a sinus tract) may be candidates for debridement, polyethylene liner exchange, and retention of prosthesis. (See 'Debridement and retention of prosthesis' above.)

• Patients who do not meet criteria for reimplantation may warrant permanent resection arthroplasty. Amputation should be the last option considered; it may be appropriate for patients who do not meet criteria for the above approaches. (See 'Permanent resection arthroplasty' above and 'Amputation' above.)

● Antibiotic regimens for treatment of PJI are outlined in the table (table 1). Antibiotic therapy should be tailored to culture and susceptibility data when available.

• For treatment of PJI due to methicillin-resistant Staphylococcus aureus, we suggest vancomycin (Grade 2C); daptomycin is an acceptable alternative agent. (See 'Staphylococcus aureus' above.)

• For patients with S. aureus PJI and residual hardware following surgery (eg, patients who undergo debridement with retention or patients who undergo one-stage exchange), we suggest adjunctive use of rifampin (in combination with at least one other anti-staphylococcal agent) (table 2 and table 1) (Grade 2C). Use of rifampin must be weighed against the likelihood of toxicity and drug interactions. (See 'Use of adjunctive rifampin' above.)

● The duration of antimicrobial therapy for treatment of PJI must be tailored to surgical management. Following completion of definitive antibiotic therapy, antibiotic suppression with an oral regimen may be warranted for individuals with retained hardware and/or necrotic bone not amenable to complete debridement (table 3). (See 'Clinical approach' above and 'Suppressive therapy' above.)

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10. El Helou OC, Berbari EF, Lahr BD, et al. Efficacy and safety of rifampin containing regimen for staphylococcal prosthetic joint infections treated with debridement and retention. Eur J Clin Microbiol Infect Dis 2010; 29:961.

11. Huotari K, Vuorinen M, Rantasalo M. High Cure Rate for Acute Streptococcal Prosthetic Joint Infections Treated With Debridement, Antimicrobials, and Implant Retention in a Specialized Tertiary Care Center. Clin Infect Dis 2018; 67:1288.

12. Fisman DN, Reilly DT, Karchmer AW, Goldie SJ. Clinical effectiveness and cost-effectiveness of 2

management strategies for infected total hip arthroplasty in the elderly. Clin Infect Dis 2001; 32:419.

13. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18.

14. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med 2004; 351:1645.

15. Gómez J, Canovas E, Baños V, et al. Linezolid plus rifampin as a salvage therapy in prosthetic joint infections treated without removing the implant. Antimicrob Agents Chemother 2011; 55:4308.

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22. Marculescu CE, Berbari EF, Hanssen AD, et al. Outcome of prosthetic joint infections treated with debridement and retention of components. Clin Infect Dis 2006; 42:471.

23. Sia IG, Berbari EF, Karchmer AW. Prosthetic joint infections. Infect Dis Clin North Am 2005; 19:885.

24. Lora-Tamayo J, Senneville É, Ribera A, et al. The Not-So-Good Prognosis of Streptococcal Periprosthetic Joint Infection Managed by Implant Retention: The Results of a Large Multicenter Study. Clin Infect Dis 2017; 64:1742.

25. Hsieh PH, Lee MS, Hsu KY, et al. Gram-negative prosthetic joint infections: risk factors and outcome of treatment. Clin Infect Dis 2009; 49:1036.

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27. Thakrar RR, Horriat S, Kayani B, Haddad FS. Indications for a single-stage exchange arthroplasty for chronic prosthetic joint infection: a systematic review. Bone Joint J 2019; 101-B:19.

28. Negus JJ, Gifford PB, Haddad FS. Single-Stage Revision Arthroplasty for Infection-An Underutilized Treatment Strategy. J Arthroplasty 2017; 32:2051.

29. Marculescu CE, Berbari EF, Hanssen AD, et al. Prosthetic joint infection diagnosed postoperatively by intraoperative culture. Clin Orthop Relat Res 2005; 439:38.

30. Zeller V, Lhotellier L, Marmor S, et al. One-stage exchange arthroplasty for chronic periprosthetic hip infection: results of a large prospective cohort study. J Bone Joint Surg Am 2014; 96:e1.

