Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 Contents lists available at ScienceDirect Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh 6 Septic arthritis Miriam García-Arias, PhD, Alejandro Balsa, MD, PhD, Emilio Martín Mola, MD, PhD * Rheumatology Unit, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain Keywords: Septic arthritis Prosthetic joint infections Gonococcal arthritis Antibiotics Joint drainage This article presents a review of the current approach to diagnostic and therapeutic conditions of septic arthritis. Acute septic arthritis is an uncommon, but potentially fatal, emergency. Early diagnosis as well as prompt and effective treatment are essential to avoid either irreversible joint destruction or even death. The clinical features of this condition are different in neonates, children and adults. The deﬁnitive diagnosis of septic arthritis requires the direct demonstration of bacteria in synovial ﬂuid or on positive culture of the pathogen. A combination of antibiotics and the prompt removal of purulent material from the affected joint constitutes the mainstay of successful treatment. In addition, this article discusses, in particular, prosthetic joint infection and gonococcal arthritis. Ó 2011 Elsevier Ltd. All rights reserved. Infections of bones and/or joints are uncommon, but potentially fatal, emergencies that are associated with signiﬁcant mortality and morbidity. Delayed or inadequate treatment can result in irreversible joint destruction, and the case-fatality rate is estimated to be approximately 11% . Therefore, early diagnosis as well as prompt and effective treatment are essential for avoiding severe outcomes. However, septic arthritis may be difﬁcult to diagnose in certain situations and in certain populations, such as among children and the elderly. In spite of advances in diagnostic techniques (particularly in the ﬁeld of imaging) and the emergence of new antibiotics, the incidence of septic arthritis appears to have been increasing over the last few years. The ageing of the population, the widespread use of more potent immunosuppressant therapies and growing resistance to conventional antibiotics are among the major causes of this increase. * Corresponding author. Tel.: þ34 917277108. E-mail address: [email protected] (E.M. Mola). 1521-6942/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2011.02.001 408 M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 Epidemiology Information concerning the epidemiology of septic arthritis is limited because of several factors. Acute septic arthritis is an uncommon disease; therefore, few reports of series containing more than 50 cases have been published, and most of the published reports are from retrospective cohorts . Moreover, the case deﬁnitions employed have, in general, restricted these studies to the investigation of bacteriologically conﬁrmed cases. The overall estimated incidence of septic arthritis in industrialised countries ranges from 2 to 6 cases per 100,000 person-years in the general population [3–5]. In particular, the reported incidence of septic arthritis in Western Europe varies from 4 to 10 cases per 100,000 patient-years in the general population [4–6]. Moreover, the incidence increases in populations with low socioeconomic status, as has been demonstrated by studies conducted in both Northern Europe  and Australia . In Australia, the prevalence is reported to be 29 cases per 100,000 patient-years in the aboriginal population, with a relative risk of 6.6 in comparison with the Australian population in the Northern Territory . Although individuals of all ages can be affected, septic arthritis is more prevalent in children and the elderly, and males are more frequently affected than females . In children, the incidence ranges from 5 to 12 cases per 100,000 person-years . Approximately one-third of the patients with septic arthritis are children younger than 2 years of age, and the disease has a lower incidence in patients younger than 3 months.  Mortality due to septic arthritis in hospitalised patients is reported to be approximately 2–10% of the total mortality in general hospitals in the United States of America [10,11]. In recent years, the incidence of septic arthritis has appeared to increase. Several factors may have contributed to this increase, including increased orthopaedic-procedure-related infections, an ageing population and an increase in the use of immunosuppressive therapy . Microbiology The causative organisms responsible for septic arthritis vary with the age of the patient. In all ages and risk groups, with the exception of children younger than 2 years, the most frequent organism is Staphylococcus aureus, which is isolated in 37–56% of cases [12,13]. In recent times, an increase in methicillin-resistant S. aureus (MRSA) infections has been reported in several health-care systems, particularly in the elderly and intravenous drug abuser populations as well as associated with orthopaedic procedures . The incidence of MRSA has been reported to account for approximately 25% of septic arthritis cases in an urban area . Furthermore, the constant evolution of the microbe has resulted in the appearance of newer resistant strains in both the United States and Europe . Practice point A recent increase in MRSA has been reported. Streptococcus spp. are the second most frequent organisms involved in infectious arthritis in adult populations [4,6,14]. Streptococcus pyogenes is usually the most commonly isolated streptococcus; it is often associated with autoimmune disorders, chronic skin infections and trauma [5,16,17]. Group B streptococci are frequently involved in infections in the elderly, especially in patients with chronic diseases such as diabetes, cirrhosis and neurological disorders . The other Gram-positive bacterial infections