Best Practice & Research Clinical Rheumatology Septic arthritis

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% [1]. 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
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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 [2].
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 [7] and Australia [5]. 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 [5].
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 [2]. In children, the incidence ranges from
5 to 12 cases per 100,000 person-years [8]. 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. [9]
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 [5].
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 [14]. The incidence of MRSA has been reported to account for approximately 25% of
septic arthritis cases in an urban area [11]. Furthermore, the constant evolution of the microbe has
resulted in the appearance of newer resistant strains in both the United States and Europe [15].
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 [18]. 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 [19]. Gram-negative bacillus infections
account for approximately 10–20% of septic arthritis cases. The most frequently involved organisms are
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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 [20]. 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 [21]. 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 [22]. 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[23]. 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 [24]. 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 [25]. 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 [26].
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 [27]. 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[28]. 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 [12]. 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 [29]. 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 [30]. 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.
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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 [3].
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. [3] 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 [31]. Following introduction of anti-TNF agents, unusual
cases of septic arthritis caused by bacteria such as Roseomonas mucosa, Salmonella or Listeria have been
described [32]. 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 [33].
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 [34]. 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 [35].
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 [36].
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 [36].
In addition, skin infections may also facilitate joint infections [3]. Finally, an increased prevalence of
musculoskeletal infections has been demonstrated in HIV-infected patients [37].
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 [29], although these
symptoms may not always be present [38]. 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 [39].
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 [40].
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 [41]. 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 [17].
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 [17].
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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 [5]. On physical examination, the
infant may flex, abduct and externally rotate the hip to relieve intra-articular pressure on the capsule
[45]. 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 [46]. It has been suggested that a careful examination by
an experienced clinician is of utmost importance when making a rapid diagnosis of septic arthritis [47].
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. [48] 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%) [48]. In a recent study, Hugle
et al. [49] demonstrated that serum procalcitonin could be used to differentiate between septic and nonseptic arthritis, but its accuracy remains to be established [49]. 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 [12].
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 [50], 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 [50].
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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 [10].
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 [51].
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 [12]. 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. [52] 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 [52]. 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. [53] PCR assays have not been demonstrated to
have any advantage over bacterial culture in staphylococcal or streptococcal infections [47], but they
are useful for the identification of K. kingae, anaerobic bacteria and Streptococcus spp [54].
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 [55]. 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 [56].
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 [57].
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% [58]. 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 [59].
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 [60]. 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 [61].
Practice point
The definitive diagnosis is made by direct demonstration of bacteria in the SF or after
culturing the pathogen
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Prognosis
Mortality reported from septic arthritis varies in different studies, but it appears to be approximately 11% for monoarticular arthritis [1]. The risk of permanent loss of joint function is nearly 40%
[6].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 [19]. High mortality (19–33%) in elderly patients is associated with comorbidities such as diabetes, other joint diseases and a reduced immune response [41]. 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
[40]. Patients with polyarticular, septic, non-gonococcal arthritis have a poor prognosis with
a mortality rate of 30% [40].
Management
The mainstay of treatment involves prompt debridement for removal of purulent material and early
treatment with antibiotics [1].
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 [39].
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., [62] 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 [63]. 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 [64]. 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 [29].
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.
[66] 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. [67] 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 [19]. 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
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skeletal destruction [68]. 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 [71].
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 [72].
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 [73]. 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 [74]. 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 [75].
‘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 [76]. 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 [77]. 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 [72]. In RA, the
incidence rate of infection is approximately 4.4% [78].
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% [79].
However, the risk following bacteraemia caused by S. aureus increases to 34% [80]. 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
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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 [72].
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% [81]. Contrast arthrography is effective for
assessing implant stability. Synovial out-pouchings and abscesses are usually signs of infection [82].
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 [72]. 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 [83]. 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 [84]. Linezolid [85]
and daptomycin [86] 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,
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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 [87]. Gonococcal arthritis develops in approximately 42–85% of patients with DGI.
[88] Gonococcal infection accounted for approximately two-thirds of the cases of septic arthritis and
tenosynovitis in North America in the 1970s [65]. 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 [89]. 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 [90]. 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 [91].
