Current Diagnosis & Treatment in Infectious Diseases

Section II - Clinical Syndromes

14. Osteomyelitis, Infectious Arthritis & Prosthetic-Joint Infection

Douglas R. Osmon MD

James M. Steckelberg MD

OSTEOMYELITIS

Essentials of Diagnosis

• Localized pain and tenderness of the involved bone is common.
• Purulent drainage from a sinus tract may or may not be present.
• Systemic symptoms and signs (eg, fever and chills) are often absent, particularly in chronic osteomyelitis.
• The erythrocyte sedimentation rate may be elevated.
• Plain radiographs may be negative. Computed tomography (CT) and magnetic resonance imaging (MRI) examinations are sensitive and specific tests for the presence of osteomyelitis but are expensive.
• Biopsy of the involved bone for pathologic examination and culture is diagnostic.

General Considerations

1. Pathogenesis.Osteomyelitis is an inflammatory disease of bone due to infection by a variety of different microorganisms (Figure 14-1). Normal bone is very resistant to infection unless there has been antecedent trauma or a foreign body is present. Certain organisms such as Staphylococcus aureuspreferentially cause osteomyelitis because the organisms bind to bone through the expression of receptors for fibronectin, laminin, collagen, or bone sialoglycoprotein and because S aureusis a frequent colonizer of the skin and anterior nares. Osteomyelitis occurs by several mechanisms, including hematogenous seeding caused by bacteremia from a focus of infection elsewhere in the body, contiguous spread from adjacent soft-tissue or joint infection, or direct inoculation of microorganisms into the bone during penetrating trauma or surgery.

Hematogenous Osteomyelitis. Hematogenous osteomyelitis occurs most often in children and the elderly. In children it usually occurs in the metaphyses of the femur, tibia, and humerus because the blood supply to these bones is derived from small capillary branches of the nutrient artery, which have few phagocytic cells and are prone to vascular obstruction from minor trauma. Once the blood supply is diminished, small areas of bone necrosis develop that are susceptible to hematogenous seeding. These areas of infected avascular bone become sequestra. In children < 1 y of age, the infection can spread to the epiphysis and joint space through capillaries that cross the growth plate. In children >1 y of age, the infection is confined to the metaphysis, with resulting lateral extension of the infection through the Haversian and Volkmann canal system, rupture of the cortex, and subperiosteal abscess formation. The exception to this rule is the development of osteomyelitis in metaphyses that are intracapsular, such as the proximal femur, humerus, and radius.

Hematogenous osteomyelitis in adults is much less common than in children and most often involves two adjacent vertebrae and the intervertebral disc space (vertebral osteomyelitis). Hematogenous seeding occurs through the arterial and venous blood supply (retrograde flow through Batson's venous plexus) with the former thought to be more common. Common sources of a bacteremia that predisposes to vertebral osteomyelitis include infections of intravenous-access devices, pneumonia, and urinary tract infection.

Contiguous-focus osteomyelitis. Contiguous-focus osteomyelitis is much more common in adults than in children and is often seen in persons >50 y of age. Contiguous-focus osteomyelitis occurs secondarily to spread of infection from adjacent soft tissue or joints or is caused by direct inoculation of microorganisms during trauma or surgery. Concomitant infection of orthopedic fixation devices is often present. Vascular insufficiency such as that seen in patients with longstanding diabetes mellitus often leads to recurrent soft-tissue infections and subsequent contiguous-focus osteomyelitis of the underlying bones.

1. Classification Schemes.Waldvogel has classified osteomyelitis as being of hematogenous origin or due to a contiguous focus of infection. Contiguous-focus osteomyelitis is further subdivided into osteomyelitis with or without vascular insufficiency. In addition, either type of osteomyelitis can be acute or chronic in its presentation. Acute infection is defined as a recently diagnosed bone infection of < 10-d duration, whereas chronic infection represents relapse of osteomyelitis at the same site or disease of > 10-d duration. Vertebral osteomyelitis can be acute or chronic and, depending on the pathogenesis of the infection, can be hematogenous in origin or caused by a contiguous focus of infection. Contiguous-focus osteomyelitis often occurs secondarily to a wound infection after surgery.

Figure 14-1. Chronic osteomyelitis of the tibia due to S aureus, illustrating sequestrum formation.

Cierney and Mader have proposed an alternative classification scheme (Table 14-1). This classification system is based on bone anatomy and the physiologic status of the host. This system is very useful in comparing medical and surgical treatment strategies in clinical trials. Examples of stage 1 disease include hematogenous osteomyelitis and infected intramedullary rods. Osteomyelitis of the surface of a bone at the base of a soft-tissue infection would be an example of stage 2 osteomyelitis. Osteomyelitis involving the full thickness of the bone, with or without cortical sequestration that can be débrided without endangering the stability of the bone, constitutes stage-3 disease. Osteomyelitis that involves the entire extent of bone and usually requires segmental resection to achieve adequate débridement (a débridement that often compromises the stability of the bone) is stage-4 osteomyelitis.

1. Microbiology and Epidemiology.The optimal selection of antimicrobial agents for the treatment of osteomyelitis depends on the definitive identification of the microorganism(s) causing infection and knowledge of its antimicrobial susceptibilities. Antimicrobial therapy should usually be withheld until all cultures from the involved tissue have been obtained.

Skin and serologic testing for unusual organisms such as mycobacteria and fungi should be done only if these infections are suspected clinically. Serologic tests to detect cell wall components of S aureus, such as teichoic acid, are not clinically helpful. Sinus tract swab cultures are not accurate in predicting polymicrobial infection but may be helpful if S aureus is the only pathogen isolated.

For culture, as much tissue and purulence as possible should be obtained at the time of bone biopsy and/or surgical débridement. All specimens should be sent immediately to the microbiology laboratory. Tissue specimens should be sent to both the pathology laboratory and the microbiology laboratory. Anaerobic cultures require anaerobic transport media.