originating from group C streptococci, Pneumococci and Gram-positive bacilli are less frequent. Gram-negative cocci are involved in at least 20% of septic arthritis cases, with Neisseria gonorrhoeae and Neisseria meningitidis being the most common causative organisms. Infection by Haemophilus inﬂuenzae is uncommon in the adult population . Gram-negative bacillus infections account for approximately 10–20% of septic arthritis cases. The most frequently involved organisms are M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 409 Escherichia coli, Proteus mirabilis, Klebsiella and Enterobacter. These usually affect the very young, the very old, patients with a previous history of intravenous drug abuse and immunocompromised patients . Anaerobic microbes are isolated in a small percentage of cases, usually involving diabetics and patients who have undergone joint prosthesis implantation or have suffered penetrating trauma . However, in human immunodeﬁciency virus (HIV)-infected patients, S. aureus is the most common pathogen as yet; opportunistic pathogens, including Streptococcus pneumoniae, mycobacterial species and fungal species, are isolated from approximately 30% of cases . Infections caused by Gram-negative bacilli are frequent in intravenous drug users. Moreover, this population is particularly susceptible to fungal infections as well as to infections by other unusual agents. In the paediatric population, the most common causative organisms involved are methicillinsensitive S. aureus, S. pneumonia and H. inﬂuenzae. However, following the introduction of the H. inﬂuenza-type B (Hib)-vaccine in this population, the overall incidence of H. inﬂuenza septic arthritis has decreased considerably . Kingella Kingae, a normal commensal present in the oropharynx of young children, may have superseded H. inﬂuenzae as the main causative agent of septic arthritis in this population, particularly in children younger than 2 years of age . S. pneumonia remains an important causal organism for septic arthritis in children in spite of the introduction of a heptavalent vaccine, and this is potentially attributed to infection by non-vaccine-treated serotypes . Furthermore, as has been described for adults, an increase in the number of joint infections from community-associated MRSA has been reported in the paediatric population . The most common causative organisms in infants younger than 2 months of age are S. aureus, Streptococcus agalactiaeand Gram-negative enteric bacteria. In children between the ages of 2 months and 5 years, the predominant agents include S. aureus, S. pyogenes, S. pneumonia and K. Kingae. Finally, in children older than 5 years, the pathogens most commonly involved are S. aureus and S. pyogenes. Table 1 summarises the main causative pathogens in each age and risk groups. Pathogenesis A joint becomes infected when an infectious agent enters the synovium. The main routes by which pathogens accumulate in the joints are the following: (a) haematogenously, with the consequent lodging of the pathogen in synovial capillaries; (b) infected contiguous foci; (c) neighbouring softtissue sepsis; and (d) by direct inoculation due to trauma or an iatrogenic event, such as diagnostic or therapeutic arthrocentesis or joint surgery. The synovium is a well-vascularised structure with no limiting basement plate, and this allows easy access by bacteria . Once bacteria reach the joint space, the low ﬂuid shear conditions allow bacterial adherence and infection. In addition, the production of host matrix proteins may promote the attachment of bacteria and the progression of the infection . Following colonisation of the synovial ﬂuid (SF), bacteria proliferate rapidly and generate an acute inﬂammatory response. Under these circumstances, the host produces inﬂammatory cytokines, such as interleukin 1-b (IL-1b) and interleukin 6 (IL-6), that promote opsonisation and activation of the complement system . Phagocytosis of the bacteria by macrophages, synoviocytes and polymorphonuclear cells is encouraged by the production of interleukins and other cytokines such as tumour necrosis factor-alpha (TNFa). When the host is immunocompetent, a protective inﬂammatory response is invoked, the pathogens are eliminated and the infection is resolved. However, if the infection is not halted, the high levels of cytokines produced by Table 1 Main causative organisms involved in each age and risk groups. All risk groups and all ages Age Risk groups S. aureus < 2 months: S. aureus and S. agalactiae 2 months- 5 years: S. aureus, S. pyogenes and Kingella kingae Rheumatoid arthritis: S. aureus Intravenous drug users: S. aureus, opportunistic pathogens, gram-negative bacilli The elderly and patients with chronic diseases: group B streptococci Immunocompromised patients: Gram-negative bacilli >5 years: S. aureus S. aureus: staphylococcus aureus; S. agalactiae: streptococcus agalactiae; S. pyogenes: streptococcus pyogenes. 410 M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 the immuno-regulatory cells may result in joint destruction. Progression of the infection generates a joint effusion that increases intra-articular pressure, which prevents blood and nutrients from reaching and supplying the joint. This situation results in the destruction of the synovium and cartilage. Predisposing factors Although septic arthritis can affect people at any age, elderly patients (especially those older than 80 years) and very young children are more frequently affected . Underlying joint diseases, such as rheumatoid arthritis (RA), osteoarthritis, crystal arthropathies and other forms of inﬂammatory arthritides, are predisposing factors for the development of infectious arthritis.  