31. Hsieh PH, Shih CH, Chang YH, et al. Two-stage revision hip arthroplasty for infection: comparison between the interim use of antibiotic-loaded cement beads and a spacer prosthesis. J Bone Joint Surg Am 2004; 86-A:1989.

32. Mont MA, Waldman BJ, Hungerford DS. Evaluation of preoperative cultures before second-stage reimplantation of a total knee prosthesis complicated by infection. A comparison-group study. J Bone Joint Surg Am 2000; 82-A:1552.

33. Hanssen AD, Spangehl MJ. Practical applications of antibiotic-loaded bone cement for treatment of infected joint replacements. Clin Orthop Relat Res 2004; :79.

34. Nelson CL. The current status of material used for depot delivery of drugs. Clin Orthop Relat Res 2004; :72.

35. Jacobs C, Christensen CP, Berend ME. Static and mobile antibiotic-impregnated cement spacers for the management of prosthetic joint infection. J Am Acad Orthop Surg 2009; 17:356.

36. Parvizi J, Saleh KJ, Ragland PS, et al. Efficacy of antibiotic-impregnated cement in total hip replacement. Acta Orthop 2008; 79:335.

37. Iarikov D, Demian H, Rubin D, et al. Choice and doses of antibacterial agents for cement spacers in treatment of prosthetic joint infections: review of published studies. Clin Infect Dis 2012; 55:1474.

38. Zheng H, Barnett AG, Merollini K, et al. Control strategies to prevent total hip replacement-related infections: a systematic review and mixed treatment comparison. BMJ Open 2014; 4:e003978.

39. Wouthuyzen-Bakker M, Kheir MM, Moya I, et al. Failure After 2-Stage Exchange Arthroplasty for Treatment of Periprosthetic Joint Infection: The Role of Antibiotics in the Cement Spacer. Clin Infect

Dis 2019; 68:2087.

40. Voleti PB, Baldwin KD, Lee GC. Use of static or articulating spacers for infection following total knee arthroplasty: a systematic literature review. J Bone Joint Surg Am 2013; 95:1594.

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42. Ghanem E, Azzam K, Seeley M, et al. Staged revision for knee arthroplasty infection: what is the role of serologic tests before reimplantation? Clin Orthop Relat Res 2009; 467:1699.

43. Shukla SK, Ward JP, Jacofsky MC, et al. Perioperative testing for persistent sepsis following resection arthroplasty of the hip for periprosthetic infection. J Arthroplasty 2010; 25:87.

44. Melendez DP, Greenwood-Quaintance KE, Berbari EF, et al. Evaluation of a Genus- and Group- Specific Rapid PCR Assay Panel on Synovial Fluid for Diagnosis of Prosthetic Knee Infection. J Clin Microbiol 2016; 54:120.

45. Tan TL, Gomez MM, Manrique J, et al. Positive Culture During Reimplantation Increases the Risk of Subsequent Failure in Two-Stage Exchange Arthroplasty. J Bone Joint Surg Am 2016; 98:1313.

46. Bejon P, Berendt A, Atkins BL, et al. Two-stage revision for prosthetic joint infection: predictors of outcome and the role of reimplantation microbiology. J Antimicrob Chemother 2010; 65:569.

47. George J, Kwiecien G, Klika AK, et al. Are Frozen Sections and MSIS Criteria Reliable at the Time of Reimplantation of Two-stage Revision Arthroplasty? Clin Orthop Relat Res 2016; 474:1619.

48. Castellanos J, Flores X, Llusà M, et al. The Girdlestone pseudarthrosis in the treatment of infected hip replacements. Int Orthop 1998; 22:178.

49. Choi HR, Freiberg AA, Malchau H, et al. The fate of unplanned retention of prosthetic articulating spacers for infected total hip and total knee arthroplasty. J Arthroplasty 2014; 29:690.

50. Salgado CD, Dash S, Cantey JR, Marculescu CE. Higher risk of failure of methicillin-resistant Staphylococcus aureus prosthetic joint infections. Clin Orthop Relat Res 2007; 461:48.

51. Valencia JCB, Abdel MP, Virk A, et al. Destination Joint Spacers, Reinfection, and Antimicrobial Suppression. Clin Infect Dis 2019; 69:1056.

52. Li HK, Rombach I, Zambellas R, et al. Oral versus Intravenous Antibiotics for Bone and Joint Infection. N Engl J Med 2019; 380:425.

