Septic Arthritis

The term Septic Arthritis (SA) represents an invasion of a joint space by a variety of microorganisms, most commonly bacteria. Various types of viruses, mycobacteria, and fungi also may be involved. This discussion will focus primarily on the bacterial pathogens. Despite timely institution of appropriate treatment, SA continues to produce significant rates of morbidity and mortality. Reactive arthritis represents a sterile inflammatory process that may be triggered by an extra-articular infection.

Approximately 20,000 cases of SA occur in the United States each year (7.8 cases per 100,000 person-years), with a similar incidence occurring in Europe.[1]  The incidence of SA-caused disseminated gonococcal infection is 2.8 cases per 100,000 person-years.

By 2030, an estimated 4 million hip and knee arthroplasties will be performed per year in the United States.[2]  The incidence of prosthetic joint infection (PJI) among all prosthesis recipients ranges from 2% to 10%. Since postoperative surveillance is limited to the operative hospital, it may result in significant underestimation of the rate of PJIs.[3, 4]  It is important to remember that any patients who have undergone treatment for infection of a native joint are at a lifetime risk for PJI after a total joint arthroplasty of that particular joint.[5]  

PJIs are classified according to the onset of symptoms following implantation of the joint:

Early PJI symptoms occur within 30 days of implantation.

Late acute PJI symptoms begin more than 30 days after implantation of the device. It is the most frequent type of PJI, and symptoms are present 7 days or fewer prior to diagnosis. There is no evidence of sinus tracts.[4]

The duration of symptoms in patients with late indeterminate PJI is between 8 and 30 days. There is no evidence of sinus tracts.

Late chronic PJI occurs more than 30 days after placement, with symptoms of greater than 30 days or the presence of a sinus tract.

Septic arthritis is increasingly common among persons older than 65 years, among immunosuppressed individuals, and among those with various comorbidities such as diabetes. Fifty-six percent of patients with septic arthritis are male.

Gonococcal and nongonococcal bacterial/suppurative arthritis

Bacterial SA is commonly described as either gonococcal or nongonococcal.[1, 2, 6, 7, 8, 9]  Neisseria gonorrhoeae remains the most common pathogen (75% of cases) among younger sexually active individuals.[10, 11, 12]  The increased incidence of S aureus parallels the rise of prosthetic joint implantation, intravenous drug abuse (IVDA), and the use of immunosuppressive agents. This pathogen causes 80% of infected joints affected by rheumatoid arthritis (RA).

Streptococcal species, such as Streptococcus viridans, S pneumoniae,[13, 14]  and group B streptococci[15]  account for 20% of cases. Aerobic gram-negative rods are involved in 20-25% of cases. Most of these infections occur among the very young and very old,[16]  patients with diabetes, immunosuppressed individuals, and people who use intravenous drugs.[17, 18]

Infection of the cartilaginous joints (sternoclavicular, sacroiliac, and pubic joints) with Pseudomonas aeruginosa or Serratia species occurs almost exclusively among people who abuse intravenous drugs. Individuals with leukemia are susceptible to Aeromonas infections.[19]

Polymicrobial joint infections (5-10% of cases) and infection with anaerobic organisms (5% of cases) are usually a consequence of trauma or abdominal infection. Individuals with multiple pathogens have a higher rate of previous native and prosthetic joint infections. The most common pathogens were coagulase-negative Staphylococcus (CoNS), MSSA, and enterococci.[5]

The pathogen of Lyme disease, Borrelia burgdorferi, commonly produces a septic arthritis picture.[18]  Occasionally, the signs and symptoms of the acute infection persist despite successful eradication of this pathogen. This appears to result from ongoing synovial inflammation due to  persistent vascular damage, and autoimmune processes that interfere with appropriate tissue healing.

Brucella may cause septic arthritis in areas where cattle are not vaccinated. The organism of Whipple disease, Mycoplasma species, and Ureaplasma species infrequently involve septic joints.[2]

A wide variety of viruses (eg, human immunodeficiency virus [HIV], lymphocytic choriomeningitis virus, hepatitis B virus, rubella virus), mycobacteria, fungi (eg, Histoplasma species, Sporothrix schenckii, Coccidioides immitis, Blastomyces species), and other pathogens produce nonsuppurative joint infections.[19]

Types of prosthetic joint infections

There are three major categories of PJIs: those that develop within 3 months of implantation; those that appear within 3 to 24 months of implantation; and those that occur later than 24 months. Most cases of early prosthetic joint infection are caused by S aureus. The 3- to 24-month group usually are caused by coagulase-negative S aureus (CoNS) or gram-negative aerobes, both of which are acquired in the operating room. Late cases of prosthetic joint infection usually are the result of hematogenous spread from a variety of infectious foci.[20, 21]  Unusually, they may arise from a dormant infection of periprosthetic tissue. 

Reactive arthritis represents a sterile inflammatory process that is triggered by a variety of extra-articular infections.[22]

See also Pediatric Septic Arthritis, Pediatric Septic Arthritis Surgery, and Septic Arthritis Surgery.

Organisms may invade the joint by direct inoculation, by contiguous spread from infected periarticular tissue, or most commonly, via the bloodstream.[9]

The normal joint has several protective components. Healthy synovial cells possess significant phagocytic activity, and synovial fluid normally posseses significant bactericidal activity. Rheumatoid arthritis and systemic lupus erythematosus hamper the defensive functions of synovial fluid and decrease chemotaxis and phagocytic function of polymorphonuclear leukocytes. Patients with deficiencies of the terminal components of complement are susceptible to both Neisserial bacteremia and joint infections.