In particular, patients with RA have an approximately 10-fold-higher incidence of septic arthritis than the general population [3,5]. In addition, several patients have been reported to be receiving immunosuppressive therapy and/or glucocorticoids, which constitutes another important risk factor associated with the development of septic arthritis. Furthermore, the use of classic diseasemodifying anti-rheumatic drugs (DMARDs) in RA patients can be an additional risk factor that facilitates the development of infectious arthritis . Following introduction of anti-TNF agents, unusual cases of septic arthritis caused by bacteria such as Roseomonas mucosa, Salmonella or Listeria have been described . Although data from observational registers have suggested an increased incidence of joint infections in patients receiving anti-TNF therapy, the incidence does not seem to be different from the risk among patients treated with classical DMARDs . Patients with other chronic and immunosuppressive diseases, such as diabetes, leukaemia, cirrhosis, granulomatous diseases, cancer and hypogammaglobulinaemia, are also at an increased risk of developing septic arthritis . Haemodialysis has been reported as an important risk factor for septic arthritis, and the prevalence is estimated to be approximately 500 cases per 100,000 patients . Recent joint surgery is also associated with an increased risk of joint infection. Thus, the prevalence of post-arthroscopic septic arthritis has been reported to be approximately 14 cases per 10 000 procedures . Therapeutic intra-articular corticosteroid injection has been considered to be another risk factor for infection. Nevertheless, this complication is rare, and although the precise risk is difﬁcult to quantify, it has been estimated to be approximately 4 cases per 10,000 injections . In addition, skin infections may also facilitate joint infections . Finally, an increased prevalence of musculoskeletal infections has been demonstrated in HIV-infected patients . Clinical features Patients with acute septic arthritis typically present with a 1–2-week history of malaise, erythema, swelling, tenderness and a decreased range of motion affecting a single joint , although these symptoms may not always be present . The onset of fever, which in most cases is mild and with only 30–40% of individuals having a temperature >39 C, is a typical characteristic . Septic arthritis is usually monoarticular; however, the possibility of polyarticular septic arthritis should be carefully considered, especially when patients are afebrile or have an underlying polyarticular joint disease such as RA. Polyarticular disease accounts for approximately 10–20% of patients with septic arthritis, and it is it more likely to occur in patients with signiﬁcant co-morbidities and systemic diseases . Non-gonococcal septic arthritis may affect any joint; however, large joints, such as knees and hips, followed by shoulders, wrists and ankles, are most frequently affected . Inter-phalangeal joints of the hand are rarely involved in bacterial arthritis, but they may be compromised in viral arthritis, and this may mimic RA . Atypical joint infections, including those involving the sacroiliac, sternoclavicular and costochondral joints, are seen among parenteral drug users. The sacroiliac joint may also be a site for brucella arthritis, and sternoclavicular septic arthritis can also be a consequence of joint bacterial migration from the adjacent subclavian veins [42–44]. Inﬂammation of multiple tendon sheaths commonly occurs in disseminated gonococcal syndrome, but it may also be seen with other agents such as Moraxella, rubeola virus and sporotrichosis . M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 411 Septic arthritis in neonates and infants deserves special mention because it is more deceptive and devastating. The diagnosis may be overlooked because of the absence of classical signs of infection. Clinical manifestations may include vague complaints such as irritability, anxiety, failure to thrive, tachycardia and anaemia. The hip joint is most frequently affected . On physical examination, the infant may ﬂex, abduct and externally rotate the hip to relieve intra-articular pressure on the capsule . In any infant with septicaemia, a careful articular examination must be performed. All bones and joints must be explored, and special attention should be given to examination of the hips. Septic arthritis is easier to diagnose in children than in small infants and neonates because they usually present with the more classical symptoms of infectious arthritis that are seen in adults. Practice point In acute joint disease, septic arthritis must be suspected Diagnosis The deﬁnitive diagnosis of septic arthritis is made by direct demonstration of bacteria in the SF or after culture of the pathogen. The diagnosis is based, in most cases, on clinical symptoms and a detailed history, a careful examination and test results . It has been suggested that a careful examination by an experienced clinician is of utmost importance when making a rapid diagnosis of septic arthritis . Laboratory ﬁndings Blood tests show increased levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and white blood cell count (WBC). However, the absence of elevated acute-phase reactants does not exclude the diagnosis of septic arthritis [7,16]. Li et al.  demonstrated that a high WBC count in the joint ﬂuid (jWBC) increases the likelihood of a diagnosis of septic arthritis. WBC counts higher than 11,000 mm3, ESR > 20 mm h1 and jWBC > 50,000 mm3 have indicated a sensitivity for diagnosing joint infection of 75%, 75% and 50%, and corresponding speciﬁcities of 55%,11% and 88%, respectively. The overall sensitivity of these three tests when combined is 100%, but the speciﬁcity is low (24%) . In a recent study, Hugle et al.  demonstrated that serum procalcitonin could be used to differentiate between septic and nonseptic arthritis, but