Infectious (Septic) Arthritis

Definition, Etiology, PathogenesisTop

Infectious arthritis is acute or chronic arthritis caused by microorganisms invading the synovium. The infection is most frequently blood-borne, direct (joint aspiration, arthroscopy, orthopedic surgery, trauma), or it spreads by continuity from adjacent tissues (infected skin ulcers, cellulitis, osteomyelitis).

Etiologic agents in adults are most commonly bacteria (Staphylococcus aureus, Streptococcus pyogenes, less frequently gram-negative pathogens, including Neisseria gonorrhoeae, Neisseria meningitidis) and less often viruses (rubella virus, hepatitis virus B and C, parvovirus B19, chikungunya virus, zika virus), fungi, and parasites.

Risk factors for bacterial arthritis include rheumatic diseases (rheumatoid arthritis [RA], systemic lupus erythematosus [SLE]), joint replacement surgery (particularly of the knee or hip), treatment with tumor necrosis factor (TNF)-alpha inhibitors, joint aspiration, advanced age, diabetes mellitus, immunosuppression (alcohol dependence, immunosuppressive treatment, HIV infection), IV drug use, renal or liver failure, and hemophilia.

Clinical Features and Natural HistoryTop

Local manifestations: Pain, swelling, erythema, warming of the joint, and a decreased range of motion. Symptoms usually appear suddenly and progress rapidly. In some cases (tuberculosis, fungal infection, bacterial infection in individuals with RA or other connective tissue disorders, elderly patients, low virulence organisms) the course of infectious arthritis may be chronic and indolent. In 90% of patients bacterial arthritis affects only one joint, while in 10% of patients it affects multiple joints and is usually due to bacteremia. In prosthetic joint infections chronic joint loosening may develop.

General manifestations: Fever, rarely with chills or rigors; elderly patients are more frequently afebrile.

Features typical for specific etiologic factors:

1) Nongonococcal bacterial arthritis: Most frequently monoarthritis (usually of the knee). In ~20% of patients 2 to 3 joints are affected; septic polyarthritis is rare (it may develop, eg, in patients with RA or sepsis). In elderly patients symptoms may be minor. Joint aspirate cultures are positive in 70% of patients and blood cultures are positive in 24% to 76% of patients. In 30% to 50% of patients septic arthritis causes permanent joint damage.

2) Gonococcal arthritis: Migrating pain or polyarthritis (affecting knees, ankles, wrists), usually in young adults; rarely acute monoarthritis. Gonococcal arthritis frequently coexists with involvement of tendon sheaths and with cutaneous lesions (hemorrhagic bullae, papules, pustules). Joint aspirate cultures are positive in <25% of patients and blood cultures are rarely positive. The prognosis is good in >95% of patients.

3) Viral arthritis: Frequently polyarthritis (wrists and fingers), occasionally resembling RA (in parvovirus B19 infection). Patients may have coexisting cutaneous lesions (urticaria, erythema, petechiae) that resolve after 2 to 3 weeks. Viral arthritis mainly affects young women (it needs to be differentiated from connective tissue diseases such as SLE). Arthritis with associated fever is the main clinical sign of chikungunya infection and less commonly of zika infection, both of which should be considered in the differential diagnosis of patients who have traveled to tropical countries.

4) Tuberculous arthritis: Most commonly chronic arthritis affecting one large joint (the hip or knee). It is usually accompanied by osteomyelitis and myelitis. Joint aspirate cultures are positive in >80% of patients; synovial membrane biopsy is necessary for rapid diagnosis. This diagnosis is frequently delayed due to nonspecific symptoms and clinical course.

5) Fungal arthritis: Usually chronic monoarthritis, less commonly severe polyarthritis (sometimes accompanied by erythema nodosum).

DiagnosisTop

Diagnostic Tests

1. Laboratory tests in most patients reveal significantly elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, leukocytosis (particularly in patients with bacterial arthritis), and hypochromic anemia (in patients with chronic arthritis, eg, tuberculous arthritis).