Pathogenic invasion

Previously damaged joints, especially those damaged by rheumatoid arthritis, are the most susceptible to infection. The synovial membranes of these joints exhibit neovascularization and increased adhesion factors; both conditions increase the chance of bacteremia, resulting in joint infection. Some microorganisms have properties that promote their tropism to the synovium. S aureus readily binds to articular sialoprotein, fibronectin, collagen, elastin, hyaluronic acid, and prosthetic material via specific tissue adhesion factors (microbial surface components recognizing adhesive matrix molecules [MSCRAMMs]). In adults, the arteriolar anastomosis between the epiphysis and the synovium permits the spread of osteomyelitis into the joint space.

The major consequence of bacterial invasion is damage to articular cartilage. This may be due to the particular organism's pathologic properties, such as the chondrocyte proteases of S aureus, as well as to the host's polymorphonuclear leukocytes response. The cells stimulate synthesis of cytokines and other inflammatory products, resulting in the hydrolysis of essential collagen and proteoglycans. Infection with N gonorrhoeae induces a relatively mild influx of white blood cells (WBCs) into the joint, explaining, in part, the minimal joint destruction observed in cases of infection with this organism relative to destruction associated with S aureus infection.

As the destructive process continues, pannus formation begins, and cartilage erosion occurs at the lateral margins of the joint. Large effusions, which can occur in infections of the hip joint, impair the blood supply and result in aseptic necrosis of bone. These destructive processes are well advanced as early as 3 days into the course of untreated infection.

Viral infections may cause direct invasion (rubella) or production of antigen/antibody complexes. Such immunologic mechanisms occur in infections with hepatitis B, parvovirus B19, and lymphocytic choriomeningitis viruses.

Reactive/postexposure process

Reactive, or postexposure, arthritis is observed more commonly in patients with human lymphocyte antigen B27 (HLA-B27) histocompatibility antigens. Although various infections can cause reactive arthritis, gastrointestinal processes are by far the most common. Gastrointestinal pathogens associated with reactive arthritis include the following[22] :

• Salmonella enteritidis
• Salmonella typhimurium
• Yersinia enterocolitica
• Campylobacter jejuni
• Clostridium difficile
• Shigella sonnei
• Entamoeba histolytica
• Cryptosporidium

Genitourinary infections, especially those due to Chlamydia trachomatis, are the second most common cause of reactive arthritis. The arthritis of Lyme disease usually results from immunologic mechanisms, with a minority of cases due to direct invasion by an organism. A reactive/postexposure process may occur months after the gastrointestinal or genitourinary process has resolved.

COVID-19 infection has been increasingly implicated as a cause of reactive arthritis especially among patients with rheumatoid arthritis.[1, 23]

PJIs

 PJIs may be a consequence of local infection, such as superficial surgical site infections/delayed wound healing (60-80% of cases).[4] Twenty to forty percent are due to continuous or transient bacteremias.[2] These may be spontaneous (ie, gingival disease) or secondary to various surgical manipulations. Delayed wound healing is a major factor behind early prosthetic joint infection. This increased risk resolves with the eventual development of a surrounding pseudocapsule, which significantly lessens the infectious risk posed by bloodstream infections.

Recommendations for the use of postoperative prophylactic antibiotics for revisions of total joint arthroplasties have yet to be established.[4]

The biofilm of coagulase-negative S aureus (CoNS) protects the pathogen from the host's defenses, as well as from various antibiotics. Polymethylmethacrylate cement inhibits WBC and complement function.

Overall, the most common organisms of prosthetic joint infections are CoNS (22% of cases) and S aureus (22% of cases). Enteric gram-negative organisms account for 25% of isolates.[21] Streptococci, including S viridans, enterococci, and the beta-hemolytic streptococci, cause 21% of cases. Anaerobes are isolated from 10% of patients.

Other distinctive host and/or situation-pathogen associations have been described, including Pasteurella multocida, Capnocytophaga species (dog and cat bites), Eikenella corrodens, anaerobes (especially Fusobacterium nucleatum and streptococcal species [human bites]), Aeromonas hydrophila (myelogenous leukemia), P aeruginosa, Serratia species, Candida species (particularly common in persons who abuse intravenous drugs), Mycobacterium marinum (water exposure), S schenckii (gardening), and S pneumoniae (sickle cell anemia).

Unlike their causative role in sickle cell osteomyelitis, Salmonella species are not associated with the septic arthritis of sickle cell anemia. Ten percent to 30% of patients with brucellosis have lumbosacral spine involvement.

The chief morbidity of septic arthritis is significant dysfunction of the joint, even if treated properly. Fifty percent of adults with septic arthritis have significant sequelae of decreased range of motion or chronic pain after infection.[1] Thirty percent of reactive arthritis cases may become chronic. Complications include dysfunctional joints, osteomyelitis, and sepsis.

Predictors of poor outcome in suppurative arthritis include the following[24] :

• Age older than 60 years
• Infection of the hip or shoulder joints
• Underlying rheumatoid arthritis
• Positive findings on synovial fluid cultures after 7 days of appropriate therapy
• Delay of 7 days or longer in instituting therapy

The mortality rate primarily depends on the causative organism. N gonorrhoeae septic arthritis carries an extremely low mortality rate, whereas that of S aureus can approach 50%.[23]  S aureus is the most common cause of septic arthritis in all age groups. Among those aged 15 to 50 years, N gonorrhea runs a close second, especially among those who are sexually active.