The microbiologist should perform a Gram stain on all specimens. Stains for fungi or acid-fast bacilli may also be useful in selected cases. Cultures for aerobic and anaerobic bacteria should be routinely obtained. When the history, physical examination, or intraoperative findings suggest an unusual infection, special culturing techniques for organisms such as fungi, mycobacteria, Mycoplasma spp., Brucella spp., or other organisms may be required. Failure to obtain specimens for these cultures at the time of initial débridement may result in unnecessary procedures to obtain further culture material or ultimately treatment failure despite adequate débridement.

Table 14-1. Cierny and Mader staging system of osteomyelitis.1

Anatomictype    Stage 1: medullary osteomyelitis    Stage 2: superficial osteomyelitis    Stage 3: localized osteomyelitis    Stage 4: diffuse osteomyelitis Physiologic Class    A Host: Normal host    B Host:       Systemic compromise (Bs)       Local compromise (Bi)       Systemic and local compromise (Bis)    C Host: Treatment worse than the disease. Systemic or local factors that affect immune surveillance, metabolism, and local vascularity    Systemic (Bs)       Malnutrition       Renal, hepatic failure       Diabetes mellitus       Chronic hypoxia       Immune disease       Malignancy       Extremes of age       Immunosuppression    Local (Bi)       Chronic lymphedema       Major vessel compromise       Small vessel disease       Vasculitis       Venous stasis       Extensive scarring       Radiation fibrosis       Neuropathy       Tobacco abuse 1Source: Mader et al 1996.

The pathologist, although primarily looking for the presence or absence of inflammation, may also find evidence of a specific type of inflammation, such as granulomas, that provide a clue to the etiology of the infection. In this circumstance, it is useful to perform additional tissue stains for fungi and mycobacteria.

Once the microorganism responsible for the infection has been identified, antimicrobial susceptibility tests should be performed. A minimal inhibitory concentration (MIC) obtained by broth or agar dilution is the best guide to therapy. When only disc diffusion (Kirby-Bauer disc sensitivities) results are available, drugs with intermediate or resistant results should not be used. Some investigators also advocate performing a serum bactericidal titer. This test quantitates the bactericidal activity of the patient's serum. It is the dilution of patient's serum that shows ≥99.9% killing of the organism in vitro. However, these tests are difficult to reproduce within and among laboratories, and their use is not advocated.

Hematogenous Osteomyelitis. S aureus is the most common cause of hematogenous osteomyelitis in children and adults (Box 14-1). Hematogenous osteomyelitis caused by beta-hemolytic streptococci and aerobic gram-negative bacilli is much less common. Some patient groups are predisposed to hematogenous infection due to certain organisms: neonates (Enterobacteriaceae, group B streptococci), patients with sickle cell disease (Salmonella spp., S aureus), and injection drug users (Pseudomonas aeruginosa, S aureus). Haemophilus influenzae causes infection in infants and children, but the incidence of invasive disease caused by H influenzae is decreasing owing to the H influenzae type b-conjugated vaccine that is now routinely administered to children. Anaerobic and polymicrobial infections are uncommon.

Vertebral Osteomyelitis. S aureus is the most common cause of vertebral osteomyelitis. Aerobic gram-negative bacilli cause ≤30% of infections, particularly those associated with hematogenous seeding from a urinary tract infection. P aeruginosa and S aureus infections are common among injection drug users. Coagulase-negative staphylococci, S aureus, and aerobic gram-negative bacilli are common causes of vertebral osteomyelitis after spine surgery with or without spinal hardware implantation. Polymicrobial infection is uncommon. Candidal infection may occur after candidemia, due to infections of intravascular devices.

Contiguous-Focus Osteomyelitis. This infection is often polymicrobial, particularly in the setting of osteomyelitis of the phalanges or metatarsals in patients with diabetes mellitus or vascular insufficiency or in osteomyelitis of the long bones after a contaminated open fracture. S aureus, beta-hemolytic streptococci, enterococci, aerobic gram-negative bacilli, and anaerobes can all be pathogens. If soil contamination is present, Clostridium spp., Bacillus spp., Stenotrophomonas maltophilia, Nocardia spp., and rarely various mycobacteria and fungi may cause infection. If orthopedic fixation devices become infected, then monomicrobial infection due to S aureus or coagulase-negative staphylococci is more common. Pasteurella multocida osteomyelitis often complicates cat bites, and P aeruginosa is a common cause of osteomyelitis of the foot after puncture injuries by nails or other sharp objects. Normal oral flora and Actinomyces spp. cause mandibular or skull osteomyelitis after periodontal infection.

BOX 14-1 Microorganisms Isolated from Patients with Bacterial Osteomyelitis1

Microorganisms Common Clinical Association Staphylococcus aureus Most frequent cause of all types of ostemyelitis Coagulase-negative staphylococci Common if orthopedic fixation devices are present Streptococci Diabetes mellitus, bite injuries Enterobacteriaceae Nosocomial infection or contaminated open fractures Pseudomonas aeruginosa Injection drug users and osteomyelitis of the foot after puncture injuries Anaerobic bacteria Osteomyelitis of the foot in patients with diabetes mellitus or after human and animal bites Salmonella spp. or Streptococcus pneumoniae, S aureus Sickle cell disease Pasteurella multocida or Eikenella corrodens Bite injuries 1Adapted from Lew & Waldvogel 1997.