its accuracy remains to be established . Thus far, there is no test with sufﬁcient sensitivity, speciﬁcity and predictive values to justify its use in routine clinical practice. However, ESR, CRP and WBC should always be measured because they are useful for monitoring the treatment response. Blood culture Blood cultures must be obtained before starting antibiotic treatment to optimise the possibility of isolating the causative bacteria. Blood cultures are reported to be positive in 50–70% of patients with non-gonococcal arthritis . Synovial ﬂuid Aspiration of SF from a swollen joint is mandatory for establishing the correct diagnosis. Once samples are obtained, they must be microscopically examined and transported rapidly to the laboratory for analysis and culture. In septic arthritis, the SF usually has a turbid appearance with a WBC > 50,000 mm3. However, other non-bacterial inﬂammatory diseases such as acute microcrystalline arthritis and reactive arthritis may have similar values for WBCs. In a study conducted by Coutlakis et al. in 2002 , infectious arthritis was diagnosed in 77% of patients with synovial jWBC > 100,000 mm3, in 47% of patients with jWBC between 50,000 and 100,000 mm3 and in 5% of patients with jWBC < 50,000 mm3. Eighty-one percent of patients with jWBC ranging from 15,000 to 50,000 had a diagnosis of RA or crystal synovitis . 412 M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 Low joint-ﬂuid glucose levels (<40 mg dl1 or less than half the serum glucose concentration) and high lactate levels are frequent ﬁndings in septic arthritis; however, they are nonspeciﬁc and, thus, may also be present in other inﬂammatory processes . The presence or absence of crystals should always be examined by polarising microscopy. The demonstration of crystals, however, does not preclude the existence of concomitant septic arthritis . The SF should be cultured for aerobic and anaerobic bacteria, mycobacteria and fungi. Gram staining of SF is important for the diagnosis of septic arthritis, and it may facilitate differentiation between Grampositive and Gram-negative bacteria, which is essential for selection of antibiotic therapy. SF cultures are positive in 67% of non-gonococcal arthritis cases, whereas Gram staining reveals positive results in only 50% cases . Culture results can be negative after initiation of antibiotic treatment. However, inoculation of the aspirated joint ﬂuid into blood culture bottles may increase the diagnostic yield compared with culture on the conventional agar plate.  Among patients with negative culture results obtained by conventional methods, one-third of those not receiving antibiotics and 50% of those receiving antibiotics had positive culture reports when cultured in blood agar bottles . In addition, sputum, urine, skin lesions and any other suspected primary foci should be considered for samples in culturing. DNA-based techniques, hybridisation probes, polymerase chain reaction (PCR)-based techniques and protein detection by mass spectroscopy provide quick results. The detection of microorganisms by PCR has shown promising results. However, the risk of contamination, the presence of background DNA, the lack of a gold standard and the fact that PCR techniques detect DNA instead of living pathogens make the interpretation of these tests difﬁcult.  PCR assays have not been demonstrated to have any advantage over bacterial culture in staphylococcal or streptococcal infections , but they are useful for the identiﬁcation of K. kingae, anaerobic bacteria and Streptococcus spp . Imaging studies Plain radiographs should always be the ﬁrst imaging technique used. In the initial stages, plain radiographs usually appear normal. Osteopaenia is usually the ﬁrst radiological manifestation; as the infection progresses, diffuse joint space narrowing may evolve. Ultrasonography is useful for detecting ﬂuid effusions as low as 1–2 ml and for examining otherwise inaccessible joints, such as the hip . Non-echo-free effusions that are seen on ultrasonography are characteristic of a septic joint. Ultrasonography is a non-invasive and inexpensive technique that permits the performance of guided diagnostic arthrocentesis in patients with suspected septic arthritis when joints are not easily accessible or the amount of ﬂuid is small. However, it is not useful in osseous infections because ultrasound waves cannot pass through the bone . Similar to plain radiographs, a computed tomography (CT) scan may not depict abnormalities during the early stages of infection. However, CT is a better imaging technique for visualisation of local oedema, bone erosions, osteitic foci and sclerosis . Magnetic resonance imaging (MRI) provides better resolution than radiography or CT for the detection of joint effusion and for differentiation between bone and soft-tissue infections. The sensitivity is reported to be nearly 100%, with a speciﬁcity of more than 75% . MRI ﬁndings in patients with septic arthritis include joint effusion, cartilage and bone destruction, soft-tissue abscesses, bone oedema and cortical interruption. As with other imaging techniques, MRI is incapable of differentiating between infective and other inﬂammatory arthritides . Radionuclide scans are useful for locating areas of inﬂammation. Leucocytes labelled with 99mTc accumulate in areas where osteoblasts are active and where there is increased vascularity . Gacitrate and 111In-chloride scans are more sensitive and speciﬁc than 99mTc, but it is difﬁcult to distinguish between bone, joint and soft-tissue inﬂammation with these techniques . Practice point The deﬁnitive diagnosis is made by direct demonstration of bacteria in the SF or after culturing the pathogen M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 413 Prognosis Mortality reported from septic arthritis varies in different