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 [89]. 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) [92], 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 [22].
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 [93].
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 [88]. 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 [88]. The joints most
frequently involved are knees, elbows and ankles [88]. 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 [89].
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 [88]. Patients with purulent
joint effusions are more likely to have positive SF and negative blood cultures [88].
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 [94]. 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 [95].
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 [89].
PCR techniques can detect N. gonorrhoeae DNA even when cultures are negative [96]. The specificity
and sensitivity of PCR have been estimated at 96.4% and 78.6%, respectively, with a false-positivity rate
of 3.6% [96]. 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 [97].
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
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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 [98]. 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 [89]. 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 [89].
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. Antibiotic
treatment is required, although the decision of which drug, route of administration and duration of
course can be determined based only on empirical data.
Conflict of interest
These authors have no conflicts of interest to declare.
References
[1] Coakley G, Mathews C, Field M, Jones A, Kingsley G, Walker D, et al. On behalf of the British Society for rheumatology
standards, guidelines and audit working group. BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hot
swollen joint in adults. Rheumatology (Oxford) 2006;45:1039–41.
[2] Nade S. Septic arthritis. Best Practice & Research Clinical Rheumatology 2003;17:183–200.
*[3] Kaandorp CJ, Van SD, Krijnen P, Habbema JD, van de Laar MA. Risk factors for septic arthritis in patients with joint disease.
A prospective study. Arthritis & Rheumatism 1995;38:1819–25.
[4] Weston VC, Jones AC, Bradbury N, Fawthrop F, Doherty M. Clinical features and outcome of septic arthritis in a single UK
Health District 1982–1991. Annals of the Rheumatic Diseases 1999;58:214–9.
[5] Morgan DS, Fisher D, Merianos A, Currie BJ. An 18 year clinical review of septic arthritis from tropical Australia.
Epidemiology and Infection 1996;117:423–8.
[6] Kaandorp CJ, Dinant HJ, van de Laar MA, Moens HJ, Prins AP, Dijkmans BA. Incidence and sources of native and prosthetic
joint infection: a community based prospective survey. Annals of the Rheumatic Diseases 1997;56:470–5.
M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421
419
[7] Gupta MN, Sturrock RD, Field M. A prospective 2-year study of 75 patients with adult-onset septic arthritis. Rheumatology (Oxford) 2001;40:24–30.
[8] Frank G, Mahoney HM, Eppes SC. Musculoskeletal infections in children. Pediatric Clinics of North America 2005;52:
1083–106.
[9] Gillespie WJ, Nade S. Musculokeletal infections. Melbourne: Blackwell Scientific Publications; 1987. pp 283–302.
*[10] Swan A, Amer H, Dieppe P. The value of synovial fluid assays in the diagnosis of joint disease: a literature survey. Annals
of the Rheumatic Diseases 2002;61:493–8.
[11] Ross JJ. Septic arthritis. Infectious Disease Clinics of North America 2005;19:799–817.
[12] Goldenberg DL. Septic arthritis. Lancet 1998;351:197–202.
*[13] Ross JJ, Davidson L. Methicillin-resistant Staphylococcus aureus septic arthritis: an emerging clinical syndrome. Rheumatology (Oxford) 2005;44:1197–8.
[14] Dubost JJ, Soubrier M, De Champs C, Ristori JM, Bussiére JL, Sauvezie B. No changes in the distribution of organisms
responsible for septic arthritis over a 20 year period. Annals of the Rheumatic Diseases 2002;61:267–9.
[15] Arnold SR, Elias D, Buckingham SC, Thomas ED, Novais E, Arkader A, et al. Changing patterns of acute hematogenous
osteomielitis and septic arthritis: emergence of community-associated methicillin-resistant Staphylococcus aureus.
Journal of Pediatric Orthopaedics 2006;26:703–8.
[16] Le Dantec L, Maury F, Flipo RM, Laskri S, Cortet B, Duquesnoy B, et al. Peripheral pyogenic arthritis: a study of one
hundred seventy-nine cases. Revue du Rhumatisme English Edition 1996;63:103–10.