 

Clinical Findings

1. Hematogenous osteomyelitis.
2. Signs and symptoms.Children most often present with severe bone pain, limitation of motion of the extremity, and fever and chills of several days to 3 wk in duration, although, in ≤40% of cases, vague symptoms of 1- to 2-mo duration occur. On examination, there may be soft-tissue swelling, erythema, and tenderness of the involved area. Neonates often have no fever and present with only a decreased range of motion of the involved limb and localized tenderness and swelling. The presence of a joint effusion is also common in neonates.
3. Laboratory findings.An elevated leukocyte count, erythrocyte sedimentation rate, and C-reactive protein are common, but the lack of any one or all of these laboratory abnormalities does not exclude the diagnosis of osteomyelitis. Blood cultures should be obtained and are positive in ≤50% of cases. Aspiration of associated soft tissue or subperiosteal abscesses or biopsy of involved bone is diagnostic. Arthrocentesis should be performed if a joint effusion is present.
4. Imaging.Plain radiographs may be negative early in the disease. Soft-tissue swelling and subperiosteal elevation are the earliest abnormalities and may not be seen for several weeks. Before lytic lesions appear, 30–50% of the bone must be destroyed, and typically these lesions do not appear for 2–6 wk after the onset of the illness. Sclerotic changes occur later and, when seen in association with periosteal new-bone formation, suggest chronicity of the infection.

Radionuclide scanning may be helpful early in the course of the disease, but the usefulness of this test is often limited by its lack of specificity. CT scans and MRI are better able to distinguish soft-tissue infection from osteomyelitis, are more sensitive than plain radiographs, and allow better identification of optimal areas for needle aspiration or biopsy.

1. Vertebral osteomyelitis.
2. Signs and symptoms.Patients are often > 50 y of age, except injection drug users, and usually present with back pain of several-months duration. The pain is often described as a continuous dull ache that is exacerbated by movement, cough, or straining. If neurologic complications (30%) are present secondary to nerve root or spinal cord compression from epidural extension of the infection, these symptoms may dominate the clinical picture. On physical examination, a draining sinus or wound is usually not present unless the infection is secondary to recent surgery. Fever is present in 20–50% of patients. Paraspinal muscle spasm and percussion tenderness of the spine are often present. The lumbar spine is most commonly involved, followed by the thoracic and cervical regions.
3. Laboratory findings.An elevated leukocyte count is often present. The erythrocyte sedimentation rate is elevated in ≤95% of patients. Blood cultures are positive in 25–50% of cases, and positive blood cultures negate the need for routine biopsy of the involved vertebra and intervertebral disc space. Needle biopsy of the involved intervertebral disc, vertebra, or associated epidural abscess is the diagnostic procedure of choice. In ≤25% of cases, the cultures from the initial needle biopsy may be negative. A second needle biopsy, an open biopsy, or both should then be performed.
4. Imaging.Plain radiographs of the spine often do not show characteristic vertebral endplate destruction, particularly in patients with a short duration of symptoms or other underlying vertebral pathology such as severe osteoarthritis. However, nonspecific abnormalities (ie, loss of disk height) on plain radiographs will be detected in the majority of cases. Gallium scans are more sensitive and specific than three-phase technetium (⁹⁹Tc) bone scans or indium-labeled leukocyte scans for the diagnosis of vertebral osteomyelitis. MRI, however, is the most sensitive and diagnostic imaging technique and, in addition, provides the best anatomic detail. Gallium scans should be used when spinal hardware is present that degrades the MRI images.
5. Contiguous-focus osteomyelitis.
6. Signs and symptoms.The patient usually presents with localized bone pain and/or drainage from a wound or sinus tract, of several-months duration. Fever and constitutional symptoms are uncommon. Overlying cellulitis may be present. A pathologic fracture may be present if extensive disease is present.
7. Laboratory findings.The leukocyte and the erythrocyte sedimentation rates are often normal. Blood cultures are usually negative. A bone biopsy is diagnostic and is usually obtained at the time of surgical débridement.
8. Imaging.Because the time from onset of infection to diagnosis of osteomyelitis is often delayed with contiguous focus osteomyelitis, plain radiographs, including tomography, often show abnormalities consistent with osteomyelitis. In the proper clinical setting, such as the presence of a draining sinus tract, plain radiography may be all that is required. In some circumstances, however, there are other pathologic processes present that mimic osteomyelitis (ie, neuropathic bone disease in patients with peripheral neuropathy), or there are partially healed fractures or orthopedic fixation devices in place that limit the usefulness of plain radiography. If the clinical situation warrants additional radiologic procedures to confirm the diagnosis of osteomyelitis or to help identify the optimal surgical therapy for the patient, MRI is the diagnostic test of choice. If orthopedic hardware is present that interferes with MRI examination, then the combination of a three-phase (⁹⁹Tc) technetium bone scan and indium-labeled leukocyte scan can be performed.

 

Differential Diagnosis

Acute hematogenous osteomyelitis in children must be distinguished from soft-tissue infection, infectious arthritis, and certain malignancies such as Ewing's sarcoma. Vertebral osteomyelitis should be distinguished from the multitude of disease entities that can cause acute to subacute onset of back pain in adults, including osteoarthritis, metastatic malignancy, and compression fractures. If recent surgery has been performed, it is often difficult to distinguish postoperative pain and radiographic changes from those secondary to infection. Contiguous-focus osteomyelitis must be distinguished from chronic soft-tissue infection and rarely malignancy. Contiguous-focus osteomyelitis of the feet in patients with diabetes mellitus must be distinguished from neuropathic bone disease.

Complications

Failure of medical and surgical therapy of osteomyelitis invariably leads to a relapse of infection. If treatment is delayed, osteomyelitis can progress from superficial to diffuse disease or from Cierney/ Mader stage 1 or 2 to stage 3 or 4 and thus become much more difficult to eradicate. In severe cases, amputation may be required for control of infection. In addition, acute hematogenous osteomyelitis in children can spread to adjacent joints and cause infectious arthritis. Vertebral osteomyelitis in adults if untreated can cause neurologic sequelae including paralysis either through extension to the epidural space or spinal column instability. Rare complications of longstanding osteomyelitis include amyloidosis, squamous cell carcinoma at the site of chronic sinus tract or primary bone malignancies such as osteogenic sarcoma.