studies, but it appears to be approximately 11% for monoarticular arthritis . The risk of permanent loss of joint function is nearly 40% .Delayed diagnosis, advanced age, underlying joint diseases and the presence of synthetic material within the joint are conditions associated with a poor prognosis. Delaying treatment for as little as 7 days can result in poor outcomes . High mortality (19–33%) in elderly patients is associated with comorbidities such as diabetes, other joint diseases and a reduced immune response . In addition, underlying joint diseases are associated with a poor prognosis because the symptoms of septic arthritis can frequently be mistaken for those of the pre-existing joint disease, and this may delay diagnosis . Patients with polyarticular, septic, non-gonococcal arthritis have a poor prognosis with a mortality rate of 30% . Management The mainstay of treatment involves prompt debridement for removal of purulent material and early treatment with antibiotics . Evidence concerning the choice and duration of antibiotic treatment is sparse because no randomised controlled trials have been conducted so far. Early antibiotic treatment should be based on clinical presentation, patient history, organisms likely to be involved and Gram-staining results [39,47]. In view of the fact that the most frequent pathogens are S. aureus and streptococci, the initial antibiotic treatment (prior to bacterial identiﬁcation) should be effective against these organisms. If necessary, the initial antibiotic treatment should be modiﬁed or adjusted based on the culture and antibiotic sensitivity results. The usual course of therapy for a non-gonococcal arthritis such as that caused by streptococci or Gram-negative cocci is 2 weeks, with 3 weeks for staphylococci and 4 weeks for pneumococci and Gram-negative bacilli . Successful management of septic arthritis also includes prompt removal of purulent material from the joint space. It has been suggested that needle aspiration is preferable as compared with surgical treatment as an initial mode of drainage, although, in a study conducted by Goldenberg et al.,  both methods achieved similar results. Moreover, needle aspiration during the ﬁrst 7 days of treatment has been demonstrated to be a successful treatment. Decreased SF volume and a lower jWBC with a smaller percentage of polymorphonuclear leucocytes indicate that the treatment was effective . When needle aspiration is incomplete and the effusion persists beyond 7 days, it is necessary to perform an arthroscopy or open drainage. Arthroscopy is useful and less invasive than open surgery for accessing deep joints such as the hip . Arthrotomy should be performed in clinical situations when urgent decompression is required to relieve neuropathy or compromised blood supply, when conservative drainage techniques have failed, when the joint is seriously damaged by pre-existing articular disease and, ﬁnally, when septic arthritis is complicated by underlying osteomyelitis . During the acute phase of infection, optimal positioning of the affected joint is essential to avoid subsequent deformities and contractures. Splints may be useful to maintain the joint in its correct functional position, and isotonic exercise has to be initiated to prevent muscular atrophy. After the acute phase, early physical therapy and mobilisation of the affected joint are imperative to ensure optimal recovery [17,65]. Some experimental studies have suggested that corticosteroids in conjunction with antibiotic treatment may be a more effective treatment than treatment with antibiotics alone. Sakiniene et al.  showed that mice treated with intra-peritoneal cloxacillin in combination with intra-peritoneal corticosteroids had better outcomes than mice treated with cloxacillin alone. In a study that enrolled 123 children with haematogenous septic arthritis, Odio et al.  found that treatment with dexamethasone in combination with antibiotics achieved better results than treatment with antibiotics alone. Similar studies have not been conducted in adults as yet, but it has been suggested that combined therapy might be beneﬁcial in all age-groups . Nevertheless, the use of corticosteroids in a patient with a serious infection should be considered carefully. In animal experimental models, the combination of bisphosphonates with intra-peritoneal corticosteroids and antibiotics results in decreased osteoclast activity and, consequently, a reduction in 414 M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 skeletal destruction . Other potential therapies that employ interleukin 10 or interleukin 12 in combination with antibiotics have been investigated in animal experimental models [69,70]. Practice point Successful treatment includes the removal of purulent material as well as the appropriate use of antibiotics A special condition: prosthetic joint infections Prosthetic joints provide a physiological niche for microorganisms and may become a site of infection. Infections associated with prosthetic joints can represent a devastating complication of joint replacement procedures . In patients with primary joint replacement, the infection rate in the ﬁrst 2 years is <1% in the hip and shoulder joints, <2% in the knees and <9% in the elbows . Prosthetic implants are often coated with host proteins, usually ﬁbronectin and ﬁbrinogen, shortly after the infection. This situation allows the prosthetic joint to act as a colonisation surface to which bacteria adhere via ﬁbronectin- and ﬁbrinogen-binding receptors . Furthermore, implants can often reduce blood ﬂow and compromise local immunity by impairing the activities of natural killer cells, lymphocytes and phagocytes. This situation results in a release of reactive oxygen products and lysosomal enzymes that may lead to host tissue damage and local vascular