The following symptoms are consistent with SA [2, 8, 9, 20, 21, 24, 25, 26] :

• Acuteness of onset of the joint pain

• Whether the pain is superimposed on chronic pain

• Previous history of joint disease or trauma, whether accidental or iatrogenic (eg, infection complicates 0.4% of arthrocenteses)

• Whether the process is monoarticular or polyarticular, and which joints are involved

• The presence of extra-articular symptoms

• History regarding the possible presence of sexually transmitted infections (STIs); exposure to ticks (Lyme disease) and drug abuse should be elicited. 

• Conditions that adversely affect the host's defenses (eg, liver disease, diabetes mellitus, lymphoma, solid tumors, complement deficiencies [C7, C8], immunosuppressive drugs, hypogammaglobulinemia) are increasingly involved in cases of SA.The most important historical factor is the existence of underlying joint disease, especially rheumatoid arthritis, and the possibility of recent injury to the joint, needle aspiration, or injections into the joint. 

Symptoms

Patients with an infected joint typically present with the triad of fever (40-60% of cases), pain (75% of cases), and impaired range of motion. These symptoms may evolve over a few days to a few weeks. Fever is usually less than 102°F. Rigors are present in only 20% of cases. Somewhat surprisingly, spiking fevers and chills are much more common with crystalline arthritis.

Lyme disease

Months after infection onset, 60% of patients with untreated Lyme disease develop swelling and pain, chiefly affecting the large joints. Usually, Lyme disease affects one to two joints at a time, with the knee most commonly involved. The distinguishing pattern is attacks extending from a few weeks to months and separated by periods of complete remission. The rate of recurrence lessens by about 15% per year. A small percentage of individuals develop chronic arthritis (ie, inflammation of a joint lasting ≥ 1 y). This type of relapsing course almost always precedes the chronic stage of Lyme arthritis.

Prosthetic joint infection

Compared with patients with infections of native joints, most patients with PJI exhibit a prolonged low-grade course with gradually increasing pain. PJI due to Gram-negative organisms may present much more acutely.

Generally, no significant fever or swelling occurs in delayed prosthetic joint infections. However, individuals with early prosthetic joint infection may present with an acute illness characterized by high-grade fever, focal swelling, and redness. Cellulitis and draining sinus tracts often develop. Because late prosthetic joint infection usually is secondary to bacteremia, the clinical picture often is dominated by the source of the bloodstream infection.

The nature of the invading organism, the type of tissue infected, and the route of infection determine presentation. A high index of suspicion is needed for identification of bacteremic and delayed prosthetic joint infection. Because of its many pathogenic mechanisms, S aureus usually is associated with a fulminant course, as opposed to the indolent course of coagulase-negative S aureus (CoNS) that dominates delayed prosthetic joint infection. Relatively devitalized tissues (eg, wound hematomas) are conducive to rapid bacterial replication and a more acute course. Bacteremic spread allows infection with fewer organisms and leads to a more muted course.

Reactive and tuberculous arthritides

Reactive arthritis usually begins several weeks after the underlying infection has resolved.[21] Few concurrent systemic symptoms occur.

Symptoms of tuberculous arthritis are quite indolent; the diagnosis may be delayed for several years. Usually, the purified protein derivative (PPD) results are negative, and no signs, past or present, of pulmonary tuberculous exist.

Viral septic arthritis

Table 1, below, provides a summary of the clinical features of arthritis caused by various viral organisms.

Table 1. Clinical Features of Viral Disease–Associated Arthritis (Open Table in a new window)

The most commonly involved joint in septic arthritis is the knee (50% of cases), followed by the hip (20%), shoulder (8%), ankle (7%), and wrists (7%). The elbow, interphalangeal, sternoclavicular, and sacroiliac joints each make up 1-4% of cases.

A thorough inspection of all joints for signs of erythema, swelling (90% of cases), warmth, and tenderness is essential for diagnosing infection. Infected joints usually exhibit an obvious effusion, which is associated with marked limitation of both active and passive ranges of motion. Frequently, these findings may be diminished or poorly localized in cases of infection of the spine, hip, and shoulder joints.[19]

Signs and symptoms of infection may be muted in people who are elderly; who are immunocompromised (especially those with rheumatoid arthritis); and in those who inject drugs.

Pattern of joint involvement

Nongonococcal bacterial/suppurative arthritis

The pattern of joint involvement is an extremely important diagnostic feature. Of cases of nongonococcal suppurative arthritis, 85-90% are monoarticular. If the disease affects more than one joint, S aureus is most commonly implicated. Polyarticular arthritis usually is observed in gonococcal disease, various viral infections, Lyme disease, reactive arthritis, and various noninfectious processes.

Group B streptococci most commonly infect the sacroiliac and sternoclavicular joints.

Gonococcal bacterial/suppurative arthritis

Gonococcal musculoskeletal involvement may present in one of two ways, as described below.[2, 8, 9, 27]

Fever, arthralgias of multiple joints, and multiple skin lesions (dermatitis-arthritis syndrome) characterize disease that develops soon after the gonococcus disseminates from the cervix, urethra, or pharynx. Usually, this disease exhibits no clinical direct joint findings, but the process is one of tenosynovitis of asymmetric distribution. Typically, hand joints most often are involved, as well as those of the knee, wrist, ankle, and elbow. Skin lesions are multiple, but seldom number more than 12, whereas lesions associated with meningococcemia may number more than 100. The lesions evolve over a few days from papular to pustular or vesicular to necrotic. This course may recur for several months. Findings on cultures of blood and mucosal surfaces often are positive; findings on cultures of joint fluid usually are negative. Sixty percent of disseminated gonococcal infections are of this type.