53. Tice AD, Hoaglund PA, Shoultz DA. Outcomes of osteomyelitis among patients treated with outpatient parenteral antimicrobial therapy. Am J Med 2003; 114:723.

54. Youngster I, Shenoy ES, Hooper DC, Nelson SB. Comparative evaluation of the tolerability of https://www.uptodate.com/...ents/prosthetic-joint-infection-treatment/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:52] Prosthetic joint infection: Treatment - UpToDate

cefazolin and nafcillin for treatment of methicillin-susceptible Staphylococcus aureus infections in the outpatient setting. Clin Infect Dis 2014; 59:369.

55. Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998; 339:520.

56. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991; 115:674.

57. Henry NK, Rouse MS, Whitesell AL, et al. Treatment of methicillin-resistant Staphylococcus aureus experimental osteomyelitis with ciprofloxacin or vancomycin alone or in combination with rifampin. Am J Med 1987; 82:73.

58. El Helou OC, Berbari EF, Marculescu CE, et al. Outcome of enterococcal prosthetic joint infection: is combination systemic therapy superior to monotherapy? Clin Infect Dis 2008; 47:903.

59. Euba G, Lora-Tamayo J, Murillo O, et al. Pilot study of ampicillin-ceftriaxone combination for treatment of orthopedic infections due to Enterococcus faecalis. Antimicrob Agents Chemother 2009; 53:4305.

60. Meehan AM, Osmon DR, Duffy MC, et al. Outcome of penicillin-susceptible streptococcal prosthetic joint infection treated with debridement and retention of the prosthesis. Clin Infect Dis 2003; 36:845.

61. Berbari EF, Marculescu C, Sia I, et al. Culture-negative prosthetic joint infection. Clin Infect Dis 2007; 45:1113.

62. Frank JM, Kayupov E, Moric M, et al. The Mark Coventry, MD, Award: Oral Antibiotics Reduce Reinfection After Two-Stage Exchange: A Multicenter, Randomized Controlled Trial. Clin Orthop Relat Res 2017; 475:56.

63. Prendki V, Ferry T, Sergent P, et al. Prolonged suppressive antibiotic therapy for prosthetic joint infection in the elderly: a national multicentre cohort study. Eur J Clin Microbiol Infect Dis 2017; 36:1577.

64. Keller SC, Cosgrove SE, Higgins Y, et al. Role of Suppressive Oral Antibiotics in Orthopedic Hardware Infections for Those Not Undergoing Two-Stage Replacement Surgery. Open Forum Infect Dis 2016; 3:ofw176.

65. Siqueira MB, Saleh A, Klika AK, et al. Chronic Suppression of Periprosthetic Joint Infections with Oral Antibiotics Increases Infection-Free Survivorship. J Bone Joint Surg Am 2015; 97:1220.

66. Yen HT, Hsieh RW, Huang CY, et al. Short-course versus long-course antibiotics in prosthetic joint infections: a systematic review and meta-analysis of one randomized controlled trial plus nine observational studies. J Antimicrob Chemother 2019; 74:2507.

67. Fillingham YA, Della Valle CJ, Suleiman LI, et al. Definition of Successful Infection Management https://www.uptodate.com/...ents/prosthetic-joint-infection-treatment/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:52] Prosthetic joint infection: Treatment - UpToDate

and Guidelines for Reporting of Outcomes After Surgical Treatment of Periprosthetic Joint Infection: From the Workgroup of the Musculoskeletal Infection Society (MSIS). J Bone Joint Surg Am 2019; 101:e69.

68. Diaz-Ledezma C, Higuera CA, Parvizi J. Success after treatment of periprosthetic joint infection: a Delphi-based international multidisciplinary consensus. Clin Orthop Relat Res 2013; 471:2374.