2. Synovial fluid examination: This should include macroscopic assessment (septic fluid is usually cloudy and yellow-grey or yellow-green) and cell counts (these are often >25×109/L to 100×109/L, including >75% of neutrophils). Gram-stained synovial fluid smears are used to guide empiric antimicrobial treatment (in patients with negative culture results this may be the only evidence of bacterial arthritis); cultures of synovial fluid should be performed (in patients with suspected gonococcal arthritis perform blood cultures and synovial fluid cultures as well as cultures/nucleic acid amplification test [NAAT] of swabs from the urethra, cervix, rectum, and throat). Synovial fluid must be examined for the presence of crystals.

3. Blood cultures or cultures of other specimens, depending on clinical features.

4. Molecular or serologic investigations depending on the suspected pathogen.

5. Imaging studies: In patients with early arthritis radiographs reveal soft tissue edema and features of effusion. After ~1 week they show periarticular osteoporosis and in severe cases also joint space narrowing (caused by destruction of articular cartilage). After ~2 weeks peripheral erosions are seen (due to destruction of subchondral bone by pannus). In patients with chronic arthritis, bony or fibrous adhesions may form. In prosthetic joint infections loosening of the prosthesis can be seen with chronic joint infection. Ultrasonography is used mainly to monitor the volume of effusions and to mark sites for aspiration. Occasionally computed tomography (CT), magnetic resonance imaging (MRI), or scintigraphy may be indicated.

Diagnostic Criteria

Diagnosis is based on clinical features, synovial fluid examination (macroscopic assessment, Gram staining, cultures), and blood cultures. In patients with gonococcal arthritis perform screening for other sexually transmitted diseases, including syphilis, Chlamydia trachomatis, and HIV infections.

Differential Diagnosis

Acute crystal-associated arthropathy (gout, pseudogout; differentiation from bacterial arthritis based solely on clinical examination is difficult, synovial fluid examination is conclusive; note that infectious arthritis may accompany gout), reactive arthritis (this may be acute monoarthritis, particularly following a genitourinary or respiratory tract infection), acute monoarthritis as part of noninfectious polyarthritis (RA [in RA exacerbations macroscopic features of synovial fluid may be similar to synovial fluid in infectious arthritis; perform cultures and withhold intra-articular administration of glucocorticoids], SLE, psoriatic arthritis), Lyme disease, hemarthrosis following joint trauma, rheumatic fever, subacute bacterial endocarditis, infections of periarticular tissues (eg, bursitis).

TreatmentTop

1. Bacterial arthritis: In patients with suspected bacterial arthritis start empiric antimicrobial therapy after obtaining appropriate specimens. Empiric coverage should include vancomycin and/or cefazolin, based on local antibiograms, for gram-positive cocci and ceftriaxone for gram-negative cocci.

1) Nongonococcal bacterial arthritis: If gram-positive organisms are found, use IV vancomycin 30 mg/kg/d (usually up to 2 g/d) in 2 to 3 divided doses if there is a high epidemiologic suspicion of methicillin-resistant Staphylococcus aureus (MRSA). In patients with low risk for MRSA, cefazolin 1 to 2 g every 8 hours could be used; if gram-negative organisms are found, use a third-generation IV cephalosporin (ceftazidime 1-2 g every 8 hours, ceftriaxone 2 g every 24 hours, or cefotaxime 2 g every 8 hours). In the case of gram-negative strains, use vancomycin in immunocompetent patients and add a third-generation cephalosporin in immunocompromised patients or patients with a history of joint trauma. Change antibiotics based on culture results. IV antimicrobial treatment is usually continued for 2 weeks and followed by 2 weeks of oral treatment; exceptions to this regimen depend on clinical response, antibiotic bioavailability (eg, treatment with fluoroquinolones can be shorter and last 4-7 days), and culture results. Oral antimicrobial drugs with high bone penetration, such as quinolones or tetracyclines, started within 7 days of the beginning of therapy have been shown to be equivalent to longer parenteral therapy and likely either can be used.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Li HK, Rombach I, Zambellas R, et al; OVIVA Trial Collaborators. Oral versus Intravenous Antibiotics for Bone and Joint Infection. N Engl J Med. 2019 Jan 31;380(5):425-436. doi: 10.1056/NEJMoa1710926. PubMed PMID: 30699315; PubMed Central PMCID: PMC6522347.