Treatment

The treatment of osteomyelitis depends on the goals of therapy and requires a multidisciplinary team of physicians, which may include the orthopedist, neurosurgeon, oral surgeon, plastic surgeon, vascular surgeon, invasive radiologist, and infectious disease specialist. If eradication of infection is the goal, then, in most circumstances, extensive débridement and resection of dead and infected bone are required, in conjunction with appropriate dead-space and soft-tissue management, rigid fixation of fractures, local antimicrobial therapy with antibiotic-impregnated polymethylmethacrylate beads, and prolonged systemic antimicrobial therapy directed at the causative organisms. In addition, modification of any physiologic factors (see Table 14-1) that may promote treatment failure, such as cessation of smoking, enhancement of the local blood supply in the area of the infection, and improved control of diabetes mellitus, should be accomplished. Often, delayed reconstructive orthopedic techniques such as bone grafting and distraction osteogenesis (Ilizarov technique) are also necessary.

Exceptions to the absolute requirement for extensive débridement to arrest osteomyelitis include acute hematogenous osteomyelitis of the long bones in children and vertebral osteomyelitis in adults. The duration of therapy is usually 3–4 wk in children and 4–6 wk in adults. In children, after 7–10 d of intravenous antimicrobial therapy, the last 2–3 wk of therapy are often administered orally. Indications for surgery for acute osteomyelitis include failure to make a specific microbiologic diagnosis with less invasive techniques, involvement of the femoral head, neurologic complications, the presence of sequestra, and failure to improve while on appropriate antimicrobial therapy. In addition, the consequences of aggressive surgical and medical treatment for chronic osteomyelitis may in selected cases be worse than the consequences of the disease itself, and local wound care with or without oral antimicrobial suppressive therapy may be an option in these situations.

There are no large randomized studies to help guide the clinician in the antimicrobial therapy of osteomyelitis. Although several clinical trials have been performed, their interpretation is limited by their small sample size, differences in inclusion and exclusion criteria, definition of treatment failure, failure to stratify patients by the type and severity of osteomyelitis present, and a short duration of follow-up. The overall failure rate among the 154 evaluable patients in these studies was 22%.

Most experts administer 4–6 wk of intravenous antimicrobial therapy after surgical débridement for the treatment of chronic osteomyelitis. This therapy can be completed as an outpatient in the majority of cases. Data from animal models of osteomyelitis suggest that the addition of rifampin to beta-lactams or vancomycin for osteomyelitis caused by S aureus may be beneficial, but confirmation in clinical trials is needed before this practice can be routinely recommended.

The choice of a specific antibiotic depends on the antimicrobial activity, pharmacokinetics, tissue penetration, and potential toxicities of the antimicrobial agents under consideration. Integration of this knowledge with information about drug allergies, current medications, concurrent remote infection, and hepatic and renal insufficiency allows for selection of the optimal antimicrobial agent and dosage. For antimicrobial agents that have potential toxicities at concentrations close to therapeutic concentrations, such as aminoglycosides or vancomycin, the dosage and frequency of administration are guided by measurement of their concentration in serum. Although the cost of an antimicrobial agent is an important consideration, it is secondary to the safety and efficacy of the antibiotic. Suggested antimicrobial agents for specific pathogens that cause osteomyelitis are shown in Box 14-2.

BOX 14-2 Antibiotic Therapy for Chronic Osteomyelitis in Aduts

Microorganisms Antibiotic Therapy1 Alternative Therapy1 Staphylococcus aureus    Methicillin sensitive   · Nafcillin sodium or oxacillin sodium, 1.5–2.0 g IV every 4 h for 4–6 wk. OR · Cefazolin (or other first-generation cephalosporins in equivalent dosages) 1 g IV every 8 h for 4–6 wk (cephalosporins should be avoided in patients with immediate-type hypersensitivity to penicillin) Vancomycin,2 30 mg/kg IV in 2 equally divided doses, not to exceed 2 g/24 h unless serum levels are monitored for 4–6 wk    Methicillin resistant · Vancomycin,2 30 mg/kg IV in 2 equally divided doses, not to exceed 2 g/24 h unless serum levels are monitored for 4–6 wk Consult infectious diseases specialist Penicillin-sensitive streptococci or pneumococci (MIC, < 0.1 µg/mL) · Aqueous crystalline penicillin G, 20 × 106 U/24 h IV either continuously or in six equally divided doses for 4–6 wk OR · Ceftriaxone, 2 g IV or IM for 4–6 wk2 OR · Cefazolin (or other first-generation cephalosporins in equivalent dosages), 1 g IV every 8 h for 4–6 wk (cephalosporins should be avoided in patients with immediate-type hypersensitivity to penicillin) · Vancomycin,2 30 mg/kg IV in 2 equally divided doses, not to exceed 2 g/24 h unless serum levels are monitored for 4–6 wk (vancomycin therapy is recommended for patients allergic to beta-lactams (immediate-type hypersensivity) Enterococci or streptococci with an MIC > 0.5 µg/mL or nutritionally variant strep-tococci (All enterococci causing osteomyelitis must be tested for antimicrobial susceptibility to select optimal therapy.) · Aqueous crystalline penicillin G, 20 × 106 U/24 IV, either continuously or in six equally divided doses for 4–6 wk, OR · Ampicillin sodium, 12 g/24h IV either continuously or in six equally divided doses (The addition of gentamicin sulfate,31 mg/kg IV or IM every 8 h for 1–2 wk is optional) · Vancomycin,2 30 mg/kg IV in 2 equally divided doses, not toexceed 2 g/24 h unless serum levels are monitored for 4–6 wk (The addition of gentamicin sulfate,3 1 mg/kg IV or IM every 8 h for 1–2 wk is optional) Enterobacteriaceae (based on in vitro susceptibility) · Ceftriaxone, 2 g IV every day for 4–6 wk2 · Ciprofloxacin, 500–750 mg orally every day for 4–6 wk Pseudomonas aeruginosa or Enterobacter spp. · Most effective single drug or combination of drugs IV for 4–6 wk 1Dosages recommended are for patients with normal renal function. IV, intravenous; IM, intramuscular. 2Vancomycin therapy is recommended for patients allergic to beta-lactams (immediate-type hypersensitvity); serum concentration of vancomycin should be obtained prior to and 1 h after completion of the infusion and should be in the range of 20–40 µg/mL for a peak and 5–10 µg/ml for a trough for twice-daily dosing. Vancomycin should be infused over at least 1 h to reduce the risk of the “red man” syndrome. 3Serum concentration of gentamicin should be obtained prior to and 30 min after completion of the infusion and should be in the range of 3–4 µg/mL for a peak and 0.5–1 µg/mL fora trough for synergistic therapy for enterococci. Relative contraindications to the use of gentamicin are age > 65 y, renal impairment, or impairment of the eighth cranial nerve. Other potentially nephrotoxic agents should be used cautiously in patients receiving gentamicin.