[17] Smith JW. Infectious arthritis. Infectious Disease Clinics of North America 1990;4:523–38.
[18] Farley MM. Group B streptococcal disease in nonpregnant adults. Clinical Infectious Diseases 2001;33:556–61.
[19] Tarkowski A. Infection and musculoskeletal conditions: Infectious arthritis. Best Practice & Research Clinical Rheumatology 2006;20:1029–44.
[20] Goldenberg DL, Brandt KD, Cathcart ES, Cohen AS. Acute arthritis caused by gram-negative bacilli: a clinical characterization. Medicine (Baltimore) 1974;53:197–208.
[21] Brook I, Frazier EH. Anaerobic osteomyelitis and arthritis in a military hospital: a 10-year experience. American Journal of
Medicine 1993;94:21–8.
[22] Saraux A, Taelman H, Blanche P, Batungwanayo J, Clerinx J, Kagame A, et al. HIV infection as a risk factor for septic
arthritis. British journal of rheumatology 1997;36:333–7.
[23] Barton L, Dunkle LM, Habit FH. Septic arthritis in childhood. A 13-year review. American Journal of Diseases of Children
1987;141:898–900.
[24] Bowerman SG, Green NE, Mencio GA. Decline of bone and joint infections attributable to Haemophilus influenza type b.
Clinical Orthopaedics and Related Research 1997;341:128–33.
[25] Yagupsky P. Kingella kingae: an emerging pediatric pathogen. Advances in Experimental Medicine & Biology 2006;582:
179–90.
*[26] Young TP, Maas L, Thorp AW, Brown L. Etiology of septic arthritis in children: an update for the new millennium. 2010 In
press.
[27] Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, McDougal LK, Carey RB, et al. Methicillin-resistant S. Aureus
infections among patients in the emergency department. New England Journal of Medicine 2006;355:666–74.
[28] Gutierrez K. Bone and joint infections in children. Pediatric Clinics of North America 2005;52:779–94.
*[29] Shirtliff ME, Mader JT. Acute septic arthritis. Clinical Microbiology Reviews 2002;15:527–44.
[30] Koch B, Lemmermeier P, Gause A, Wilmowsky H, Heisel J, Pfreundschuh Ml. Demonstration of interleukin-1 beta and
interleukin-6 in cells of synovial fluids by flow cytometry. European Journal of Medical Research 1996;1:244–8.
[31] Edwards CJ, Cooper C, Fisher D, Field M, van Staa TP, Arden NK. The importance of the disease-modifying antirheumatic
drug treatment in the development of septic arthritis in patients with rheumatoid arthritis. Arthritis & Rheumatism
2007;57:1151–7.
[32] Strangfeld A, Listing J. Infection and musculoskeletal conditions: Bacterial and opportunistic infections during anti-TNF
therapy. Best Practice & Research Clinical Rheumatology 2006;20:1181–95.
[33] Dixon WG, Symmons DP, Lunt M, Watson KD, Hyrich KL. Serious infection following anti-tumor necrosis factor alpha
therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis &
Rheumatism 2007;56:2896–904.
[34] Rozadilla A, Nolla JM, Mateo L, Blanco J, Valverde J, Roig D. Septic arthritis induced by pyogenic germs in patients without
parenteral drug addiction. Analysis of 44 cases. Clinical Medicine 1992;98:527–30.
[35] Al Nammari SS, Gulati V, Patel R, Bejjanki N, Wright M. Septic arthritis in haemodialysis patients: a seven-year multicentre review. Journal of Orthopaedic Surgery (Hong Kong) 2008;16:54–7.
[36] Geirsson AJ, Statkevivius S, Vikingsson A. Septic arthritis in Iceland 1990-2002: increasing incidence due to iatrogenic
infections. Annals of the Rheumatic Diseases 2008;67:638–43.
[37] Ventura G, Gasparini G, Luci MB, Tumbarello M, Tacconelli E, Caldarola G, et al. Osteoarticular bacterial infections are rare in
HIV-infected patients: 14 cases found among 4.023 HIV-infected patients. Acta Orthopaedica Scandinavica 1997;68:554–8.
