Bone and Joint Infections

Infectious Arthritis

Infectious arthritis is defined as infection of one or more joints. It can be caused by bacteria, fungi, viruses, and parasites.

Acute Bacterial Arthritis

Introduction

Native joint septic arthritis is an uncommon illness, with a reported incidence in the United States of 2 to 10 cases per 100,000 persons per year. However, the incidence appears to be rising, in part due to an increasing number of joint surgical procedures performed in the United States and because of a larger “at-risk population.” The incidence of septic arthritis is higher in certain at-risk groups, including patients with rheumatoid arthritis and patients with a low socioeconomic status. Bacterial septic arthritis accounts for 8% to 27% of patients presenting with one or more acutely painful joints in the emergency room (ER). The knee joint is the most commonly affected joint. Septic arthritis is associated with significant morbidity; near half of the patients report decreased joint mobility after the infection. This, however, also depends on previous underlying joint disease and the type of microorganism involved. Bacterial arthritis is generally acquired hematogenously. Underlying joint architectural abnormality increases the risk of pyogenic arthritis. An important factor to consider is that the synovial membrane is a highly vascularized structure that lacks a basement membrane and is susceptible to hematogenous deposition of bacteria. Other routes of infection include trauma; animal bites; joint puncture from a nail, needle, or thorn; iatrogenic infection; and contiguous infection from adjacent soft tissue or bone. After knee arthroscopy, the infection risk is 0.04% to 0.4%, and after arthroscopic reconstruction, the risk is 0.14% to 1.7%. Rarely, septic arthritis has occurred in clusters after intraarticular injection of contaminated methylprednisolone.

Predisposing Factors

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Rheumatoid arthritis
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Old age
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Diabetes mellitus
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Renal insufficiency
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Penetrating joint trauma
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Intravenous (IV) drug use
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Endocarditis
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Immunocompromise
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Crystal-induced arthritis (gout and pseudogout), osteoarthritis, and Charcot arthropathy
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Chronic systemic diseases, including collagen vascular diseases, malignancy, chronic liver disease, sickle cell disease, and alcoholism
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Hypogammaglobulinemia
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Intraarticular injections
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Low socioeconomic status

Underlying joint disease especially due to rheumatoid arthritis is an important risk factor. Additionally, being treated with immunosuppressive medications such as penicillamine, sulfasalazine, anti–tumor necrosis factor alpha (anti-TNF) agents (doubles the risk according to one study), and corticosteroids further increase the risk. HIV infection, however, has not been associated with septic arthritis. In many cases, no predisposing risk factor is isolated.

Nongonococcal Arthritis

Pathogenesis

Adherence of bacteria to the synovial membrane followed by colonization and replication in synovial fluid is then followed by production of inflammatory cytokines and modulators. Bacteria such as Staphylococcus aureus have cell surface receptors that bind to joint extracellular matrix, promoting invasion. Joint damage results both directly from bacterial toxins and the host inflammatory response. Purulence is observed as a result of accumulation of acute and chronic inflammatory cells. This leads to destruction of joint cartilage. Joint effusion also leads to raised intraarticular pressure predisposing to decreased blood flow and tissue necrosis. Eventually, a joint space becomes narrow, and erosion of bone and cartilage occurs if arthritis is untreated.

Microbiology

In adults, Gram-positive cocci such as S. aureus or streptococci are responsible for the majority of native arthritis. S. aureus is responsible for 37% to 65% of the cases, with a higher incidence in patients with underlying rheumatoid arthritis.

Methicillin-resistant S. aureus (MRSA) is seen in elderly, those with recent orthopedic surgery, and those who are colonized with MRSA. Of the streptococci, Streptococcus agalactiae is a cause of bacterial arthritis in neonates, adults with malignancy, diabetes, and urogenital anatomic abnormalities and predisposes to polyarticular infection. Streptococcus bovis subgroup gallolyticus septic arthritis could be a manifestation of infective endocarditis; thus these patients should be evaluated for endocarditis and colonic malignancy.

Gram-negative rods account for 9% to 17% of all cases, and anaerobes are identified in 1% to 3%. Again, elderly and immunocompromised patients and IV drug users are at a higher risk. Pseudomonas aeruginosa is seen frequently in IV drug users and is also recognized as a cause of iatrogenic septic arthritis. In young infants, Haemophilus influenzae has now been replaced by Kingella kingae , a resident of oral flora.