Topic 7665 Version 40.0

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GRAPHICS

Antibiotic therapy for treatment of osteomyelitis or prosthetic joint infection in adults

Infectious agent Antibiotic regimen Dosing

Empiric therapy Vancomycin PLUS a third- or fourth-generation As summarized below cephalosporin (such as ceftriaxone, ceftazidime, or cefepime)

Pathogen-specific therapy

Staphylococci, Nafcillin 2 g IV every 4 hours methicillin Oxacillin 2 g IV every 4 hours susceptible* Cefazolin 2 g IV every 8 hours

Flucloxacillin 2 g IV every 6 hours

Ceftriaxone¶ 2 g IV every 24 hours

Staphylococci, Regimen of choice: methicillin VancomycinΔ 20 mg/kg loading dose, then 15 mg/kg/dose IV resistant* every 12 hours, not to exceed 2 g per dose initially

Alternative regimens:◊

Daptomycin§ 6 to 10 mg/kg IV once daily

Teicoplanin (where available)¥‡ 12 mg/kg IV every 12 hours for 3 to 5 doses, followed by 12 mg/kg once daily

Staphylococci, Rifampin 300 to 450 mg orally twice daily adjunctive agents* Fusidic acid (where available)¥ 500 mg orally 3 times daily

Gram-negative Ciprofloxacin†,**,¶¶ 750 mg orally twice daily or 400 mg IV every organisms 12 hours; if treating Pseudomonas, increase IV dose to 400 mg IV every 8 hours

Levofloxacin**,¶¶ 750 mg orally or IV once daily

CeftriaxoneΔΔ 2 g IV every 24 hours

Ceftazidime** 2 g IV every 8 hours

Cefepime** 2 g IV every 8 to 12 hours

ErtapenemΔΔ 1 g IV every 24 hours

Meropenem** 1 g IV every 8 hours

Enterococci◊◊ Monotherapy regimens:

Ampicillin 12 g IV every 24 hours, either continuously or in 6 equally divided doses

Aqueous crystalline penicillin G 20 to 24 million units IV every 24 hours, either continuously or in 6 equally divided doses

VancomycinΔ 20 mg/kg loading dose, then 15 mg/kg IV every 12 hours, not to exceed 2 g per dose

Daptomycin§ 6 to 10 mg/kg IV once daily

Teicoplanin (where available)¥‡ 12 mg/kg IV every 12 hours for 3 to 5 doses, followed by 12 mg/kg once daily

Combination therapy regimen:

Ampicillin 12 g IV every 24 hours, given either continuously or in 6 equally divided doses

PLUS

Ceftriaxone 2 g IV every 12 to 24 hours

Streptococci, One of the following: penicillin sensitive https://www.uptodate.com/...ents/prosthetic-joint-infection-treatment/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:52] Prosthetic joint infection: Treatment - UpToDate

Aqueous crystalline penicillin G 20 to 24 million units IV every 24 hours, either continuously or in 6 equally divided doses

Ampicillin 12 g IV every 24 hours, either continuously or in 6 equally divided doses

Ceftriaxone 2 g IV every 24 hours

VancomycinΔ 20 mg/kg loading dose, then 15 mg/kg/dose IV every 12 hours, not to exceed 2 g per dose, initially

Cutibacterium One of the following: (formerly Aqueous crystalline penicillin G 20 million units IV every 24 hours, either Propionibacterium) continuously or in 6 divided doses acnes§§ Ceftriaxone 2 g IV every 24 hours

In stable patients, antibiotics may be held pending establishment of microbiologic diagnosis or obtaining cultures from bone debridement or biopsy. The total duration of antibiotic therapy depends on individual patient circumstances (refer to the UpToDate content on treatment of osteomyelitis and prosthetic joint infection for further discussion). The doses in this table are intended for adults with normal renal function. The doses of many of these agents must be adjusted in the setting of renal insufficiency; refer to the Lexicomp drug-specific monographs for renal dose adjustments.