2) Gonococcal arthritis: Use ceftriaxone 1 g IM or IV or cefotaxime 1 g IV every 8 hours for 7 days; alternatively use ciprofloxacin 400 mg IV every 12 hours. Investigate and treat comorbid Chlamydia trachomatis infection as well as other sexually transmitted infections (eg, HIV, syphilis).

3) Tuberculous arthritis: The choice of drugs is as in pulmonary tuberculosis (TB; see Tuberculosis: Active Disease). Treatment should be continued for a minimum of 9 to 12 months (longer than in pulmonary TB).

4) Infection following joint replacement surgery usually warrants removal of the implant, either in 1-stage or 2-stage revision, and prolonged long-term antimicrobial therapy. In cases of a 1-stage revision with retained hardware, parenteral therapy combined with oral rifampin (INN rifampicin) 600 mg daily is added on for biofilm formation, followed by step-down to a highly bioavailable oral option, such as a quinolone, combined with rifampin for 3 to 6 months, based on clinical response. For patients with 2-stage revision, 6 weeks of therapy is recommended, followed by eventual long-term joint replacement.

2. Nonbacterial infection:

1) Viral arthritis: Nonsteroidal anti-inflammatory drugs (NSAIDs).

2) Fungal arthritis: In patients with candidiasis use fluconazole 400 mg/d (6 mg/kg/d) for ≥6 weeks or amphotericin B (lipid formulation) 3 to 5 mg/kg/d for ≥2 weeks, followed by fluconazole 400 mg/d for an additional 4 weeks. Alternative treatments include an IV echinocandin (caspofungin 50-70 mg/d, anidulafungin 100 mg/d, or micafungin 100 mg/d) or amphotericin B (deoxycholate) 0.5 to 1 mg/kg/d for ≥2 weeks, followed by fluconazole 400 mg/d for ≥6 weeks. Surgical debridement of the necrotic tissues is necessary; in case of osteomyelitis treatment should be extended to 6 to 12 months.

3. Source control: Open surgical debridement or repeated evacuation of joint effusion by joint aspiration using a large-bore needle and followed by lavage of the joint space may be required to obtain source control. Source control must be considered until negative culture results are obtained. Intra-articular administration of antimicrobial agents is not recommended. If joint aspirations are ineffective (ie, it is impossible to evacuate the entire volume of effusion), visually guided arthroscopic joint irrigation is recommended (particularly for knee or shoulder joint effusions) using high volumes of 0.9% saline. An alternative to arthroscopy is surgical arthrotomy with open drainage (this is the method of choice in patients with infectious arthritis of the hip).

4. For the first few days of treatment the joint should be immobilized in a splint (usually in extension). Beginning from day 3, passive mobilization should be started, followed by active mobilization after the resolution of pain; this promotes healing and regeneration of the cartilage and periarticular tissues as well as prevents contractures and adhesions within the joint.

5. Control pain using analgesics.

6. The risk of infectious arthritis and delayed wound healing after surgery (eg, joint replacement) is increased in patients treated with biologic agents (eg, anti-TNF agents, anti-interleukin-17 [anti-IL-17] agents, anti-IL-6 agents, anti-CD20 antibodies) or Janus kinase (JAK) inhibitors (tofacitinib, baricitinib). According to the American College of Rheumatology (ACR), it is suggested to discontinue the drug and perform joint (hip, knee) replacement a week after the planned date for a consecutive dose and restart treatment after the wound has completely healed (2-4 weeks after surgery) when there are no signs of local or systemic infection.