Advances in the Management of Bacterial Septic Arthritis

Myo M Lynn; Catherine J Mathews

Int J Clin Rheumatol. 2012;7(3):335-342.

Epidemiology & Pathogenesis of Bacterial Septic Arthritis

The annual incidence of septic arthritis remains four to ten cases per 100,000 patient-years per year in western Europe.^[1–3] The estimated incidence of septic arthritis in industrialized countries is six per 100,000 of population per year.^[3] If patients have underlying joint disease, or prosthetic joints, the incidence increases to approximately 30–60 per 100,000 of the population per year.^[4,5] There are no specific incidence data available for septic arthritis in developing countries. There are two age groups that are particularly susceptible to septic arthritis: young children and the elderly. Other at-risk groups for the development of septic arthritis include the immunocompromised, patients with diabetes, patients who are on hemodialysis^[6] and intravenous drug users.^[2,7] Any joint that carries underlying pathology, such as in rheumatoid arthritis, osteoarthritis or if a joint is prosthetic, has a significantly higher risk of developing intra-articular sepsis.^[1,2,7,8] Lower socioeconomic status, alcoholism, previous intra-articular steroid injection and cutaneous ulceration have also been documented as significant risk factors.^[8] Interestingly the incidence of septic arthritis appears to be rising, which could be attributable to the increasing use of immunosuppression, an aging population and the rise in frequency of invasive investigative and therapeutic procedures across all specialities.^[3]

There are two main possible routes by which pathogens can enter the joint: by direct inoculation into the joint or, much more commonly, by hematogenous spread following a septicemic or bacteremic episode. Direct invasion of pathogens into the joint can result from orthopedic procedures and joint surgery, joint aspiration, intra-articular injection and via intra-articular extension from a nearby contiguous source. A community-based prospective survey showed that the most common causes of direct pathogen invasion are orthopedic procedures including joint surgery and arthroscopy, followed by trauma.^[8] This survey also revealed that infected cutaneous lesions are the most common focus of infection that leads to hematogenous spread and secondary joint involvement. Lower respiratory tract infections and urinary tract infections were the second and the third most common sources leading to secondary bacterial septic arthritis.^[8] Septic arthritis due to intra-articular injection is uncommon with an estimated prevalence of four cases per 10,000 injections,^[3] while the prevalence of septic arthritis following arthroscopic procedures is estimated at 14 cases per 10,000 procedures (0.14%).^[3]

Staphylococcus aureus and other Gram-positive organisms such as streptococci remain the most common pathogenic organisms in bacterial septic arthritis. The emergence of antibiotic-resistant strains, such as β-lactam-resistant Streptococcus pneumoniae, ceftriaxone-resistant strains of gonococci, Panton-Valentine leucocidin-positive methicillin-resistant S. aureus,^[9–11] as well as increasingly atypical organisms has made the management of septic arthritis a real challenge. There have been recent case reports of the identification of organisms such as Streptococcus suis (swine pathogen), Kingella kingae, Fugobacterium necrophorum and Clostridium cadaveris in the synovial fluid of patients with septic arthritis.^[12–15] Certainly there are patient groups that are more at risk of harboring atypical organisms, such as elderly patients, immunocompromised patients and intravenous drug abusers. Intravenous drug abusers are susceptible to mixed bacterial infections as well as fungal infections and the incidence of Gram-negative infection is demonstrably higher in the older population, presumably due to the presence of comorbidities, such as skin ulceration and urinary tract infection.^[1,8]

Advances in our understanding of the pathogenesis of septic arthritis, as well as clues to future therapeutic options, have emerged from animal studies using experimental mouse models of both staphylococcal and streptococcal septic arthritis.^[16] Tarkowski and colleagues model of staphylococcal arthritis closely mimics the pathogenesis of human disease. The pathogen is injected intravenously and the joints are thereby inoculated via hematogenous spread.^[17] As soon as bacteria invade the blood stream, various virulence factors, such as extracellular toxins, enzymes, adhesins, bacterial and cell wall proteins, are produced, which initiate the inflammatory process via T-cell, B-cell and macrophage stimulation. As a consequence, proinflammatory molecules including TNF-α, IL-1β and IL-6, immunomodulatory (IL-4, IL-12) and anti-inflammatory (IL-4 and IL-10) cytokines are produced by monocytes, macrophages and synovial fibroblasts.^[17–19] Experimental manipulation of this mouse model has shown that the degree of joint damage and the severity of disease, including the resulting mortality, can be altered by genetically manipulating these host factors. For example, the depletion of proinflammatory cytokines (such as IL-1 and TNF-α) using knockout mice increases the mortality rate in S. aureus septic arthritis. Tissi and colleagues mouse model of streptococcal B-mediated septic arthritis similarly sheds light on the molecular pathogenesis of disease, showing that the lack of B7-1 and B7-2 immunoregulatory molecules modulates the severity of group B streptococcal sepsis.^[20]

The role of Toll-like receptors (TLR), a class of proteins within the innate immune system, has been discussed in recent studies in the context of both Gram-positive and -negative septic arthritis.^[21,22] Papathanasiou et al. showed higher levels of both TLR mRNA expression and MMP-13 mRNA expression in chondrocytes isolated from septic joints compared with normal chondrocytes suggesting that modulation of TLR-mediated signalling could be a potential future therapeutic target in the prevention of cartilage damage in septic arthritis.^[22]

Much of this experimental work is, of course, confined to the laboratory at present. The translation of these findings from bench to bedside, however, could herald the development of novel therapeutic options for the treatment of septic arthritis.