Zoonotic pathogens such as Pasteurella multocida and Capnocytophaga spp. can occasionally cause contiguous septic arthritis after a dog or cat bite. Streptobacillius moniliformis , the cause of rat bite fever, can cause polyarticular arthritis after a rat bite. Cases of bacterial arthritis where a pathogen is not isolated from blood or joint fluid using conventional culture techniques are Mycoplasma hominis, Ureaplasma urealyticum, Borrelia burgdorferi and Tropheryma whipplei.

Clinical Presentation

The knee is the most common joint involved in nongonococcal septic arthritis followed by the hip, shoulder, wrist, and ankle. Arthritis of the small joints of the foot are seen generally in diabetics with adjacent skin and soft tissue ulceration. Polyarticular presentation may be seen in patients who are immunosuppressed (such as patients with rheumatoid arthritis [RA]) or patients with high-grade bacteremia (especially with S. aureus ). In cases of S. aureus bacteremia, sacroiliitis can also be seen.

The typical presentation is one of progressive pain, loss of function, and loss of range of motion of the involved joint seen over a period of several days, up to 2 weeks, depending on the organism and patient. Other symptoms include joint swelling, redness, and warmth. Fever and malaise can also be seen, though high-grade fever with rigors is rare, unless accompanied by bloodstream infection. Physical examination typically demonstrates joint tenderness, effusion and limitation of active and passive range of motion, and painful weight bearing. However, in older and immunocompromised patients, these symptoms may be subtle, leading to a delay in diagnosis.

Laboratory Screening

There is no single laboratory finding that is sensitive or specific for native septic arthritis. Leukocytosis, elevated erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) are helpful when present.

Synovial Fluid Analysis/Microbiologic Diagnosis

Aspiration of the joint space will often yield synovial fluid that is low viscosity and purulent. Synovial fluid white blood cell (WBC) count is typically 50,000 cells/mm ³ with a neutrophilic predominance, although lower counts are regularly seen and should not be ignored. Gram staining lacks sensitivity for the diagnosis of septic arthritis and is only diagnostic in 50% of cases. On the other hand, among patients who have not received prior antibiotics, synovial fluid culture will yield bacterial growth more than 60% of the time in nongonococcal infection. Blood cultures should always be drawn, as they can be positive in 50% of the cases. The synovial fluid broad-range polymerase chain reaction (PCR) test holds promise but is not available in all clinical microbiology labs. It is particularly useful in cases of slow-growing microorganisms such as K. kingae, Coxiella burnetii, Bartonella henselae, and Mycobacterium tuberculosis . It can be helpful in situations where patients have already received systemic antibiotics.

Radiologic Evaluation

Early in the course of bacterial arthritis, plain radiography will show periarticular soft tissue swelling, but the bony structures are normal. Later, as the infection progresses, loss of joint space, periosteal reaction, periarticular osteoporosis, and subchondral bone destruction can be seen. Plain films help rule out the presence of any foreign body.

Ultrasound is another technique that can be used to assess for the presence of effusion and for assistance in joint aspiration. Computed tomography (CT) scan and magnetic resonance imaging (MRI) are additional and sensitive imaging modalities, especially in detecting early septic arthritis, as well as detecting periarticular fistulas, abscesses, and adjacent/periarticular cellulitis and tenosynovitis.

Gonococcal Arthritis

Native septic arthritis due to infection with Neisseria gonorrhoeae results from a complication of mucosal gonococcal infection. Risk factors associated with gonococcal arthritis are similar to those for genital gonococcal infection, including low socioeconomic status, men who have sex with men, illicit drug use, and having multiple sexual partners.

Pathogenesis

After mucosal inflammation and infection with N. gonorrhoeae , occult bacteremia results. Mucosal infection may be asymptomatic. Bacteremia can result in wide dissemination from the infected mucosa, resulting in several joints being involved (disseminated gonococcal infection). N. gonorrhoeae possesses several virulence factors that help in its attachment to the mucosal and synovial membranes, including a long pili. The pili also prevents it from undergoing host leukocyte phagocytosis.

Clinical Presentation

Generally, disseminated gonococcal infection is characterized by a triad of dermatitis, tenosynovitis, and a migratory polyarthralgia/polyarthritis. Patients present with fever, chills, and malaise, with painful tenosynovitis of fingers and hands and occasionally lower limb joints. Less than half of the patients will have true septic joint effusion. A rash involves the palms and soles and can range from macules to papules and a pustular rash as well. Isolated septic gonococcal arthritis without accompanying tendinopathy and skin manifestations is less common, with knees, wrists, and ankles being most commonly affected. This is characterized by an inflamed and swollen joint with an effusion.