 

 

For osteomyelitis caused by susceptible aerobic gram-negative bacilli, some practitioners use initial oral antimicrobial therapy with fluoroquinolones such as ciprofloxacin or levofloxacin or completion of antimicrobial therapy with oral agents after intravenous therapy. Hyperbaric oxygen therapy for chronic osteomyelitis remains controversial.

Prognosis

Despite state-of-the-art medical and surgical therapy for osteomyelitis, relapse of infection occurs. Relapse is more common in cases of chronic osteomyelitis than acute osteomyelitis and can occur in ≤25–30% of cases. Relapse of infection is most often caused by suboptimal surgical débridement rather than a failure of antimicrobial therapy. Therefore, it is probably best not to think in terms of a cure for osteomyelitis but prolonged arrest of the disease process.

Prevention

Specific strategies to prevent osteomyelitis depend on the type of osteomyelitis. Decreasing the incidence of infections that predispose to transient or sustained bacteremia will prevent hematogenous osteomyelitis. Therefore, efforts to reduce the incidence of community- and nosocomially acquired infections such as pneumonia, urinary tract infections and soft-tissue infections through vaccination, infection control measures, and early treatment of established infection will prevent hematogenous osteomyelitis. The incidence of contiguous-focus osteomyelitis can be reduced through efforts such as improved foot care in patients with diabetes mellitus and infection control efforts to reduce the incidence of surgical-site infections after orthopedic and neurosurgical procedures.

INFECTIOUS ARTHRITIS

Essentials of Diagnosis

• Monoarticular arthritis of the knee, hip, or shoulder is most typical, but involvement of any joint can occur.
• Risk factors include systemic immune defects, a history of prior joint trauma or arthritis, or both.
• Fever and infection elsewhere in the body are common.
• Arthrocentesis commonly reveals a synovial-fluid leukocyte count of >100,000/µl with a predominance of polymorphonuclear leukocytes.
• Gout and pseudogout must be excluded.

General Considerations

Infectious arthritis is an inflammatory disease of a joint (Figure 14-2). It is usually caused by hematogenous seeding of the joint. Synovial tissue has a rich vascular supply and no basement membrane and therefore is at increased risk of hematogenous infection should bacteremia occur, owing to a focus of infection elsewhere.

7. Epidemiology.An estimated 20,000 cases, or 7.8 cases per 100,000 person years, of infectious arthritis occurred in the United States in 1993, of which 56% were male and 45% were ≥65 y of age. Host factors that have been associated with an increased risk of acquiring infectious arthritis include systemic immune defects, as seen in patients with rheumatoid arthritis, diabetes mellitus, and malignancy and local abnormalities of host defenses owing to the presence of prior joint damage, which predisposes the joint to hematogenous infection. In addition, factors that increase the risk of bacteremia, such as intravenous drug use and chronic skin infection, or that allow direct inoculation of microorganisms, such as therapeutic arthrocentesis, predispose to infection.

Disseminated gonococcal infection is more common among sexually active menstruating women.

Figure 14-2. Intraoperative photograph of infectious arthritis of the knee due to S aureus, revealing severe joint destruction. Reprinted from: Armstrong D, Cohen J (eds), Infectious Diseases. Mosby-Year Book, 1999.

1. Microbiology.A multitude of microorganisms can cause infectious arthritis, although bacteria cause the majority of cases in children and adults. Fungi, mycobacteria, Borrelia burgdorferi, and viruses, as well as other microorganisms, also cause infectious arthritis and are discussed in their specific chapters. Group B streptococci and gonococci cause ≤95% of community-acquired infections in neonates. In children, S aureus, H influenzae, and streptococci are the major pathogens. The frequency of disease caused by H influenzaeis decreasing, owing to the use of the H influenzae b conjugate vaccine.

In persons 15–40 y of age, 94% of infectious arthritis cases are due to Neisseria gonorrhoeae. The most common pathogens among adults are shown in Box 14-3. Infection in patients with rheumatoid arthritis or polyarticular infectious arthritis is caused by S aureus in ≤90% of patients. Infectious arthritis caused by gram-negative bacilli is more common in the elderly and patients with other comorbid illnesses. Enterococcal or anaerobic infection is uncommon. P aeruginosa and S aureus are common pathogens among injection drug users. Mycoplasma spp. cause infection in patients who are hypogammaglobulinemic.