IV: intravenously; PJI: prosthetic joint infection. * For patients with Staphylococcus aureus PJI and residual hardware following surgery, we favor use of adjunctive rifampin. To mitigate the emergence of resistance, rifampin should not be started until the patient has received several days of anti- staphylococcal therapy. We favor administration of rifampin 450 orally twice daily; the dose may be reduced to 300 mg orally twice daily in the setting of nausea. There should be careful screening drug-drug interactions prior to initiation of rifampin. ¶ Use of ceftriaxone for treatment of staphylococcal osteomyelitis is not universally accepted. In our practice, we use it as an alternative regimen for isolates with oxacillin minimum inhibitory concentration <0.5 mcg/mL in the absence of concomitant bacteremia; once-daily dosing is a convenient outpatient regimen. Δ In adults, vancomycin is dosed based on actual body weight. Target troughs for vancomycin should be chosen with the guidance of a local infectious disease physician based on the pathogen, in vitro susceptibility, and the use of rifampin or local vancomycin therapy, with a target trough concentration of at least 10 mcg/mL. It is unknown if a higher vancomycin trough level of 15 to 20 mcg/mL is routinely needed. Refer to the UpToDate topic review on vancomycin parenteral dosing and serum concentration monitoring in adults. ◊ Ceftaroline has been used successfully for treatment of osteomyelitis but has been associated with increased risk of neutropenia. Pending further study, use of ceftaroline should be reserved for patients unable to receive other therapies. Ceftaroline susceptibility must be confirmed; the prevalence of resistance is high in some regions. Daptomycin may be used for vancomycin-resistant enterococci; confirm susceptibility. § Standard daptomycin dosing (as approved by the US Food and Drug Administration) for treatment of bacteremia or osteomyelitis is 6 mg/kg IV once daily. Because daptomycin exhibits concentration-dependent killing, some experts recommend doses of up to 8 to 10 mg/kg IV once daily, which appear safe; further study is needed. ¥ Not available in the United States. Fusidic acid should not be used alone; it must be combined with a second active agent to reduce the likelihood of selection for drug resistance. When rifampin is combined with fusidic acid, fusidic levels may be reduced. ‡ The teicoplanin dose should be adjusted to attain a trough concentration of >20 mcg/mL. † Oral ciprofloxacin at dose shown in table achieves therapeutic levels for treatment of Pseudomonas aeruginosa. ** Ciprofloxacin, levofloxacin, ceftazidime, cefepime, and meropenem have activity against P. aeruginosa; confirm susceptibility. ¶¶ The possibility of prolonged QTc interval, tendinopathy, neuropathy, or development of an aneurysm should be reviewed and monitored when using fluoroquinolones. For more information, please refer to the UpToDate topic on fluoroquinolones. ΔΔ Ceftriaxone and ertapenem have no activity against P. aeruginosa, but are appropriate for other gram-negative organisms, if susceptible. ◊◊ For treatment of infection due to penicillin-susceptible enterococci, it is unclear whether combination therapy is superior to monotherapy, particularly if thorough debridement is performed. In the setting of retained hardware, we favor combination therapy for PJI due to Enterococcus faecalis with ampicillin and ceftriaxone. We do not use this approach for treatment of PJI due to non-faecalis species of penicillin-susceptible enterococci because synergy with these agents in vitro is variable and clinical data are not available in patients with PJI due to non-faecalis species [11]. If antibiotic-impregnated material containing gentamicin is implanted at the time of debridement, then monotherapy is likely sufficient and we favor treatment with either intravenous ampicillin or penicillin (vancomycin or daptomycin are acceptable alternative agents for patients with proven beta- lactam hypersensitivity). For treatment of infection due to penicillin-resistant enterococci, the preferred agent is vancomycin; daptomycin or teicoplanin (where available) are acceptable alternative agents. §§ For patients with Cutibacterium spp infection and beta-lactam hypersensitivity, reasonable alternative agents include vancomycin, a tetracycline (doxycycline or minocycline), or moxifloxacin.

Data from: 1. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice https://www.uptodate.com/...ents/prosthetic-joint-infection-treatment/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:52] Prosthetic joint infection: Treatment - UpToDate

guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013; 56:e1. 2. Berbari EF, Kanj SS, Kowalski TJ, et al. 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis 2015; 61:e26. 3. Figueroa DA, Mangini E, Amodio-Groton M, et al. Safety of high-dose intravenous daptomycin treatment: three-year cumulative experience in a clinical program. Clin Infect Dis 2009; 49:177. 4. Benvenuto M, Benziger DP, Yankelev S, Vigliani G. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Ther Chemother 2006; 50:3245. 5. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:285. 6. Teicoplanin. The UK electronic Medicines Compendium (eMC) summary of product characteristics. Last updated February 01, 2018. UK electronic Medicines Compendium. (Available online at https://www.medicines.org.uk/emc/ (Accessed January 28, 2019)). 7. Sodium fusidate. The UK electronic Medicines Compendium (eMC) summary of product characteristics. Last updated August 30, 2018. UK electronic Medicines Compendium. (Available online at https://www.medicines.org.uk/emc/ (Accessed January 28, 2019)). 8. Euba G, Lora-Tamayo J, Murillo O, et al. Pilot study of ampicillin-ceftriaxone combination for treatment of orthopedic infections due to Enterococcus faecalis. Antimicrob Agents Chemother 2009; 53:4305. 9. Calhoun JH, Manring MM. Adult osteomyelitis. Infect Dis Clin North Am 2005; 19:765. 10. Pushkin R, Iglesias-Ussel MD, Keedy K, et al. A randomized study evaluating oral fusidic acid (CEM-102) in combination with oral rifampin compared with standard-of-care antibiotics for treatment of prosthetic joint infections: A newly identified drug-drug interaction. Clin Infect Dis 2016; 63:1599. 11. Lorenzo MP, Kidd JM, Jenkins SG, et al. In vitro activity of ampicillin and ceftriaxone against ampicillin-susceptible Enterococcus faecium. J Antimicrob Chemother 2019; 74:2269.

Graphic 121445 Version 6.0

Δ ◊

Treatment of Staphylococcus aureus prosthetic joint infection in adults with retained hardware following debridement and completion of intravenous therapy: Oral antibiotic continuation therapy *¶

Antibiotic regimen Dosing

Preferred regimens include:

One of the following:

Levofloxacin 500 to 750 mg daily

Ciprofloxacin 500 to 750 mg twice daily

PLUS

RifampinΔ 300 to 450 mg twice daily◊

Alternative regimens include:

One of the following agents:§

Trimethoprim-sulfamethoxazole 1 double-strength tablet twice daily

Doxycycline 100 mg twice daily

Minocycline 100 mg twice daily

Dicloxacillin 500 mg 3 or 4 times daily

Cefadroxil 500 mg twice daily

Cephalexin 500 mg 3 or 4 times daily

Flucloxacillin 500 mg 3 or 4 times daily

Fusidic acid (where available)¥ 500 mg 3 times daily

PLUS

RifampinΔ 300 to 450 mg twice daily◊

The doses recommended above are intended for adults with normal renal function; the doses of some of these agents must be adjusted in patients with renal insufficiency. Refer to the Lexicomp drug-specific monographs for renal dose adjustments.

PJI: Prosthetic joint infection. * For patients with S. aureus PJI with retained hardware following debridement (eg, debridement and retention of prosthesis or 1-stage exchange), antibiotic therapy consists of pathogen-specific intravenous therapy in combination with rifampin for 2 to 6 weeks (refer to the UpToDate topic on treatment of PJI for further discussion). Thereafter, subsequent therapy for patients who undergo debridement and retention of hip, elbow, shoulder, or ankle PJI consists of pathogen-specific oral therapy in combination with rifampin to complete a total duration of 3 months. Subsequent therapy for patients who undergo debridement and retention of knee PJI consists of pathogen-specific oral therapy in combination with rifampin to complete a total duration of 6 months. Subsequent therapy for patients who undergo 1-stage exchange consists of pathogen-specific oral therapy in combination with rifampin to complete a total duration of 3 months. ¶ Following administration of antibiotic therapy as summarized in this table, indefinite antibiotic suppression with an oral regimen may be warranted in some patients; refer to the UpToDate topic on treatment of PJI for further discussion. Δ Patients who cannot take rifampin because of drug resistance, allergy, toxicity, intolerance, or drug-drug interactions should remain on intravenous antistaphylococcal therapy for 4 to 6 weeks (before transitioning to antibiotic suppression with an oral regimen, if warranted). ◊ We favor administration of rifampin 450 orally twice daily; the dose may be reduced to 300 mg orally twice daily in the setting of nausea. § Alternative agents given with rifampin are recommended for patients who cannot take a fluoroquinolone due to allergies, intolerances, or resistance. If an alternative agent is used, confirm susceptibility. ¥ Not available in the United States. Fusidic acid should not be used alone; it must be combined with a second active agent to reduce the likelihood of selection for drug resistance. When rifampin is combined with fusidic acid, fusidic levels may be reduced.