Monoarticular arthritis without associated systemic symptoms, tenosynovitis, or skin lesions characterizes gonococcal disease that begins later after gonococcal dissemination than does dermatitis arthritis syndrome.[26] Dermatitis-arthritis syndrome may or may not precede this phase. In a joint infected by the Lyme organism, swelling may be disproportionate to the level of pain. Baker cysts are a frequent feature of this type of infectious arthritis. Because the pain of an infected hip joint may not be localized directly and swelling of the joint is inconspicuous, perform specific maneuvers, such as the Fabere maneuver. Infection of the sacroiliac joint often presents as buttock, hip, or anterior thigh pain. Direct pressure usually elicits tenderness in the joint. Alternatively, hyperextension of the hip and leg while the patient is lying down (ie, Gaenslen maneuver) elicits pain in a suppurative sacroiliac joint.

Septic bursitis most commonly involves the olecranon and prepatellar bursae. Swelling and pain are present. However, an infected bursa does not limit the range of motion of the underlying joint the way an actual joint infection does.[28]

Prosthetic joint infections

Physical findings of PJI, such as swelling, usually are minimal. The most distinctive is a draining sinus presumed to originate in the underlying infected prosthetic joint.

Reactive, viral, and tuberculous arthritides

Most cases of reactive arthritis involve a few large joints in an asymmetric fashion, whereas viral arthritis usually exhibits symmetric involvement of the smaller joints, especially the hands, with a concurrent rash. The joints of tuberculous arthritis can appear to be boggy on palpation.[29]

An acutely inflamed joint calls for a rapid workup of the synovial fluid (See Joint Fluid Analysis below). This should include examining the synovial fluid for uric acid crystals with polarizing microscopy and for organisms via Gram stain. Serum levels of uric acid may be normal during an acute gouty attack. If crystals are present and the Gram stain findings are negative, treatment for crystal-associated arthritis should be initiated. An exception to this would be the presence of significant risk factors for infection such as areas of infection elsewhere that could lead to bacteremia (pneumonia or pyelonephritis). Therapeutic decisions should not be delayed until results of the synovial fluid culture are available. The Musculoskeletal Infection Society (MSIS) has updated its criteria for diagnosing joint infection on the basis of culture results, synovial fluid studies, and inflammatory markers.[31]

If crystals are not detected, the patient should presumptively be treated for infection even in the face of a negative Gram stain. Its sensitivity in those who have not received antibiotics may be as low as 65%. Always send the fluid for culture. A joint damaged by gout or pseudogout has increased susceptibility to becoming infected. Culture of synovial tissue may be necessary to detect mycobacterial or fungal involvement.

If the patient's condition does not improve significantly after 5 days, the joint should be reexamined. Most septic joints have a white blood cell (WBC) count that exceeds 50,000/μL with a marked shift. Various sterile inflammatory processes may exhibit the same cellular profile.

Other considerations

The fluid of an infected bursa can mimic that of a bacterial joint infection.[20]

Measurements of C-reactive protein (CRP) and serum procalcitonin are useful in establishing acute inflammation of a joint as well as when following the patient's response to treatment (See below).[32]

Appropriate serologic tests for the diagnosis of various vasculitides or rheumatologic disorders often are required.[33]

Always perform joint aspiration under the most sterile conditions possible to prevent the introduction of infection.[34]

Normal joint fluid is clear and colorless and produces a stringlike structure when ejected from a syringe, indicating normal viscosity. Infected joint fluid typically is yellow-green due to elevated levels of nucleated cells, and the cell count usually is markedly elevated, demonstrating a predominance of polymorphonuclear leukocytes. An evaluation of the synovial fluid (ie, via leukocyte count, appearance on Gram stain, polarizing microscopy examination, culture) is the most rewarding approach in assessing a potentially infected joint. Additional stains and/or cultures should be obtained depending on the differential diagnosis considered.[27, 34, 35, 36] Alterations in the glucose and protein concentrations of the synovial fluid are nonspecific and so are generally not helpful in establishing a specific diagnosis.

Culture results in patients with non-gonococcal septic arthritis almost always are positive, unless the patient has received antibiotics before the joint aspiration. Cultures of the joint fluid in gonococcal infections yield positive results in only about 25% of cases. If this diagnosis is suspected, the organism can be cultured from other sites, such as the cervix, urethra, or throat.  

Lyme disease

Findings from examination of the synovial fluid in Lyme arthritis are similar to those found in infection caused by any other type of bacterium. Positive serology results (ie, antibody measurements, Western blot, polymerase chain reaction [PCR] for Lyme disease) do not establish the diagnosis of Lyme arthritis. A positive result on any of these tests simply indicates that the patient has encountered B burgdorferi; a positive result does not necessarily establish a connection between the patient's musculoskeletal symptoms and Lyme disease.[18]

Silver stains can be used to detect organisms in 5% of cases of Lyme arthritis.

Prosthetic joint infection

Evaluation of a possibly infected prosthetic joint is similar to that of a native joint.[2, 29, 31]  The presence of leukocytes in the aspirated fluid is variable. Because many of the potential pathogens are also classic contaminating organisms (eg, coagulase-negative S aureus [CoNS], Propionibacterium species, Corynebacterium species), repeat aspirates often are required to confirm the diagnosis. The use of multiple types of media with prolonged incubation times may increase both the sensitivity and specificity of the culture in prosthetic joint infection. The sensitivity of periprosthetic-tissue culture ranges from 65% to 94%.[28]  Material from fistulous tracts is associated with a high rate of contamination and probably is best avoided.

See Other Laboratory Tests, below.

