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Bacterial septic arthritis: diagnosis and treatment

Sumeet Chander MSc MRCP(UK)
Specialist Registrar,
Department of Rheumatology,
Royal Sussex County Hospital,
Brighton, UK
Bacterial septic arthritis is a common rheumatological emergency presenting on the acute medical admission ward. Diagnosing septic arthritis can be challenging, but delaying diagnosis and treatment can lead to irreversible joint damage and mortality in 11% of patients; this rises to 50% with polyarticular involvement.(1) The incidence of septic arthritis is increasing, especially in ageing populations, immunocompromised patients and patients with prosthetic joints. The emergence of pathogens resistant to conventional antibiotics further increases this burden.
The incidence of proven and probable septic arthritis in Western Europe is 5.7 per 100,000 patient-years per year.(2) Predisposing factors such as antimicrobial resistance, ageing, immunosuppression, alcohol excess, intravenous (IV) drug usage, diabetes mellitus, prosthetic joints, skin infection or ulceration, patients undergoing invasive or orthopaedic procedures, previous joint pathology (including rheumatoid arthritis/inflammatory arthritis, osteoarthritis and crystal arthropathy) and intra-articular steroid injections increase the risk of septic arthritis.
Staphylococci and streptococci remain the most common organisms in patients presenting with septic arthritis. The isolation of methicillin-resistant Staphylococcus aureus (MRSA) from cultures is a growing problem as studies report rates of 50%, especially in patients with a history of IV drug use.(3) Gram-negative organisms are more common in older and immunocompromised patients, with anaerobes commonly being isolated in patients with trauma and IV drug use. Infection in the joint can occur as a result of direct inoculation or haematogenous spread. Elderly, immunocompromised and immunosuppressed patients and patients with previous joint damage are at increased risk of septic arthritis. Hospital inpatients, especially those undergoing invasive procedures or with in-dwelling catheters/devices are also at an increased risk of bacteraemia. Septic arthritis can also occur in the presence of bacterial meningitis or infective endocarditis. The inflammatory process is initiated by bacterial and cell wall proteins, adhesions, toxins (staphylococcal toxic shock syndrome toxin) and enzymes. This leads to release of cytokines and proteases which lead to joint destruction. The role of cytokines has been studied in mouse models, where deletion of macrophage-derived cytokines such as lymphotoxin-alpha, tumour necrosis factor-alpha (TNF-α) and interleukin-1 receptor led to reduced host protection in S. aureus sepsis.(4,5) Some strains of S. aureus are also positive for Panton-Valentine leucocidin (PVL) cytotoxins, which are associated with fulminant infections as the toxin enables the bacteria to survive in neutrophils.(6,7) The presence of adhesions on the surface of bacteria further facilitates the inflammatory process by mediating bacterial adherence to intra-articular proteins. 
Clinical features
Septic arthritis presents as a hot, swollen and painful joint with a diminished range of movements. Symptoms are usually present for less than two weeks. However, there can be a delayed presentation with infected prosthetic joints, low virulence organisms or tuberculosis or another focus of infection.(1,8) Patients with pre-existing inflammatory joint disease present with inflammatory activity in the septic joint that is out of proportion to disease activity in the other joints. The large joints, especially the knees, are more commonly affected with nearly 20% of patients having more than one joint involvement.(9) Patients usually present with the typical features of infection, but this is not always the case. Fever is present in only 60% of patients presenting with septic arthritis. This may be secondary to risk factors such as immunocompromised state, elderly age and diabetes.
Differential diagnosis
Other conditions can manifest with acute, hot, swollen joints mimicking septic arthritis. Crystal arthropathy (gout and pseudo-gout), rheumatoid arthritis, viral arthritis and reactive arthritis can manifest as an acute, hot, swollen joint. A good clinical history, examination, pattern of joint involvement, radiographs, synovial fluid analysis along with cultures, blood investigations and serological tests should help to exclude these conditions. The synovial aspirate from gout and pseudo gout reveal urate crystals and calcium pyrophosphate crystals, respectively, on polarised light microscopy. Rarely, patients can manifest with co-existing septic arthritis and gout affecting the same joint. Therefore, all patients presenting with an acute, hot, swollen joint should be treated as septic arthritis unless proved otherwise.
Laboratory investigations 
The definitive diagnosis of septic arthritis remains isolation of bacteria from synovial fluid. Blood and synovial cultures should always be taken prior to starting antibiotic treatment to increase the chances of a positive result. It is also essential to send relevant cultures (urine/sputum) when other symptoms are present to ascertain the causative organism and the source of infection. In many cases with high clinical suspicion of septic arthritis, cultures fail to grow any bacteria. Cultures are less sensitive if patients have had prior treatment with antibiotics or if there is an infection with a fastidious organism. In these scenarios, polymerase chain reaction techniques can be used to aid the diagnostic process. Patients should also have urine, respiratory secretions or skin swabs sent for cultures if indicated, which may help provide a clue about the offending pathogen. Gram-staining can be positive in few cases, but this has a low sensitivity.