1. Pathogenesis.S aureusis the most common cause of joint infection, in part because of its ability to bind to sialoprotein, a glycoprotein found in joints. Direct inoculation of microorganisms caused by trauma, arthrotomy, arthroscopy, or arthrocentesis also occurs. Infection caused by contiguous soft-tissue infection or periarticular osteomyelitis is rare. The presence of bacteria in the synovial tissue results in an influx of polymorphonuclear leukocytes that release enzymes, which destroy the ground substance of the articular surface, erode the cartilage, and eventually narrow the joint space.

BOX 14-3 Microbiology of Infectious Arthritis in Adults1,2

Microorganisms Percentage S aureus 66 Streptococci3 20 H influenzae 1 Aerobic gram-negative bacilli 10 Polymicrobial and miscellaneous 1 Unknown — 1Source: Adopted from Roberts & Mock 1996. 2Excluding Neisseria gonorrhoeae. 3Includes beta-hemolytic streptococci, viridans group streptococci, and Streptococcus pneumoniae.

Clinical Findings

1. Signs and Symptoms.Acute onset of an inflammatory arthritis of a weight-bearing joint over hours to days is typical. A chronic disease process is more common with infectious arthritis caused by mycobacteria or fungi. The knee, hip, and shoulder are the most commonly involved joints in adults. Infection of the hip or the knee is most common in children. Sacroiliac or sternoclavicular joint infection is common among injection drug users. Polyarticular infection occurs in ~10% of patients and is more common among patients with rheumatoid arthritis. Fever is often present but is mild.

Physical examination usually reveals a large effusion and a marked decrease in range of motion of the joint, although these findings may be minimal or absent in patients with rheumatoid arthritis. Tenosynovitis, a macular, vesicular, pustular or petechial rash, and polyarticular involvement are commonly seen with disseminated gonococcal infection, whereas monoarticular involvement without rash or tenosynovial involvement is common in later stages of the disease.

1. Laboratory Findings.The erythrocyte sedimentation rate and leukocyte count are elevated in the majority of cases. The diagnostic procedure of choice is an arthrocentesis. Synovial fluid is often purulent, and the leukocyte count is usually >50,000/mm³and often >100,000/mm³, with >75% polymorphonuclear leukocytes. Unfortunately these findings can also be seen in patients with rheumatoid arthritis and crystal deposition arthritis. A low glucose is common but is not specific for infection. The Gram stain will be positive in 35–65% of patients. Synovial fluid should be cultured for both aerobes and anaerobes and other organisms depending on the clinical circumstances. All synovial fluid from adults should be examined for uric acid and calcium pyrophosphate dihydrate crystals. The role of the powlymerase chain reaction in detecting bacterial pathogens remains to be defined although the technique seems a promising tool for the detection of infectious arthritis due to B burgdorferi. Synovial tissue cultures are indicated only for chronic infectious arthritis when mycobacterial or fungal arthritis is suspected. Blood cultures are positive in ≤30% of all patients and more often in patients with polyarticular involvement. In disseminated gonococcal disease, the blood cultures and/or cultures from the urethra, cervix, rectum, or pharynx are positive whereas synovial fluid cultures are negative. In monoarticular gonococcal arthritis, the synovial fluid cultures are usually positive, and the blood cultures negative.
2. Imaging.Periarticular soft-tissue swelling is the most common abnormality seen on plain radiography. Joint space narrowing from cartilage destruction occurs later. It is often difficult to distinguish infection from inflammatory arthritis by using radiographic methods in the setting of rheumatoid arthritis, but the development of a rapid destructive arthritis in one or two joints suggests infection. CT scans and MRI are more useful than radionuclide studies in identifying concomitant periarticular osteomyelitis. Sacroiliac or sternoclavicular joint disease can be evaluated with all three modalities.

Differential Diagnosis

In adults, the differential of patients with an acute onset of fever, chills, and an inflammatory arthritis of one or more joints revolves around infectious arthritis, gout, pseudogout, rheumatic fever, reactive arthritis, and rheumatic illnesses such as rheumatoid and psoriatic arthritis. In children, as stated previously, concomitant osteomyelitis is common and must be excluded. In addition, a painful hip and fever in a child should raise the possibility of acute transient synovitis of the hip.

Treatment

The principles in the management of infectious arthritis include drainage of the purulent synovial fluid, débridement of any concomitant periarticular osteomyelitis, and the administration of appropriate parenteral antimicrobial therapy. Experimental models of infectious arthritis suggest that early drainage and antimicrobial therapy prevent cartilage destruction. Local antimicrobial as opposed to systemic therapy is unnecessary. Joint immobilization and elevation are useful for symptomatic relief of pain early in the course of the disease, but early active range-of-motion therapy is beneficial for ultimate functional outcome.

The optimal method of drainage of an infected joint remains controversial, in part because no well-controlled randomized trials exist to guide therapy. Most children, except patients with infectious arthritis of the hip, and patients with gonococcal infection do not require repeated joint aspirations or arthrotomy. Historically, most adults with infectious arthritis have been managed with repeated joint aspirations, not surgical débridement. Arthrotomy has been reserved for cases in which there is failure to improve within 7 d of conservative therapy, inability to adequately drain the infected joint by aspiration either due to location (hip and shoulder) or loculations of purulence within the joint, and longstanding infectious arthritis. The exact role of arthroscopy remains unknown but is an attractive option for the initial therapy of infectious arthritis because of the minimal morbidity of the procedure and its improved ability to adequately drain purulent material from the joint compared with joint aspiration. Randomized trials are urgently needed to evaluate all of these modalities.

The principles of antimicrobial therapy, as well as the drugs of choice and their dosages for specific pathogens that cause infectious arthritis in adults, are the same as for osteomyelitis (Box 14-2). Most experts, however, recommend 2–4 wk of parenteral antimicrobial therapy for nongonococcal infectious arthritis instead of the usual 4–6 wk recommended for osteomyelitis. Oral antimicrobial therapy with an effective agent with excellent bioavailability, such as ciprofloxacin or cotrimoxazole, is also acceptable particularly if the patient has rapidly improved on intravenous therapy.