Reactive and tuberculous arthritides

The synovial fluid of reactive arthritis demonstrates few signs of inflammation. PCR may reveal the DNA of the purported causative organism.

The synovial fluid of a joint infected with Mycobacterium tuberculosis shows marked leukocytosis. Although findings on acid-fast stains usually are negative, culture results are positive in 80% of cases. Culture results of synovial biopsies are positive in 94% of specimens.

Obtain at least 3 sets of blood cultures to document a bacteremic origin of the septic joint. The bloodstream infection may be continuous or intermittent in nature.

In the setting of possible gonococcal infection, obtaining cultures from the patient's rectum, cervix, urethra, and pharynx and from any skin lesions is most helpful. Immediate plating of the joint fluid directly onto appropriate media and/or rapid delivery of the specimen to the laboratory for appropriate plating and culturing are of benefit in improving the relatively low yield.[37]

Markers of inflammatory processes are becoming more appreciated in making the diagnosis of infection as well as monitoring its response to various therapeutic interventions. Procalcitonin and C-reactive protein are the most widely clinically available; other examples include the JAK-STAT pathway. Procalcitonin usually is secreted solely by the thyroid. During times of severe inflammation, such as sepsis, it may be produced by a wide variety of organs. Unlike the other inflammatory markers, its secretion is not triggered by viral infections.[38]

Polymerase chain reaction (PCR) holds promise for detection of bacterial DNA in joint fluid and synovial tissue.[32] PCR has led to diagnosis of infective arthritis due to Yersinia species, B burgdorferi, Chlamydia species, N gonorrhoeae, and Ureaplasma species. However, caveats concerning this approach are raised, because it cannot be used to distinguish between live and dead organisms, and it is susceptible to contamination. PCR techniques hold promise in detecting pathogens in patients who have recently received antibiotics. Unfortunately, many patients receive empirically administered antibiotics prior to sampling the synovial fluid.[38]

At times, imaging studies may be required to determine the significance of a given culture.

Radiography and ultrasonography

Plain radiography is of limited value in evaluating a joint for infection.[23]  Periarticular soft-tissue swelling is the most common finding. This imaging modality is most useful in ruling out underlying osteomyelitis or periarticular osteomyelitis caused by the joint infection itself.

In addition, plain radiography can reveal the linear deposition of calcium pyrophosphate. The radiographic findings of reactive arthritis usually are limited to those of soft-tissue swelling or periarticular osteoporosis. 

A 30-year-old man who was taking steroids presented with a joint effusion and knee pain. Anteroposterior view of the knee demonstrates patchy demineralization of the tibia and femur and joint-space narrowing. This was caused by tuberculoid infection of the joint.

Septic arthritis. Anteroposterior view of the shoulder demonstrates subchondral erosions and sclerosis in the humeral head. These are relatively late findings of septic arthritis. Periosteal reaction due to coincident osteomyelitis is present adjacent to the surgical neck of the humerus.

During the progression of infectious arthritis of the hip, this image was obtained early in the disease and shows only concentric joint-space loss.

Ultrasonography may be used to diagnose effusions in chronically distorted joints (secondary to trauma or rheumatoid arthritis). It is an underutilized technique.[39]  

CT scanning, MRI, and radionuclide scanning

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) are more sensitive for distinguishing osteomyelitis, periarticular abscesses, and joint effusions. The information gained usually does not justify the increased cost; however, these tests are most helpful in patients with sacroiliac or sternoclavicular joint infection to rule out extension into the mediastinum or pelvis. MRI is preferred because of its greater ability to image soft tissue.

Radionuclide scans (ie, technetium-99m [99m Tc], gallium-67 [67 Ga], indium-111 [111 In] leukocyte scans) are used to nonspecifically localize areas of inflammation. They cannot be used to distinguish infectious from sterile processes. Radionuclide scans may be of use in diagnosing septic arthritis in relatively sequestered areas, such as the hip and sacroiliac joints.

Imaging in prosthetic joint infection

The sensitivity of all the available types of imaging studies is inadequate in documenting PJI. 

In PJI, plain radiography can reveal new subperiosteal bone growth and transcortical sinus tracts.[2, 40] These findings are quite specific for infection. Arthrography can demonstrate loosening of the prosthesis and abscesses. Nuclear scans of all types are of limited diagnostic use in patients with prosthetic joint infection, and MRIs are limited by the type of implanted material (this diagnostic modality can safely image only titanium or tantalum devices). Fludeoxyglucose-positron emission tomography (FDG-PET) scans may hold some promise in diagnosing lower-extremity prosthetic joint infections. However, this approach cannot differentiate aseptic loosening from infection.[35, 40]  CT scans are quite insensitive in detecting periprosthetic soft tissue infection of implanted joints.[39]

Medical management of infectious arthritis should be focused on adequate and timely drainage of the infected synovial fluid; administration of appropriate antibiotic(s); and debridement of any associated osteomyelitis or soft tissue infection with immobilization of the joint to control pain. The major challenges are duration of oral and intravenous antibiotic administration, especially in the setting of PJI.

Acute PJI (< 3 wks in duration) can be cured medically if it is of the early type or secondary to hematogenous spread without any evidence of periarticular soft-tissue involvement or joint instability.[10]  However, it is imperative to monitor therapy by repeat ultrasounds or other imaging studies of the joint, as well as inflammatory markers such as CRP.