[38] Bayer AS. Gonococcal arthritis syndromes: an update on diagnosis and management. Journal of Postgraduate Medicine
1980;67:200–8.
*[39] Smith JW, Chalupa P, Shabaz HM. Infectious arthritis: clinical features, laboratory findings and treatment. Clinical
Microbiology and Infections 2006;12:309–14.
[40] Dubost JJ, Fis I, Denis P, Lopitaux R, Soubrier M, Ristori JM, et al. Polyarticular septic arthritis. Medicine (Baltimore) 1993;
72:296–310.
[41] Vincent GM, Amirault JD. Septic arthritis in the elderly. Clinical Orthopaedics 1990;251:241–5.
[42] Ariza J, Pujol M, Valverde J, Nolla JM, Rufí G, Viladrich PF, et al. Brucellar sacroiliitis: findings in 63 episodes and current
relevance. Clinical Infectious Diseases 1993;16:761–5.
[43] Vyskocil JJ, McIlroy MA, Brennan TA, Wilson FM. Pyogenic infection of the sacroiliac joint. Case reports and review of the
literature. Medicine (Baltimore) 1991;70:188–97.
[44] Ross JJ, Hu LT. Septic arthritis of the pubic symphysis: review of 100 cases. Medicine (Baltimore) 2003;82:340–5.
420
M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421
[45] Buxton RA, Moran M. Septic arthritis of the hip in the infant and young chil. Current Orthopaedics 2003;17:458–64.
[46] Newman JH. Review of septic arthritis throughout the antibiotic era. Annals of the Rheumatic Diseases 1976;35:198–205.
*[47] Mathews CJ, Kingsley G, Field M, Jones A, Weston VC, Phillips M, et al. Management of septic arthritis: a systematic
review. Annals of the Rheumatic Diseases 2007;66:440–5.
[48] Li SF, Cassidy C, Chang C, Gharib S, Torres J. Diagnostic utility of laboratory tests in septic arthritis. Emergency Medicine
Journal 2007;24:75–7.
[49] Hugle T, Schuetz P, Muller B, Laifer G, et al. Serum procalcitonin for discrimination between septic and non-septic
arthritis. Clinical and experimental rheumatology 2008;26:453–6.
[50] Coutlakis PJ, Roberts WN, Wise CM. Another look at synovial fluid leukocytosis and infection. Journal of Clinical Rheumatology 2002;8:67–71.
[51] Baer PA, Tenenbbaum J, Fam AG, Little FH. Coexistent septic and crystal arthritis. Report of four cases and literature
review. Journal of Rheumatology 1986;13:604–7.
[52] von ER, Holtta A. Improved method of isolating bacteria from joint fluids by the use of blood culture bottles. Annals of the
Rheumatic Diseases 1986;45:454–7.
[53] Peters RP, van Agtmael MA, Danner SA, Savelkoul PH, Vandenbroucke-Grauls CM. New developments in the diagnosis of
bloodstream infections. Lancet Infectious Diseases 2004;4:751–60.
[54] Fenollar F, Levy PY, Raoult D. Usefulness of broad-range PCR for the diagnosis of osteoarticular infections. Current
Opinion in Rheumatology 2008;20:463–70.
[55] Zieger M, Dorr MU, Schulz RD. Ultrasonography of hip joint effusions. Skeletal Radiology 1987;16:607–11.
[56] Tien YC, Chih HW, Lin GT, Hsien SH, Lin SY. Clinical application of ultrasonography for detection of septic arthritis in
children. Kaohsiung Journal of Medical Sciences 1999;15:542–9.
[57] Seltzer SE. Value of computed tomography in planning medical and surgical treatment of chronic osteomyelitis. Journal
of Computer Assisted Tomography 1984;8:482–7.
[58] Christian S, Kraas J, Conway WF. Musculoskeletal infections. Seminar Roentgenol 2007;42:92–101.
[59] Graif M, Schweitzer ME, Deely D, Matteucci T. The septic versus nonseptic inflamed joint: MRI characteristics. Skeletal
Radiology 1999;28:616–20.