Up-to-date treatment guidelines for gonococcal arthritis can be obtained from the CDC but currently include 7–10 d of ceftriaxone (1 g IV daily) or intravenous penicillin (10 million U daily administered continuously or in divided doses) depending on in vitro susceptibility testing. If the patients improve substantially within 72 h, oral antimicrobial therapy with cefixime, ciprofloxacin, or amoxicillin, depending on in vitro susceptibility testing, can be substituted for intravenous therapy. As discussed previously children that are improving can usually be switched to oral antimicrobial therapy within 7–10 d. Compliance with therapy must be assured.

Prognosis

Patients with infectious arthritis have an estimated case fatality rate of 9%, but, in patients with polyarticular infectious arthritis and rheumatoid arthritis, it is ≤56%. Of patients who survive, ≤42% will have a permanent loss of joint function. Predictors of morbidity and mortality include older age, the presence of rheumatoid arthritis, infection in the hip or shoulder, >1-wk duration of symptoms before treatment, involvement of more than four joints, persistently positive cultures after 7 d of appropriate therapy, and the presence of bacteremia.

Prevention

Infectious arthritis can be prevented in certain patient populations through promotion of efforts by state and national officials to eradicate injection drug use, decrease the incidence of animal bites and nosocomial infections, and promote improved foot care in patients with diabetes mellitus. The routine use of H influenzae b conjugate vaccine in children has been shown to decrease the incidence of infectious arthritis caused by this microorganism.

PROSTHETIC-JOINT INFECTION

Essentials of Diagnosis

• Prosthetic-joint infection is most common in the first 2 y after prosthesis implantation.
• Clinical presentation can be one of either an acute infectious arthritis or chronic pain due to prosthesis failure without constitutional symptoms.
• A draining sinus is present in 30–40% of patients.

• Multiple positive cultures either from preoperative joint aspirations or intraoperatively obtained tissue are diagnostic.

General Considerations

6. Epidemiology.The overall rate of prosthetic-joint infection among the ~430,000 total hip and knee arthroplasties is highest in the first 6 mo postsurgery and declines thereafter. At the Mayo Clinic, the postoperative incidence rates of total hip and knee arthroplasty during the first year, second year, and after 2 y are ~6.5, 3.2, and 1.4 per 1000 joint years, respectively.

Most prosthetic-joint infections occur in immunocompetent hosts. The primary factors predisposing to infection appear to be local abnormalities of host defenses caused by the presence of the foreign body itself. Well-known risk factors for prosthetic-joint infection include prior joint surgery, perioperative wound complications, and rheumatoid arthritis. Other less-well-documented risk factors include diabetes mellitus, the use of steroids, obesity, extreme age, joint dislocation, poor nutrition, distant infection, psoriasis, hemophilia, sickle cell hemoglobinopathy, joint implantation for malignancy, prior infectious arthritis, and the presence of a hinged knee prosthesis.

4. Microbiology.The microbiology of prosthetic-joint infection in a large case series is detailed in Box 14-4. A common characteristic among the microorganisms that cause prosthetic-joint infection is their ability to adhere to foreign materials.
5. Pathogenesis.The majority of prosthetic-joint infections are acquired in the operating room either through direct inoculation during prosthesis implantation or as a result of airborne contamination of the wound. Hematogenous seeding during a bacteremia or through direct contiguous spread from an adjacent focus of infection also occurs but is much less common.

BOX 14-4 Microbiology of 1033 Definite Prosthetic-Joint Infections (PJI) Seen at Mayo Clinic between 1969 and 1991

Microorganisms Number (%) of PJI Coagulase-negative staphylococci 254 (25) S aureus 240 (23) Polymicrobial 147 (14) Gram-negative bacilli 114 (11) Streptococci1 79 (8) Unknown2 83 (8) Anaerobes 62 (6) Enterococci 29 (3) Other microorganisms 25 (2) Total 1033 (100) 1Includes beta-hemolytic streptococci and viridans group streptococci. 2Includes cases in which there was no growth on routine bacterial cultures, routine bacterial cultures were not obtained, or microbiologic information was not available.

Clinical Findings

1. Signs and Symptoms.Patients may present with a range of clinical signs and symptoms varying from a syndrome of acute infectious arthritis to a syndrome of chronic pain without constitutional symptoms, which is difficult to distinguish from aseptic loosening of the prosthesis. On physical examination, limitation of the range of motion of the joint is present, and a draining sinus tract is present in 30–40% of patients. Virulent organisms such as S aureusor pyogenic beta-hemolytic streptococci more often cause the acute infectious arthritis syndrome, while infection with less virulent microorganisms such as coagulase-negative staphylococci often follows a more chronic course.
2. Laboratory Findings.As for all bone and joint infections, an elevated leukocyte count, erythrocyte sedimentation rate, or C-reactive protein is often present but is not sufficient to definitively make the diagnosis of prosthetic-joint infection. Multiple positive cultures from either a preoperative joint aspiration or an intraoperatively obtained tissue are diagnostic for prosthetic-joint infection. Blood cultures should be obtained if fever is present. In addition the presence of acute inflammation on a frozen section of periprosthetic tissue is an accurate way to identify infection intraoperatively at the time of revision surgery prior to the culture results. Because of the importance of making a microbiologic diagnosis antimicrobial therapy should usually be withheld until all aspirates have been obtained and/or the surgeon has obtained intraoperative cultures from the joint. If antimicrobial therapy has already been started, when possible it should be stopped for 10-14 d before any diagnostic procedure to avoid false-negative culture results. As much fluid for culture as possible should be obtained at the time of diagnostic joint aspiration.
3. Imaging.Plain radiographs, arthrograms, and radionuclide imaging are often useful in diagnosing prosthetic-joint infection (Figure 14-3). Abnormalities that can be seen on plain radiography include loosening of the prosthesis, lucency at the bone-cement interface, and periostitis or other evidence of osteomyelitis. An arthrogram can confirm the presence of a loose prosthesis and often allows for simultaneous aspiration of the joint for culture. The combination of a three-phase ⁹⁹Tc bone scan and an indium-labeled leukocyte scan is the most sensitive and specific radionuclide test for the presence of prosthetic-joint infection.