Overall, the mean length of hospitalization for septic arthritis is 11.5 days. However, outpatient antibiotic therapy in stable patients can significantly reduce hospital stays.[41]

Consultations

Typically, care providers have consulted orthopedic and /or infectious disease consultants in their management of septic arthritis. However, the ever-increasing amount of prosthetic joint surgery infections along with the lack of clearly defined approaches to their infectious complications have led to recommendations of interdisciplinary boards to oversee the care of these patients.[42, 43]  

In native joint infections, antibiotics usually are administered parenterally for at least 2 weeks. As a rule, the SA of disseminated gonorrhea responds to 2 weeks of intravenous antibiotic.[37]  However, each case must be evaluated independently. The medical dogma that infection with either methicillin-resistant S aureus (MRSA) or methicillin-susceptible S aureus (MSSA) requires at least 4 full weeks of intravenous treatment has recently been challenged.

In a randomized controlled study of 1054 patients(OVIVA trial), 61% had hardware-associated infections, 38% were infected with S aureus, and 27% were infected with CoNS. In the OVIVA trial, standard intravenous antibiotic therapy was begun within 7 days of surgery and administered for at least 6 weeks. In the other arm of the study, patients received oral antibiotic therapy. Both groups of patients could receive follow-up oral antibiotics. At the end of 1 year, there did not seem to be a significant difference in the rate of failure between both groups. Standard treatment failed in 14.6 % of the IV group and 13.2% of the oral group.[41] The oral agents were generally quinolones or penicillins. Intravenous agents usually were the glycopeptides and cephalosporins. In both groups, therapy was “tweaked" to meet the therapeutic challenges of each subject. More data are emerging to support shortened antibiotic courses for septic arthritis of native joints.[44]  

The DATIPO study compared the efficacy of 6 weeks versus 12 weeks of antibiotic therapy in patients with PJI who had undergone appropriate surgical procedures to eradicate associated osteomyelitis and soft issue infection or joint replacement by 1 or 2 stage procedure. The medium duration of IV antibiotic administration was 9 days for both groups. The failure rate to eradicate joint infection was 18.1% for the 6-week group and 9.4% for the 12-week group.[45]  The biggest risk for failure was among those who underwent one simple debridement without removal of the prosthetic material.

Remaining therapeutic challenges include types of antibiotics; total duration of their administration, including both IV and PO routes; and treatment of late PJI. From a functional perspective, antibiotic therapy along with debridement of infected periprosthetic tissue while retaining the infected prosthesis has the potential for providing optimum results.[46]

In summary, the study emphasized the importance of implant removal. Optimal duration of therapy needs to balance the increased risk for side effects related to prolonged exposure to these agents against treatment failure.

Caveats to this shortened course of IV antibiotic therapy include the presence of extensive periarticular osteomyelitis, leukopenia, or other immunosuppressive states. In patients with blood cultures that are positive for S aureus, it is imperative to exclude underlying valvular infection. More and more, it appears that prolonged antibiotic administration(>1 year) in periprosthetic PJI serves to suppress and not cure the periprosthetic PJI. Measuring the response of various inflammatory markers must be strongly considered to augment the clinical response to antibiotic treatment.

See Surgical Intervention in Prosthetic Joint Infection, below.

Antibiotic selection

Initial antibiotic choices must be empirical, based on the sensitivity pattern of the pathogens of the community. Consider the rise of resistance among potential bacteria when choosing an initial antibiotic regimen. If local incidence of MRSA is high (in particular, marked increase in the resistance of the pneumococcus), prescribe alternate antibiotics initially. Because many isolates of group B streptococci have become tolerant of penicillin, use a combination of penicillin and gentamicin or a later-generation cephalosporin. MRSA is becoming established outside of the hospital setting. Enterobacteriaceae and P aeruginosa are becoming more resistant to multiple antibiotics. Knowing the resistance patterns in the community, as well as in the hospital, is most important.

Preferably, the antibiotic should be bactericidal with some effect against the slow-growing organisms that are protected within a biofilm (eg, coagulase-negative S aureus [CoNS]) and S aureus. Rifampin fulfills these requirements. This agent should never be used alone because of the rapid development of bacterial resistance to the drug.

If, after 5 days of therapy, the joint shows some degree of improvement, consider an empirical trial of an anti-inflammatory agent for increased symptomatic relief. If the joint fails to respond after 5 days of appropriate antibiotic therapy (eg, presence of clinically significant fever, continued synovial purulence, persistently positive findings on culture), reassess the therapeutic approach, as follows:

• Follow up on the response of the inflammatory markers (CRP, procalcitonin) with the caveat that normalization of these may represent suppression and not eradication of the infection
• Reculture the fluid and reexamine for crystals
• Perform appropriate serologies for diagnosis of Lyme disease; if these are positive, treat per guidelines
• If fungal or mycobacterial infection is possible, consider obtaining a synovial biopsy
• Consider the possibility of reactive arthritis; nonsteroidal anti-inflammatory drugs (NSAIDs) are the primary therapeutic agents for reactive arthritis
• Perform imaging studies, either radiographs or magnetic resonance imaging (MRI), to rule out periarticular osteomyelitis.
• Candida auris is a very recently isolated fungus that contaminates surfaces and sources of water ithroughout a healthcare facility. It  tenaciously colonizes the skin of those suffering from COVID-19 ^[47]

Antibiotics have a role in suppressing associated chronic osteomyelitis and chronically infected prosthetic material that cannot be removed for various reasons.

The use of fluoroquinolones for an extended period should be considered when the removal of an infected prosthesis is not possible. Cure rates as high as 62% have been documented in relatively small series. Generally, such prolonged therapy is seen as suppressive and not curative.[25]

Usually, immobilization of the infected joint to control pain is not necessary after the first few days. If the patient's condition responds adequately after 5 days of treatment, begin gentle mobilization of the infected joint. Most patients require aggressive physical therapy to allow maximum post-infection functioning of the joint.