insufﬁciency. Therefore, implants not only comprise a substrate on which bacteria can adhere but also limit the ability of the host to counter the infection . Following bacterial colonisation of a prosthesis, the bacteria form a slimy layer, called a bioﬁlm, which functions as the basic survival mechanism that allows microbes to resist external and internal environmental factors . ‘Aseptic prosthetic failure’ is a clinical picture that may mimic infection of prosthesis and should always be considered during the differential diagnosis. Debris from the wearing of implants can cause osteolysis and is known to be the major cause of aseptic loosening . Particles are deposited in the space between the implant and the bone and are phagocytosed by macrophages, and this results in the formation of granulomatous tissue and the release of inﬂammatory mediators, which then stimulate osteoclastic bone absorption. Migration of macrophages into the joint cavity may result in loosening of the prosthesis. Other mechanisms that can lead to aseptic loosening include inappropriate mechanical load, implant motion and SF hydrodynamic pressure . The treatment for ‘aseptic prosthetic failure’ involves replacement of the prosthesis. Risk factors for prosthetic joint infections include a variety of conditions, such as RA, psoriasis, immunosuppression, poor nutritional status, obesity, diabetes mellitus, advanced age, malignancy, remote infection, prior native joint infection and a superﬁcial surgical site infection . In RA, the incidence rate of infection is approximately 4.4% . In addition, bacteraemia is a risk factor for haematogenous prosthetic joint infection. The overall risk for joint infection following bacteraemia including all pathogens is approximately 0.3% . However, the risk following bacteraemia caused by S. aureus increases to 34% . The risk for haematogenous infection appears to be higher in knee rather than in hip prostheses. Prosthetic joint infections may have varied manifestations. In early infections (occurring <3 months following surgery), patients may present with fever and systemic symptoms as well as local signs of postoperative infection. Early infections are caused mainly by high-virulence microorganisms such as S. aureus and Gram-negative bacilli. Delayed infections (occurring 3–24 months following surgery) are often caused by less virulent agents such as coagulase-negative staphylococci and Propionibacterium acnes. Symptoms are often nonspeciﬁc (i.e., persistent moderate pain), and this may explain why prosthesis infections are often overlooked. Although patients usually have an elevated ESR, leucocytosis may be absent and patients may remain afebrile. Finally, late infections (occurring >2 years after surgery) are often due to haematogenous spread, where the main origin of the bacteraemia is from M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 415 skin, respiratory tract, dental and urinary tract infections. The most frequently isolated bacterium is S. Aureus, followed by Streptococcus spp., Gram-negative bacilli and anaerobes. Patients usually complain of sudden local joint pain and general symptoms. At present, there are no deﬁned criteria for diagnosing prosthetic joint infections, although the presence of at least one of the following ﬁndings may be highly suggestive: growth of an identical microorganism in two or more cultures; purulent SF at the implant site; granulocytes on histopathological examination of periprosthetic tissue; and a sinus-tract communication with the prosthesis . Infection should be diagnosed before deciding on a new surgical intervention, as this allows antimicrobial treatment to be started preoperatively and the most appropriate surgical management to be planned. Preoperative joint aspiration followed by cell and microbiological examination of the SF needs to be performed to differentiate infection from an aseptic process. Radiographic ﬁndings, such as radiolucency, osteolysis and migration, are present in both infectious and aseptic loosening. However, these changes appear much earlier in infection than in aseptic loosening. The development of a radiolucent line measuring at least 2 mm or focal osteolysis within 6–12 months following prosthesis implantation is often associated with infection. The reported sensitivity of these ﬁndings is good (84%), but their speciﬁcity is only 57% . Contrast arthrography is effective for assessing implant stability. Synovial out-pouchings and abscesses are usually signs of infection . Computed tomography (CT) is more sensitive than conventional radiography for evaluating the joint space, and it can allow guided arthrocentesis. MRI has greater resolution than CT or radiography and permits visualisation of anatomical details to a larger degree than radionuclide scans. The main disadvantage of both CT and MRI is imaging interference in the vicinity of metal implants. Ultrasonography is useful for detecting joint effusions around implants and can be used to guide arthrocentesis. All nuclear imaging techniques are sensitive, but their speciﬁcity varies. When a prosthetic joint infection is diagnosed in the early period following surgery, treatment with antibiotics alone or in combination with debridement may be sufﬁcient. In most cases, the infection has progressed and a two-stage procedure comprising prosthesis removal and debridement (Stage 1) and re-implantation (Stage 2) is recommended. The recommended duration of antibiotic treatment is 3 months for hip prostheses and 6 months for knee prostheses . Intravenous treatment should be administered for the ﬁrst 2–4 weeks, and this is followed by oral therapy. The optimal antimicrobial therapy for staphylococcal infections includes rifampicin, but this must always be combined with another drug to prevent the appearance of resistant strains . Quinolones should be combined with rifampicin due to their good bioavailability, activity and safety. Because of increasing resistance to quinolones, however, co-trimoxazole, minocycline and fusidic acid have also been used in combination with rifampicin with good results . Linezolid  and daptomycin  are also active against Gram-positive bacteria, including MRSA. Practice points Each postoperative local infection after joint replacement should be considered as a prosthetic joint infection. Prosthetic joint infections are difﬁcult to eradicate due to the resistance of bioﬁlm-associated microorganisms. Successful treatment must include antimicrobial therapy combined with the most appropriate surgical treatment Gonococcal arthritis Gonococcal arthritis is the result of infection with N. gonorrhoeae acquired from a primary sexually transmitted mucosal infection. Gonococci may infect mucosal surfaces such as the urethra, endocervix, 416 M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 pharynx, rectum and cervico-vaginal mucosa. In a minority of patients, especially in those untreated, the infection can progress to induce endometriosis, salpingitis, prostatitis, dermatitis, arthritis and disseminated gonococcal infection (DGI). Epidemiology Gonococcal infection was earlier an important cause of septic arthritis, especially in sexually active young adults. The frequency of DGI has been reported to be 0.5–3% in patients with an untreated mucosal infection . Gonococcal arthritis develops in approximately 42–85% of patients with DGI.  Gonococcal infection accounted for approximately two-thirds of the cases of septic arthritis and tenosynovitis in North America in the 1970s . The incidence has subsequently decreased mainly due to the implementation of effective control programmes, and, at present, gonococcal infections are rare in Europe and North America [4,6,7,14]. For example, in France and the UK, N. gonorrhoeae is reported to be responsible for 1.6% and 0.06% of all septic arthritis cases, respectively . However, gonococcal arthritis is still prevalent in other parts of the world, particularly in developing countries and geographical areas (such as aboriginal communities in Australia and Rwanda) that have restricted access to public health programmes [5,22]. Pathogenesis N. gonorrhoeae is a small, Gram-negative, non-motile and non-spore-forming bacterium that characteristically grows in pairs (diplococci). Its virulence is associated with several surface structures. Initial attachment to the host epithelium is mediated by long, hair-like proteinaceous projections called phase-variation pili. Protein I is the main protein on the membrane. It is a porin which is expressed in two different forms: a protein IA variant, which is nearly always associated with disseminated infections, and a protein IB variant, which is associated with localised infections. Protein IA reduces the efﬁcacy of the host complement system by deactivating C3b into iC3b . This porin may also be able to prevent phagolysosome fusion in polymorphonuclear leucocytes and reduce their oxidative burst, enabling survival within these cells. Another extracellular gonococcal protein is protein II, which is thought to participate in the more intimate attachment process following the initial pilus interaction. In addition, protein II is capable of attaching to lipooligosaccharides of other N. gonorrhoeae microbes, thereby enabling cell binding and the formation of microcolonies. These microcolonies may also contribute to the initiation of mucosal surface attachment. Protein II avoids clearance by the host immune system. Protein III is another porin located on the bacterial surface and acts by stimulating antibodies that block serum bactericidal action directed against N. gonorrhoeae . The host may control a gonococcal infection by the action of the innate immune response, particularly that of the complement system. However, during early pregnancy, puerperium and menstruation, the accompanying alterations in vaginal pH, cervical mucus and genital ﬂora as well as the exposure of the endometrium to submucosal vessels may predispose females to N. gonorrhoeae invasion and DGI. Risk factors Females have a fourfold greater risk than males of developing gonococcal arthritis . The elevated prevalence in women can be attributed to the delay in diagnosis because of the asymptomatic nature of gonococcal infections in women. Because clearance of a gonococcal infection depends on an effective complement-mediated immune response, a complement deﬁciency, particularly in the terminal components (C5–C8) , is a risk factor for developing gonococcal arthritis. Other conditions such as menstruation, pregnancy, puerperium, multiple sexual partners, low socioeconomic status and intravenous drug use increase the risk of gonococcal infection. Gonococcal arthritis has been reported in HIV-infected patients, and it may be the ﬁrst manifestation of an HIV infection in some cases . M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 417 Clinical manifestations DGI can be classiﬁed into a ‘bacteraemic form’, which is less frequent at present, and a ‘suppurative form’. It has been proposed that these two presentations are two different phases of the infectious process, and several patients may present clinical features of both stages . The usual presentation of the ‘bacteraemic form’ includes asymmetric polyarthralgia (migratory or additive) associated with moderate fever, chills, dermatitis and tenosynovitis. Most of these patients have asymptomatic genital, anal or pharyngeal gonococcal infections . Skin lesions occur in 75% of the cases and they usually consist of non-pruritic, small erythematous papules, which often progress to vesicular or pustular lesions. The extremities and the trunk are the most frequently affected areas, whereas