Data from: 1. 1. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013; 56:e1. 2. Berbari EF, Kanj SS, Kowalski TJ, et al. 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis 2015; 61:e26. 3. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18. https://www.uptodate.com/...ents/prosthetic-joint-infection-treatment/print?search=Bacterial%20arthritis&topicRef=7666&source=see_link[19.03.2020 15:39:52] Prosthetic joint infection: Treatment - UpToDate

4. Leijtens B, Elbers JB, Sturm PD, et al. Clindamycin-rifampin combination therapy for staphylococcal periprosthetic joint infections: a retrospective observational study. BMC Infect Dis 2017; 17:321. 5. Zimmerli W, Widmer AF, Blatter M, et al. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA 1998; 279:1537. 6. Byren I, Bejon P, Atkins BL, et al. One hundred and twelve infected arthroplasties treated with 'DAIR' (debridement, antibiotics and implant retention): antibiotic duration and outcome. J Antimicrob Chemother 2009;63:1264. 7. Berdal JE, Skråmm I, Mowinckel P, et al. Use of rifampicin and ciprofloxacin combination therapy after surgical debridement in the treatment of early manifestation prosthetic joint infections. Clin Microbiol Infect 2005; 11:843. 8. Senneville E, Poissy J, Legout L, et al. Safety of prolonged high-dose levofloxacin therapy for bone infections. J Chemother 2007; 19:688. 9. Soriano A, García S, Bori G, et al. Treatment of acute post-surgical infection of joint arthroplasty. Clin Microbiol Infect 2006; 12:930. 10. Pushkin R, Iglesias-Ussel MD, Keedy K, et al. A randomized study evaluating oral fusidic acid (CEM-102) in combination with oral rifampin compared with standard-of-care antibiotics for treatment of prosthetic joint infections: A newly identified drug-drug interaction. Clin Infect Dis 2016; 63:1599.

Graphic 119914 Version 4.0

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Suppression of osteomyelitis or prosthetic joint infection in adults: Oral antibiotic regimens*

Infectious agent Antibiotic regimen¶ Dosing

Staphylococci, One of the following: methicillin Cefadroxil 500 to 1000 mg twice daily susceptible Cephalexin 500 mg 3 or 4 times daily, or 1000 mg 2 or 3 times daily

Dicloxacillin 500 mg 3 or 4 times daily

Flucloxacillin 500 mg 3 or 4 times daily

Staphylococci, One of the following: methicillin Trimethoprim-sulfamethoxazole 1 double-strength tablet twice daily resistantΔ Doxycycline 100 mg twice daily

Minocycline 100 mg twice daily

Clindamycin 600 mg 3 times daily

Gram-negative One of the following: organisms Trimethoprim-sulfamethoxazole 1 double-strength tablet twice daily

Ciprofloxacin◊ 500 mg twice daily

Levofloxacin◊ 500 mg once daily

Penicillin-sensitive One of the following: streptococci and Amoxicillin 500 mg 2 to 3 times daily enterococci Penicillin V K 500 mg 2 to 3 times daily

Cutibacterium One of the following: (formerly Amoxicillin 500 mg 2 to 3 times daily Propionibacterium) acnes Penicillin V K 500 mg 2 to 3 times daily

PJI: Prosthetic joint infection. * Initial treatment of PJI consists of definitive antibiotic therapy (refer to the separate UpToDate table); suppressive therapy is warranted only for individuals with retained hardware and/or necrotic bone not amenable to complete debridement. The optimal duration of oral suppressive antibiotic therapy is uncertain. Refer to the UpToDate topic on the treatment of PJI for further discussion. ¶ The choice of antibiotic regimen should be based on susceptibility, as well as patient drug allergies, intolerances, and potential drug-drug interactions or contraindications to a specific agent. Δ The agents listed for methicillin-resistant staphylococci may be used for suppression of methicillin-susceptible staphylococci in patients with beta-lactam allergy or intolerance, provided the organism is susceptible. ◊ Ciprofloxacin and levofloxacin have activity against Pseudomonas aeruginosa.

Data from: 1. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013; 56:e1. 2. Berbari EF, Kanj SS, Kowalski TJ, et al. 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis 2015; 61:e26.

Graphic 119913 Version 4.0

Contributor Disclosures

Conflict of interest policy

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