Initial physical therapy consists of maintaining the joint in its functional position and providing passive range-of-motion exercises. The joint should bear no weight until the clinical signs and symptoms of synovitis have resolved. Aggressive physical therapy often is required to achieve maximum therapeutic benefit.

The choice of the type of drainage, whether percutaneous or surgical, has not been resolved completely.[10, 33, 48] In general, use a needle aspirate initially, repeating joint taps frequently enough to prevent significant reaccumulation of fluid. Aspirating the joint two to three times a day may be necessary during the first few days. If such drainage is required past this point, surgical drainage should be initiated.

Purulent gonococcal arthritis requires frequent joint drainage. However, the joints of patients with disseminated gonococcemia characterized by the triad of tenosynovitis, dermatitis, and polyarthralgia rarely require surgical drainage.[49]

Surgical drainage is indicated when one or more of the following occur:

• The appropriate choice of antibiotic and vigorous percutaneous drainage fails to clear the infection after 5 to 7 days
• The infected joints are difficult to aspirate (eg, hip)
• Adjacent soft tissue is infected

Routine arthroscopic lavage rarely is indicated. However, drainage through the arthroscope is replacing open surgical drainage. With arthroscopic drainage, the operator can visualize the interior of the joint and can drain pus, debride, and lyse adhesions.

Debridement and retention of the prosthesis can be considered in patients who develop periprosthetic joint infection (PJI) within 30 days of implantation or in those whose PJI presented within 3 weeks of the development of symptoms, if the prosthesis appears to be well fixed and is without a sinus tract.[24] The DAIR technique is to leave the prosthesis in place, perform aggressive wound debridement, and treat with appropriate antibiotics (See below). 

The PIANO Study reviewed the success rate of the DAIR approach. It was curative in 74% of early PJIs; 49% in LA-PJI; and 44% in chronic PJIs. This progressive loss of efficacy of the DAIR approach may be due to a number of factors:

1. Persistence of the periarticular soft tissue and/ or bony infection that escape detection by current imaging techniques (radionuclide scans, ultrasonograhy, MRIs). There often are periarticular areas of necrotic soft tissue and bone. These "safe havens" may promote resistance to the initially administered antibiotics (See Antibiotic Therapy, below). Intermittent short repeat courses of antibiotic promote development of bacterial resistance by decreasing the permeability of the bacteria's cellular membrane or by increasing the efflux of the antibiotic from the cellular interior. ^[38]
2. Because of the above, the choice of antibiotic and its dosing regimen should not be based solely on the initial data set. Essentially, the pathogen may have become resistant. A new regimen, often members of the tetracycline family, should be started. Even if not, a change in renal function or liver function may necessitate an overhaul of the therapeutic plan. 

Otherwise, removal of all the prosthetic material is mandatory. First, remove the prosthesis and follow with an appropriate antibiotic. Then, place the new joint, impregnating the methylmethacrylate cement with an anti-infective agent (ie, gentamicin, tobramycin). Antibiotic diffusion into the surrounding tissues is the goal. The success rate for this approach is approximately 95% for both hip and knee joints.

An intermediate method is to exchange the new joint for the infected joint in a 1-stage surgical procedure with concomitant antibiotic therapy. This method, with concurrent use of antibiotic cement, may be successful in 70-90% of cases. What is unclear is the total duration of post procedural antibiotic therapy. A recent study compared the effectiveness of 6 weeks versus 12 weeks of total antibiotic therapy.[41]  Forty-one percent underwent debridement alone; 37% underwent a one-stage exchange; and 22% received a two-stage exchange of the implants.

Thirty-eight percent of S aureus infections received 6 weeks of antibiotic therapy, whereas 30% received 12 weeks of antibiotics. Thirty percent of CoNS received 6 weeks and 35% received 12 weeks of antimicrobials. Both received 9 days of parenteral antimicrobials. The fluoroquinolones and rifampin were the most frequently employed.

The design of this study is problematic in that there was a wide variety of surgical interventions employed as well as specific antibiotic regimens. Even the 12-week course generally is shorter than that usually followed in the United States. It is consistent with recent studies.[44]  The response to antibiotic therapy needs to be monitored by follow-up exams and appropriate imaging studies and measurement of inflammatory markers.

Strictly adhere to sterile procedures whenever the joint space is invaded (eg, in aspiration or arthroscopic procedures).

Antibiotic prophylaxis with an anti-staphylococcal antibiotic has been demonstrated to reduce wound infections in joint replacement surgery. Polymethylmethacrylate cement impregnated with antibiotics may decrease perioperative infections.

Using antibiotic prophylaxis on the same theoretic basis as that for cardiac valvular disease has been advocated. Whenever a sustained bacteremia may be encountered, be aware of the possibility of joint involvement, especially for prosthetic joints. Consideration should be given to more prolonged treatment of the bacteremia to cover the possibility of very early joint infection (secondary prophylaxis). The implanted hardware most likely is at greatest risk for bacteremia infection within a few months of placement. The risk probably decreases as a pseudocapsule evolves. During this time, prophylaxis is probably most beneficial. The results of a recent well-designed study support the recommendation that all joint replacement patients require antibiotic prophylaxis prior to dental procedures.[50]  The author will continue to provide such prophylaxis.

Treat any infection promptly to lessen the chance of bloodstream invasion. In addition, decreasing the incidence of underlying infections best prevents reactive arthritis.

Patient education

Instruct patients with a prosthetic joint in place to recognize early signs of joint infection and, more importantly, to recognize bacterial infections in other parts of their bodies to prevent associated bacteremias.