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Next Section

Abstract and Introduction
Epidemiology & Pathogenesis of Bacterial Septic Arthritis
Diagnosis of Bacterial Septic Arthritis
Current Treatment of Bacterial Septic Arthritis
Future Developments
Summary
References
Sidebar

Table 1. Summary of UK recommendations for initial antibiotic choice in suspected septic arthritis.
Patient group	Antibiotic choice
No risk factors for atypical organism	Intravenous flucloxacillin (2 g four-times a day). Local policy might add oral fusidic acid (500 mg three-times a day) or intravenous gentamycin. If allergic to penicillin, use clindamycin (450–600 mg four-times a day) or second- or third-generation cephalosporin
High risk of Gram-negative sepsis (elderly or frail individual, recurrent urinary tract infection, recent abdominal surgery)	Second- or third-generation cephalosporin (e.g., cefuroxine 1.5 g three-times a day). Local policy might add flucloxacillin. Discuss strategy for patients allergic to specific antibiotics with microbiologist. Gram stain could affect antibiotics choice
MRSA risk (known MRSA, recent inpatient, nursing home resident, leg ulcers or catheters, or other risk factors)	Vancomycin plus second- and third-generation cephalosporin
Suspected gonococcus and meningococcus	Ceftriaxone or similar, dependent on local policy or resistance
Intravenous drug abusers	Discuss with microbiologist
Patients in intensive care unit, known colonization of other organs (e.g., cystic fibrosis)	Discuss with microbiologist

Antibiotic choice will need to be modified after results of Gram stain and culture, and should be reviewed locally by a microbiology department.
MRSA: Methicillin-resistant Staphylococcus aureus.

Sidebar

Executive Summary

Clinical Presentation of Septic Arthritis

The clinical presentation of a patient with one or more hot, swollen joints is a common one, however, the most serious potential cause is bacterial septic arthritis although differential diagnosis is broad.
The management of bacterial septic arthritis relies on early recognition, diagnosis and timely drainage of purulent material together with prompt administration of antibiotic therapy.

Epidemiology & Pathogenesis

The annual incidence of septic arthritis remains four to ten cases per 100,000 patient-years per year in western Europe. The estimated incidence of septic arthritis in industrialized countries is six per 100,000 of the population per year. The incidence increases to approximately 30–60 per 100,000 of the population per year in patients with underlying joint disease and prosthetic joints.
There are two main routes by which pathogens can enter the joint: by direct inoculation into the joint or, more commonly, by hematogenous spread following a septicemic or bacteremic episode.
Staphylococcus aureus and other Gram-positive organisms, such as streptococci, remain the most common pathogenic organisms. The emergence of antibiotic-resistant strains as well as increasingly atypical organisms has made the management of septic arthritis a real challenge.
There are patient groups that are more at risk of harboring atypical organisms, such as elderly patients, immunocompromized patients and intravenous drug abusers.

Diagnosis of Bacterial Septic Arthritis

The initial suspicion of the diagnosis of septic arthritis comes with the typical clinical presentation of a short, 1–2 week duration of an acutely hot and swollen joint (or joints).
Any acute hot swollen joint should be always aspirated before the initiation of antibiotics and sent for urgent Gram stain and culture.

Current Treatment of Bacterial Septic Arthritis

Prompt initiation of appropriate antibiotic therapy and drainage of purulent material remains the mainstay of treatment of bacterial septic arthritis.
There are no randomized controlled trials regarding the duration and choice of antibiotic regimen to date.
Initial empirical choice of antibiotic therapy depends on the individual risk factors, local drug resistance and the geographic variation of pathogens.

Future Development

Concomitant dexamethasone therapy had a favorable outcome compared with those without dexamethasone in pediatric studies, however, there are no equivalent studies conducted in adult patients.
In animal models, use of intraperitoneal bisphosphonates has been shown to be effective in the reduction of bone destruction.
Combination of anti-TNF-α (etanercept) therapy and antibiotic treatment (cloxacillin) has been shown to be beneficial on the outcome of staphylococcal arthritis and sepsis in a recent animal study from 2011.
Whether these novel targeted therapies could reduce the disease burden in adult bacterial septic arthritis in humans remains to be seen.

Summary

The key to preventing the morbidity and mortality associated with bacterial septic arthritis depends on awareness of risk factors, early diagnosis, timely investigation and management of patients suspected of having joint sepsis.

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Advances in the Management of Bacterial Septic Arthritis

Epidemiology & Pathogenesis of Bacterial Septic Arthritis

Tables

References

Authors and Disclosures

Authors and Disclosures

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Sidebar

Executive Summary

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