the face and scalp are usually spared. Tenosynovitis occurs in up to 68% of patients, particularly on the extensor areas of the hands, wrists, ﬁngers, toes and ankles . The joints most frequently involved are knees, elbows and ankles . In the ‘suppurative form’, arthritis is the main feature. Septic arthritis occurs in approximately 50% of DGI cases, and usually only one joint is affected. Although any joint can become infected, knees, wrists, ankles and ﬁngers are the most commonly affected joints. The involvement of hips, sternoclavicular joints and intervertebral discs is rare. Systemic complications, including endocarditis, myocarditis, pyomyositis, hepatitis (known as Fitz– Hugh–Curtis syndrome), meningitis and adult respiratory syndrome, may occur in DGI cases. Following the advent of antibiotics, however, these complications have become rare . Diagnosis Leucocytosis as well as elevated ESR and CRP are present in at least half of the patients. N. gonorrhoeae is isolated from blood and synovial cultures in approximately 50% of patients with gonococcal arthritis, and Gram staining is positive in <50% of culture-positive ﬂuids . Patients with purulent joint effusions are more likely to have positive SF and negative blood cultures . Blood and SF samples should be plated immediately on prewarmed chocolate agar, whereas genitourinary, rectal and pharyngeal samples should be plated on prewarmed Thayer–Martin or modiﬁed New York medium with appropriate antibiotic supplementation . To improve the culture yield, plates should be incubated at 37 C within 15 min in a moist chamber. Cultures from the uterine endocervix have a sensitivity that ranges from 50% to 70% and a speciﬁcity of >90%. The sensitivity and speciﬁcity for urethral smears in men is 90% and 95%, respectively, whereas pharyngeal and rectal mucosal cultures are positive in approximately 20% and 15% of men, respectively . Culturing of skin lesions is also indicated, but it is usually negative. Samples from suspected infected areas of sexual partners should also be obtained for Gram-staining and culture investigations. Furthermore, Chlamydia infection needs to be ruled out because it coincides with approximately 30% of gonococcal infections, and its treatment requires speciﬁc antibiotics . PCR techniques can detect N. gonorrhoeae DNA even when cultures are negative . The speciﬁcity and sensitivity of PCR have been estimated at 96.4% and 78.6%, respectively, with a false-positivity rate of 3.6% . However, PCR has not replaced culture as the gold standard for diagnosis as PCR techniques do not provide information about antibiotic sensitivity or resistance. Management Before microorganism resistance to penicillin increased, the initial management of gonococcal arthritis was based on intravenous infusion of 10 million IU of penicillin G per day. High-level resistance to penicillin has prompted the Centre for Disease Control and Prevention to change their recommendations for the treatment of DGI, and third-generation cephalosporins are the ﬁrst-choice treatment. Penicillin resistance is mediated by either the acquisition of plasmids that encode b-lactamase or chromosomal mutation . The initial recommended treatment is based on a third-generation cephalosporin, such as ceftriaxone (1 g i.m. or i.v.), ceftizoxime (1 g i.m. or i.v. 8 h) and cefotaxime (1 g i.v. every 8 h). For patients 418 M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421 who are intolerant to penicillin, intramuscular spectinomycin at a dose of 2 g every 12 h is a good alternative. Intravenous treatment should be continued for 24–48 h until symptoms have improved or resolved and oral therapy should then be started to complete 7 days of antimicrobial therapy. In addition, ceﬁxime at a dose of 400 mg every 12 h; ceﬁxime in suspension (200 mg/5 ml) at a dose of 400 mg every 12 h; or cefpodoxime at a dose of 400 mg orally every 12 h can be used . After a minimum of 5 days following treatment, performing cultures from all previously infected sites is recommended to ensure that the gonococcal infection has resolved . When a chlamydial infection is identiﬁed, antibiotic treatment with azithromycin or doxycycline for 7 days must be included. Surgical treatment is often unnecessary, but the affected joint should be aspirated to remove the purulent material. Tidal irrigation, arthroscopic drainage and arthrotomy are rarely necessary, but they may be useful in infections that do not improve after a few days of treatment. Sexual partners should also be examined and treated to prevent gonococcal re-infection and dissemination . Practice points Isolation of the gonococcus from blood, SF, mucosal sites and skin lesions should be attempted before starting antibiotics. Samples from suspected infected areas of sexual partners should also be obtained. The initial recommended treatment is based on a third-generation cephalosporin. Patients should be also tested for Chlamydia infection, which is frequently associated with gonococcal infections, and its treatment requires speciﬁc antibiotics Conclusion Septic arthritis can result in irreversible joint destruction. The main factors for avoiding severe outcomes are an early, prompt and effective treatment, using both appropriate antibiotics and joint lavage. In acute joint disease, with one or more swollen, hot and painful joints, septic arthritis should be suspected. The deﬁnitive diagnosis of septic arthritis is made by direct demonstration of bacteria in the SF or after culturing the pathogen. However, there is little quality evidence to guide clinicians in the diagnosis of septic arthritis. The overall impression of physicians experienced in the diagnosis and management of rheumatic diseases is the gold standard for diagnosing septic arthritis. 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