For patient education information, see Arthritis Center as well as Knee Pain and Ticks.

The risk for repeat arthroplasty performed for septic arthritis is six times that of repeat arthroplasty for other indications. Patients with septic arthritis who underwent arthroplasty also exhibited a significantly increased mortality rate over the 15 years after the procedure.[51, 52]

For various reasons, joint infection may fail to respond to combined surgical and antibiotic therapy.[51] In such cases, an orally administered suppressive antibiotic therapy usually is administered. The increasing prevalence of resistant organisms among these individuals is eliminating this option; subcutaneous injection of beta-lactam drugs provides another option.[52]

The empiric choice of antibiotic therapy is based on results of the Gram stain, the clinical picture, and the medical background of the patient. When the Gram stain fails to reveal any microorganisms (40-50% of cases), the individual's age and sexual activity become the major determinants to differentiate gonococcal from nongonococcal arthritis. When there is no evidence supporting any extra-articular infection, antibiotics must cover S aureus, streptococcal species, and gonococci (in patients who are sexually active). Synovial fluid examination may be helpful in approximately 50% of cases. Because of the significant adverse consequences of inadequate therapy, the author empirically covers for the presence of MSSA, MRSA, CoNS, N gonnorhea, and gram-negative aerobes. A typical combination would be ceftriaxone and vancomycin. In the presence of implanted material, rifampin should be added because of its unique ability to penetrate the biofilms of infected prosthetic devices.[53, 54, 55]  

Evidence exists that earlier initiation of an appropriate antibiotic regimen produces better functional results. Generally, treatment is administered intravenously for 3 to 4 weeks. The major exception to this is gonococcal infection, for which total therapy is approximately 2 weeks with an eventual switch to oral therapy.

No indication exists for direct installation of antibiotics into the joint cavity. Such a practice may increase the inflammatory surge that can add to permanent joint damage.

The following section presents antibiotics frequently used by the author.[56]

Documenting the efficacy of the antibiotic regimen by serial improvement and eventual normalization of inflammatory markers is key in managing PJI.

Please see the following articles on empiric and organism-specific therapy of native and prosthetic septic arthritis for more detailed discussion of antibiotic choices as well as dosing strategies:

Septic Arthritis of Native Joints Empiric Therapy; Septic Arthritis of Native Joints Organism-Specific Therapy; Septic Arthritis of Prosthetic Joints Empiric Therapy; and Septic Arthritis of Prosthetic Joints Organism-Specific Therapy.

Ciprofloxacin (Cipro)

Ciprofloxacin is an alternative antibiotic to ceftriaxone to treat N gonorrhoeae and gram-negative enteric rods.

Linezolid (Zyvox)

Linezolid is an alternative antibiotic that is used in patients allergic to vancomycin and for the treatment of vancomycin-resistant enterococci.

Oxacillin

Oxacillin and nafcillin are bactericidal semisynthetic penicillins that inhibit cell wall synthesis. Useful against methicillin-sensitive S aureus (MSSA). Nafcillin has the advantage in not requiring adjustment in renal failure and does not lead to leukopenia and thrombocytopenia with prolonged usage.

Dalbavancin (Dalvance)

The prolonged half-life (360 hours) allows weekly dosing of dalbavancin. In addition, its effectiveness against gram-positive cocci, including biofilm producers, makes it a very desirable agent for the outpatient treatment of native and prosthetic joint infections.

Cefixime (Suprax)

Cefixime is a third-generation oral cephalosporin with broad activity against gram-negative bacteria. By binding to one or more of the penicillin-binding proteins, this agent arrests bacterial cell wall synthesis and inhibits bacterial growth.

Oral cefixime is used as a follow-up to intravenous (IV) ceftriaxone to treat N gonorrhoeae.

Ceftriaxone

Cephalosporin with long half-life effective against essentially all the gram-negative and enteric organisms involved in SA.

Linezolid

Linezolid is effective against many positive pathogens including MSSA, MRSA, VSE, VRE. Serum levels are essentially equal whether given either by oral or intravenous administration. Dosing does not need to be adjusted according to renal function. Side effects include potential severe hepatotoxicity. After 2 weeks of administration, the risk for severe leukopenia and thrombocytopenia and various types of neuropathy markedly increase.

Vancomycin (Vancocin)

Vancomycin is an anti-infective agent used against MSSA, MRSA, methicillin-resistant CoNS, and ampicillin-resistant enterococci, and in patients allergic to penicillin. It is key to ensure that therapeutic serum levels have been achieved (trough level 5-12mcg/ml). In the face of fluctuating renal function, this may be an impossible task. Switching to linezolid is advisable.

Daptomycin (Cubicin)

Prior vancomycin administration may induce resistance to this medication.

Concurrent use of nafcillin or ampicillin may potentiate its bactericidal effect. 

Dosing may range from 4mg/kg -12mg/kg per 24 hrs.

.

Rifampin

Rifampin is used in combination with other drugs. It inhibits RNA synthesis in bacteria by binding to the beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription. It has the unique ability to penetrate the protective biofilms of S aureus and CoNS that form on prosthetic material. It is essential in treating Staphylococcal infections. Many pathogens rapidly develop resistance to it; 2 appropriate antibiotics should be administered several days before starting rifampin and to protect the rifampin. They should be continued throughout the course of rifampin.

Class Summary

Cefepime is effective against enterococcal streptococci, MSSA, CoNS, and most aerobic gram negatives including Pseudomonas. It is not effective against ESBL producers.

Class Summary

Minocycline doxycycline