Diagnostic Testing

ESR is raised in half of the patients, accompanied by mild leukocytosis. Joint aspiration reveals a pyogenic aspirate, with WBC count ranging from 50,000 to 100,000 WBCs/mm ³ (mainly neutrophils), but lower cell counts are seen in patients with disseminated gonococcal infection with less intense pyogenic process. Gram stain of the joint aspirate reveals intracellular and extracellular Gram-negative diplococci in 25% of the cases. PCR assay of the synovial fluid is another technique for detecting the presence of N. gonorrhoeae. It is also reasonable to perform mucosal swabs and send them for culture, as recovery of N. gonorrhoeae from the mucosal sites is higher than from synovial fluid or blood cultures. Nucleic acid amplification tests (NAATs) can also be performed on urine and swabs from cervical or urethral swabs.

Differential Diagnosis

It is important to differentiate bacterial arthritis from noninfectious causes. Situations such as an acute attack of gout, pseudogout, and other crystalline joint arthropathies can mimic acute bacterial arthritis, as symptoms and signs can overlap.

Presence of crystals in joint fluid does not rule out bacterial arthritis. Gram stain and culture along with cell count with differential should be performed on all joint aspirates. Recognition of bacterial arthritis in patients with underlying rheumatoid arthritis is important as well. Gonococcal arthritis (when it presents as part of disseminated gonococcal infection [DGI]) should be differentiated from reactive arthritis, which is typically seen after a recent gastrointestinal or genitourinary infection. The typical rash of DGI is not seen in reactive arthritis; these patients generally have concurrent sacroiliitis, conjunctivitis, and penile manifestations such as circinate balanitis and keratoderma blennorrhagica.

Treatment

Acute septic arthritis requires prompt joint drainage and is an infectious diseases emergency. Whether it requires arthroscopy or open arthrotomy depends on the clinical situation and on the surgeon. Another approach is to drain the joint through daily closed needle aspiration until clinical improvement is seen. For bacterial infections involving the knee, shoulder, and wrist, arthroscopy is preferred; however, open arthrotomy is often required for the management of septic arthritis of the hip joint. In the published literature, there are no significant differences in the outcome between arthroscopy and arthrotomy for the initial drainage of the knee, hip, and other joints.

If infection has already destroyed the articular surface and underlying bone, then resection of the infected area is considered as well. In a case of severe hip septic arthritis, this would mean resection of the femoral head (Girdlestone procedure). Alternatively, arthrodesis may be performed, in which surgical fusion of the bones across former synovial space occurs, typically performed after septic arthritis of the knee or ankle. Amputation is indicated only in overwhelming and life-threatening infections or persistent local infection with significant bone loss, where the functional benefit after amputation is superior to limb salvage.

Along with joint drainage, concomitant antimicrobial therapy is must ( Table 13.1 ). In general, parenteral therapy or use of highly bioavailable therapy is preferred over the use of other oral agents. Whether or not Gram stain reveals Gram-positive cocci, given increasing prevalence of health care–associated MRSA and community acquired (CA)–MRSA, vancomycin should be included in the initial empirical therapy. If the Gram stain is noted for Gram-negative rods (or if Gram-negative organisms are suspected), then patients should also be started on an antipseudomonal cephalosporin. If specific epidemiologic or clinical factors raise concern for β-lactamase–producing pathogens, then a carbapenem antibiotic is indicated. If methicillin-susceptible S. aureus is identified, vancomycin can be de-escalated to an antistaphylococcal penicillin such as nafcillin or a first-generation cephalosporin such as cefazolin. Alternatives to vancomycin for MRSA septic arthritis include daptomycin, ceftaroline, and linezolid. These alternatives are used when a patient has an allergy or is intolerant to vancomycin. If vancomycin-resistant Enterococcus is recovered in cultures, then daptomycin or linezolid may be used. Adverse effects of daptomycin include muscular toxicity, evident by elevated creatine kinase or, rarely, eosinophilic pneumonia. Linezolid inhibits ribosomal proteins and can be given intravenously or orally at equivalent doses. Adverse effects of linezolid include peripheral or optic neuropathy, anemia, thrombocytopenia, and lactic acidosis. Other drugs with Gram-positive activity include tigecycline, ceftaroline, trimethoprim/sulfamethoxazole, and doxycycline or minocycline. In cases of septic arthritis due to human or animal bites, ampicillin–sulbactam or amoxicillin–clavulanate are preferred due to their activity against oral anaerobes. In cases of gonococcal arthritis, ceftriaxone 1 g IV daily is preferred. Fluoroquinolones are also used due to their Gram-negative spectrum. In all situations, definitive therapy should be chosen based on the antimicrobial susceptibility testing, with input based on cost and adverse effects, individualized to the patient.