[60] Rosenthal L, Lisbona R, Hernandez M, Hadjipavlou A. 99mTc-PP and 67Ga imaging following insertion of orthopedic
devices. Radiology 1979;133:717–21.
[61] Bittini A, Dominguez PL, Martinez ML, Lopez FJ, Monteagudo I, Carreño L. Comparison of bone and gallium-67 imaging in
heroin users0 arthritis. Journal of Nuclear Medicine 1985;26:1377–81.
[62] Goldenberg DL, Brandt KD, Cohen AS, Cathcart ES. Treatment of septic arthritis: comparison of needle aspiration and
surgery as initial modes of joint drainage. Arthritis & Rheumatism 1975;18:83–90.
[63] Ho GJ, Su EY. Therapy for septic arthritis. Journal of the American Medical Association 1982;247:797–800.
[64] Goldenberg DL, Cohen AS. Acute infectious arthritis. A review of patients with nongonococcal joint infections (with
emphasis on therapy and prognosis). American Journal of Medicine 1976;60:369–77.
[65] Sharp JT, Lidsky MD, Duffy J, Duncan MW. Infectious arthritis. Archives of Internal Medicine 1979;139:1125–30.
[66] Sakiniene E, Bremell T, Tarkowski A. Addition of corticosteroids to antibiotic treatment ameliorates the course of
experimental Staphylococcus aureus arthritis. Arthritis & Rheumatism 1996;39:1596–605.
[67] Odio CM, Ramirez T, Arias G, Abdelnour A, Hidalgo I, Herrera ML, et al. Double blind, randomized, placebo-controlled
study of dexamethasone therapy for hematogenous septic arthritis in children. Journal of Pediatric Infectious Diseases
2003;22:883–8.
[68] Verdrengh M, Carlsten H, Ohlsson C, Tarkowski A. Addition of bisphosphonate to antibiotic and anti-inflammatory
treatment reduces bone resorption in experimental Staphylococcus aureus-induced arthritis. Journal of Orthopaedic
Research 2007;25:304–10.
[69] Puliti M, von Hunolstein C, Verwaerde C, Bistoni F, Orefici G, Tissi L. Regulatory role of interleukin-10 in experimental
group B streptococcal arthritis. Infection and Immunity 2002;70:2862–8.
[70] Puliti M, von Hunolstein C, Bistoni F, Mosci P, Orefici G, Tissi L. The beneficial effect of interleukin-12 on arthritis induced
by group B streptococci in mediated by interferon-gamma and interleukin-10 production. Arthritis & Rheumatism 2002;
46:806–17.
[71] Steckelberg JM, Osmon DB. In: Bisno AL, Waldvogel FA, editors. Prosthetic joint infection. 3rd ed. Washington, DC:
American Society for Microbiology; 2000. p. 173–209.
*[72] Zimmerli W, Trampuz A, Oschner PE. Prosthetic-joint infections. New England Journal of Medicine 2004;351:1645–54.
[73] Francois P, Vaudaux P, Lew PD. Role of plasma and extracellular matrix proteins in the physiopathology of foreign body
infections. Annals of Vascular Surgery 1998;12:34–40.
[74] Roisman FR, Walz DT, Finkeslstein AE. Superoxide radical production by human leukocytes exposed to immune
complexes: inhibitory action of gold compounds. Inflammation 1983;7:355–62.
[75] Costerton JW, Steward PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections. Science 1999;284:1318–22.
[76] Kadoya Y, Kobayashi A, Ohashi H. Wear and osteolysis in total joint replacements. Acta Orthopaedica Scandinavica 1998;
278:1–16.
[77] Bauer TW, Schils J. The pathology of total joint arthroplasty: II: Mechanisms of implant failure. Skeletal Radiology 1999;
28:483–97.
[78] Bengston S, Knutson K. The infected knee arthroplasty. A 6-year follow-up pf 357 cases. Acta Orthopaedica Scandinavica
1991;62:301–11.
[79] Ainscow DA, Denham RA. The risk of haematogenous infection in total joint replacements. The Journal of Bone and Joint
Surgery 1984;66:580–2.