Figure 14-3. Plain radiograph of an infected total hip arthoplasty, illustrating lucency at the bone-cement interface of the femoral component.

Differential Diagnosis

When an acute infection occurs or if a draining sinus tract is present, the diagnosis of prosthetic-joint infection is clear. If only chronic pain is present then infection must be distinguished from aseptic loosening.

Complications

Failure of diagnosis and treatment of prosthetic joint infection may lead to chronic pain, loosening and failure of the prosthesis, loss of limb function, and rarely amputation. Squamous cell carcinoma may rarely complicate a draining sinus tract.

Treatment & Prognosis

A number of medical and surgical approaches have been described for the treatment of prosthetic-joint infection; however, there are no controlled trials to guide the clinician on which one may be best for the individual patient. The goal of treatment is a pain-free functional joint. Eradication of infection is the most direct method to achieve this goal but may not be possible in certain instances. Basic treatment options include chronic suppressive antimicrobial therapy, surgical débridement with retention of the prosthesis, resection arthroplasty, arthrodesis, amputation, and one- or two-stage reimplantation.

Long-term eradication of infection can be achieved in between 85% and 95% of cases by removal of the infected prosthesis with or without subsequent staged reimplantation of another prosthesis, followed by 4–6 wk of intravenous antimicrobial therapy directed at the pathogens causing infection. The best functional results occur when another prosthesis can be reimplanted. Specific antimicrobial regimens are similar to those shown in Box 14-2.

If removal of the prosthesis is not feasible, then 4- to 6-wk intravenous antimicrobial therapy is administered after débridement of the prosthesis. This treatment option has been successful in between 50% and 70% percent of patients when the débridement has occurred within 1 mo of prosthesis implantation or within several days of the onset of an acute infection. Overall, however, this technique has a success rate of only 20–30%.

Occasionally chronic suppressive antibiotics may be used. Proposed criteria for the selection of appropriate candidates for chronic antimicrobial suppression include the following: (1) removal of the prosthesis is not feasible; (2) the microorganism is of low virulence and is highly susceptible to orally administered antimicrobial agents; (3) there are no signs of systemic infection; (4) the patient is compliant and tolerant of the antimicrobial agent; and (5) the prosthesis is not already loose.

Prevention

1. Perioperative Infection.The preponderance of evidence in multiple clinical trials favors the use of antimicrobial prophylaxis at the time of joint placement compared with no prophylaxis. Prophylactic antimicrobial agents should be directed against the common organisms that cause postoperative wound infection. Because staphylococci and streptococci are the most common organisms to cause these infections, agents directed against these pathogens, such as penicillinase-resistant penicillins and first-generation cephalosporins, are often used. Recent studies also suggest that antibiotic-impregnated cement may be effective in the prophylaxis of deep wound infection after total joint replacement. Further studies with longer follow-up periods are needed before this practice can be endorsed. The utility of laminar airflow devices in preventing prosthetic-joint infection remains controversial.
2. Hematogenous Infection.The majority of hematogenous infections are caused by S aureus, coagulase-negative staphylococci, and beta-hemolytic streptococci, presumably from a skin source. Urinary tract and respiratory tract infections have also been implicated as sources of infection. It seems prudent to aggressively diagnose and treat systemic infections in patients with a prosthetic joint, to prevent hematogenous seeding of the prosthesis. Optimal antimicrobial therapy for these infections will depend on the source of infection, in vitro susceptibility of the organism causing infection, and the patient's history of antibiotic allergies.

Antimicrobial prophylaxis is controversial for patients with a prosthetic joint who undergo a dental procedure or invasive procedures such as endoscopy and cystoscopy. Guidelines for this practice have recently been published.

REFERENCES

Carragee EJ: Pyogenic vertebral osteomyelitis. J Bone J Surg 1997;79:874. (Most recent review from surgical perspective.)

Fitzgerald RH et al: Advisory statement: antibiotic prophylaxis for dental patients with total joint replacements. American Dental Association–American Academy of Orthopedic Surgeons. J Am Dent Assoc 1997;128:1004.

Haas DW, McAndrew MP: Bacterial osteomyelitis in adults: evolving considerations in diagnosis and treatment. Am J Med 1996;101:550. (Excellent review of antimicrobial therapy.)

Lew DP, Waldvogel FA: Osteomyelitis. N Engl J Med 1997;336:999. (Most recent review.)

Mader JT, Oritz M, Calhoun JH: Update on the diagnosis and management of osteomyelitis. Clin Podiatr Med Surg 1996;4:701. (Review from surgical perspective.)

Nolan RL, Chapman SW: Osteomyelitis and diabetic foot infections. In Reese RE, Betts RF, eds: A Practical Approach to Infectious Diseases, 4th ed. Little, Brown, 1996. (Concise review from infectious diseases experts.)

Roberts NJ, Mock DJ: Joint infections. In Reese RE, Betts RF, eds: A Practical Approach to Infectious Diseases, 4th ed. Little, Brown, 1996. (Concise review from infectious diseases experts.)

Smith JW, Piercy EA: Infectious arthritis. Clin Infect Dis 1995;20:225.(Excellent review.)

Steckelberg JM, Osmon DR: Prosthetic joint infection. In Bisno AL, Waldvogel FA, eds: Infections Associated with Indwelling Medical Devices, 2nd ed. Am Soc Microbiol, 1994. (Concise review.)