Synovial fluid analysis helps in diagnosing septic arthritis. Synovial aspirate from septic joints reveals changes in viscosity and appearance, which along with a positive gram-staining and synovial fluid culture can be a guide regarding the choice of antibiotic treatment. The diagnostic yield of synovial fluid white cell count remains debatable. White cell counts of >50,000cells/µl increase the likelihood of septic arthritis. However, similar results can also be seen in patients with an acute episode of crystal arthropathy or inflammatory arthritis. 
Blood investigations show raised inflammatory markers, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and white cell counts. However, absence of an inflammatory response does not rule out septic arthritis.(1,10) Serial CRP, ESR and white cell counts are helpful to monitor response to antibiotic therapy. 
X-rays have little value as a tool to diagnose septic arthritis. Technetium bone scans and computed tomography scans are unable to distinguish between active inflammation and infection, but magnetic resonance imaging (MRI) can give detailed information in musculoskeletal infections, especially if there is any evidence of osteomyelitis or a deep seated infection.(11) The diagnostic yield of MRIs could be increased further with gadolinium enhancement.(12)
Prompt antibiotic therapy and drainage of septic joints to dryness remains the mainstay of treatment. There is no clear consensus regarding the choice and duration of antibiotic treatment. The choice of antibiotic should be guided by the likelihood of the organism involved, considering all the local sensitivity patterns. Empirical antibiotic treatment should be revised once results of gram-staining and cultures are available. The most common bacteria involved in septic arthritis are S. aureus and streptococci. Therefore, the initial antibiotic therapy should have bactericidal activity against both. In the UK, the recommended empirical treatment is flucloxacillin with fusidic acid or gentamycin. In the USA, empirical treatment is recommended with vancomycin. If allergic, clindamycin or a third-generation cephalosporin may be used.(11) Oral flucloxacillin, clindamycin or cephalexin may be used after IV antibiotics are ceased.  
Patients who are at an increased risk of contracting MRSA infection should be treated with vancomycin (a glycopeptide antibiotic) along with a second- or third-generation cephalosporin, followed by oral clindamycin or linezolid. Resistance to vancomycin is an emerging problem, especially in patients receiving long-term treatment with this antibiotic. Newer antibiotics such as daptomycin (a lipopeptide antibiotic) and linezolid (an oxazolidinone antibiotic) have shown promising results in treatment of soft tissue and articular infections, although there are no data to compare these antibiotics with the older ones. 
Patients with in-dwelling urinary catheters or recurrent urinary tract infections or patients who are immunosuppressed are at an increased risk of gram-negative sepsis. In these patient groups, empirical treatment is recommended with a third-generation cephalosporin, (for example, cephtriaxone, cephtazidime or cephotaxime). When a pseudomonas infection is suspected (as in IV drug users), cephtazidime is preferred. Local policy may be to add gentamycin, particularly in patients with sepsis. In those patients who are cephalosporin-allergic, ciprofloxacin is recommended. In patients with confirmed gram-negative infection, IV antibiotics are usually followed by a course of oral antibiotics (for example, cephalexin).(11) Choice of antibiotics should be guided by culture sensitivities. The problem increases with emerging multidrug resistance, especially Escherichia coli that are positive for extended spectrum β-lactamases. These bacteria are resistant to the second- and third-generation cephalosporins, thereby increasing the need to use carbapenems. Expert advice from microbiologists should always be sought when dealing with complex or multi drug resistant organisms. 
Immunosuppression in patients with septic arthritis has been studied as a novel therapy in a randomised, controlled trial in children. It revealed that steroids given at the start of antibiotic treatment in children with septic arthritis were safe and led to a significantly more rapid clinical improvement with no adverse events reported. This also led to shortened hospital stay as compared with those treated with antibiotic alone.(13) Whether this approach can be used more commonly in routine clinical practice needs to be explored further.  
There are no reliable data to suggest duration of antibiotic treatment or when the antibiotic should be changed from the parenteral to oral route. Studies have reported no significant difference when the antibiotic is changed from parenteral to oral route, either in the early or late stages of the disease.(14) One study suggested that IV antibiotics should be switched over to oral once the CRP level returns to normal.(15) Typically, the patients receive two weeks of IV antibiotic therapy followed by four weeks of oral therapy.
The incidence of septic arthritis is increasing due to an ageing population and multiple other risk factors. Despite the advances in diagnostic techniques, the diagnosis of septic arthritis can be very challenging. The gold standard for diagnosing septic arthritis still remains isolation of the culprit bacteria from blood and synovial cultures. Prompt diagnosis and early initiation of antibiotic therapy are required to prevent joint damage and reduce morbidity and mortality. The emergence of MRSA and gram-negative bacilli positive for extended spectrum β-lactamases that cannot be treated with conventional regimens has led to resistance against the conventional antibiotics. This situation has led to development and use of newer antimicrobials such as daptomycin and linezolid. The use of steroids along with antibiotics is an interesting prospect which needs to be studied further. As we gain a better understanding of the interplay between the host factors, bacterial toxins and proteins, we could use this knowledge to develop tools and markers which will aid in diagnosing septic arthritis and allow development of targeted therapies leading to a better outcome.
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