[80] Murdoch DR, Roberts SA, Fowler jr JV, Shah MA, Taylor SL, Morris AJ, et al. Infection of orthopedic prostheses after
Staphylococcus aureus bacteriemia. Clinical Infectious Diseases 2001;32:647–9.
[81] Stumpe KD, Notzli HP, Zanetti M, Kamel EM, Hany TF, Görres GW, et al. FDG PET for differentiation of infection and aseptic
loosening in total hip replacements: comparison with conventional radiography and three-phase bone scintigraphy.
Radiology 2004;231(2):333–41.
M. García-Arias et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 407–421
421
*[82] Zimmerli W, Ochsner PE. Management of infection associated with prosthetic joints. Infection 2003;31(2):99–108.
[83] Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampicin for treatment of orthopedic implant-related
staphylococcal infections: a randomized controlled trial. Foreign Body Infection (FBI) Study Group. Journal of the
American Medical Association 1998;279:1537–41.
[84] Trampuz A, Zimmerli W. New strategies for the treatment of infections associated with prosthetic joints. Current Opinion
in Investigational Drugs 2005;6:185–90.
[85] Razonable RR, Osmon DR, Steckelberg JM. Linezolid therapy for orthopedic infections. Mayo Clinic Proceedings 2004;79:
1137–344.
[86] Carpenter CF, Chambers HF. Daptomycin another novel agent for treating infections due to drug-resistant gram-positive
pathogens. Clinical Infectious Diseases 2004;38:994–1000.
[87] Britingan BE, Cohen MS, Sparling PF. Gonococcal infection: a model of molecular pathogenesis. New England Journal of
Medicine 1985;312:1683–94.
[88] O’Brien JP, Goldenberg DL, Rice PA. Disseminated gonococcal infection: a prospective analysis of 49 patients and a review
of pathophysiology and immune mechanisms. Medicine (Baltimore) 1983;62:395–406.
*[89] Bardin T. Gonococcal arthritis. Best Practice & Research Clinical Rheumatology 2003;17:201–8.
[90] Ram S, Mackinnon FG, Gulati S, McQuillen DP, Vogel U, Frosch M, et al. The contrasting mechanisms of serum resistance
of Neisseria gonorrhoeae and group B Neisseria meningitidis. Molecular Immunology 1999;36:915–28.
[91] Rice PA, Kasper DL. Characterization of serum resistance of Neisseria gonorrhoeae that disseminate. Roles of blocking
antibody and gonococcal outer membrane proteins. Journal of Clinical Investigation 1982;70:157–97.
[92] Petersen BH, Lee TJ, Snyderman R, Brooks GF. Neisseria meningitis and Neisseria gonorrhoeae bacteriemia associated
with C6, C7 and C8 deficiences. Annals of Internal Medicine 1979;90:917–20.
[93] Gelfand SG, Masi AT, García-Kurzbach A. Spectrum of gonococcal arthritis: evidence for sequential stages and clinical
subgroups. Journal of Rheumatology 1975;2:83–90.
[94] Cucurull E, Espinoza LR. Gonococcal arthritis. Rheumatic Disease Clinics of North America 1998;2(4):305–22.
[95] Ng LK, Martin IE. The laboratory diagnosis of Neisseria gonorrhoeae. Canadian Journal of Infectious Diseases & Medical
Microbiology 2005;16:15–25.
[96] Liebling MR, Arkfeld DG, Micheline GA. Detection of Neisseria gonorrhoeae in synovial fluid, using polymerase chain
reaction. Arthritis and Rheumatism 1994;37:702–9.
[97] Ison CA, Dillon JA, Tapsall JW. The epidemiology of global antibiotic resistance among Neisseria gonorrhoeae and Haemophilus ducreyi. Lancet 1998;3(351 Suppl):8–11.
[98] Centers for Disease Control and Prevention.. Updated recommended treatment regimens for gonococcal infections and
associated conditions - United States; April 2007. Morb.Mortal.Wkly.Rep. 2007, April 13. 2009. Ref Type: Generic.
`