Table 13.1

Antibiotic Choices Based on Identified Pathogen

Microorganisms	Treatment of Choice (IV)	Alternatives (IV)
Gram-positive cocci	Vancomycin	Daptomycin ^a
Methicillin-susceptible S. aureus	Cefazolin, nafcillin, or oxacillin	Ceftriaxone or vancomycin ^b
Methicillin-resistant S. aureus	Vancomycin	Daptomycin or teicoplanin (where available)
Streptococcus spp.	Penicillin G	Ceftriaxone or vancomycin ^b
Gram-negative rods	Ceftriaxone or ceftazidime or cefepime ^c	Ciprofloxacin or levofloxacin or carbapenem
Anaerobes	Clindamycin	Metronidazole
Enterococci	Ampicillin, penicillin G	Vancomycin or daptomycin
Gonococcal arthritis	Ceftriaxone
Gram-stain negative (but cell count consistent with septic arthritis)	Vancomycin ^a plus cefepime or ceftazidime	Daptomycin ^a plus piperacillin–tazobactam or fluoroquinolone or carbapenem

d Vancomycin alone can be used if immunocompetent and in the absence of trauma.

a For patients who are allergic or intolerant to vancomycin.

b For β-lactam hypersensitivity, vancomycin is the alternative.

c Cefepime, ceftazidime, ciprofloxacin, and levofloxacin have antipseudomonal activity.

There is a lack of consensus with regard to the optimal duration of therapy for septic arthritis. Generally, 2 weeks IV therapy for streptococci, 3 to 4 weeks IV therapy for staphylococci and Gram-negative bacteria, and greater than 4 weeks may be needed for immunocompromised patients and other host comorbidities such as extent of joint damage. For gonococcal arthritis, 7 to 14 days of therapy with ceftriaxone is the standard.

Fungal Arthritis

Generally, fungal arthritis affects immunocompromised patients, such as patients with RA or inflammatory bowel disease who are on high-dose corticosteroids or TNF-alpha inhibitor therapy. Common pathogens include Candida spp., Cryptococcus spp., Aspergillus spp., and other molds. Except for Candida species, most of these fungal pathogens have primary pulmonary infection with secondary hematogenous seeding of a joint in the setting of augmentation of immunosuppression. Occasionally, healthy hosts can develop fungal arthritis; this is typically seen in endemic mycoses and include Blastomyces dermatitidis , Histoplasma capsulatum, Coccidioides spp., and Sporothrix spp.

Candidal Arthritis

Risk factors for candidal arthritis include diabetes, malignancy, hemodialysis, IV drug abuse, and immunosuppressive medications, as well as prolonged use of broad-spectrum antibiotics. Infection is mostly acquired hematogenously. Candida albicans is the most common species, and the knee joint is most commonly affected. Synovial fluid analysis reveals low glucose and polymorphonuclear leukocytes, typically in excess of 50,000 cells/mm ³ .

Cryptococcal Arthritis

The causative organism is Cryptococcus neoformans, with arthritis typically seen concomitantly with cryptococcal osteomyelitis. The knee joint is commonly affected, and immunosuppression is the main risk factor. In addition to synovial fluid fungal cultures needed for diagnosis, serum cryptococcal antigen must be sent.

Coccidioidal Arthritis

This is typically seen in the southwestern regions of the United States. Causative fungi are Coccidioides immitis and Coccidioides posadasii . Infection generally is introduced via inhalation, followed by pneumonitis and polyarticular arthritis seen in one-third of the patients. Disseminated coccidioidomycosis is seen in ≈1%. Patients typically present with chronic granulomatous infection of bones and joints. The knee joint is the most commonly affected, and many times, infection is indolent in its course. Synovial fluid has a lymphocytic predominance, and spherules can be seen as well. Serologic testing includes serum coccidioides antibody testing and is confirmed on fungal culture of synovial fluid.

Blastomycosis

This primary infection due to B. dermatitidis usually involves the pulmonary tract and can disseminate, with joint involvement seen in patients with subjacent osteomyelitis. Occasionally, draining sinus tracts are seen as well. Diagnosis is made by cytologic examination of synovial fluid and confirmed upon performing synovial fluid fungal cultures.

Other Fungi

Fungal arthritis due to Histoplasma capsulatum is rare, but should be considered in patients from endemic areas with chronic joint infection. Arthritis due to S porothrix is generally seen in the setting of traumatic injury with a foreign body contaminated with soil. Diabetes and immunosuppression are risk factors, and diagnosis is often challenging due to synovial fluid cultures being frequently negative. Other fungal species that cause arthritis include Aspergillus , Fusarium spp., and Scedosporium spp., organisms that are typically seen in immunocompromised hosts.

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