Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

96. Bone and Joint Infections

Edward P. Armstrong and Ziad Shehab


KEY CONCEPTS

 Images The most common cause of osteomyelitis (particularly that acquired by hematogenous spread) and infectious arthritis is Staphylococcus aureus.

 Images Culture and susceptibility information are essential as a guide for antimicrobial treatment of osteomyelitis and infectious arthritis.

 Images Joint aspiration and examination of synovial fluid are extremely important to evaluate the possibility of infectious arthritis.

 Images The most important treatment modality of acute osteomyelitis is the administration of appropriate antibiotics in adequate doses for a sufficient length of time.

 Images Antibiotics generally are given in high doses so that adequate antimicrobial concentrations are reached within infected bone and joints.

 Images The standard duration of antimicrobial treatment for acute osteomyelitis is 4 to 6 weeks.

 Images Oral antimicrobial therapies can be used for osteomyelitis to complete a parenteral regimen in children who have had a good clinical response to IV antibiotics and in adults without diabetes mellitus or peripheral vascular disease when the organism is susceptible to the oral antimicrobial, a suitable oral agent is available, and compliance is ensured.

 Images The three most important therapeutic approaches to the management of infectious arthritis are appropriate antibiotics, joint drainage, and joint rest.

 Images Monitoring of antibiotic therapy is important and typically involves noting clinical signs of inflammation, periodic white blood cell (WBC) counts, C-reactive protein, erythrocyte sedimentation rate (ESR) determinations, and radiographic findings.


Bone and joint infections are comprised of two disease processes known, respectively, as osteomyelitis and septic or infectious arthritis. They are unique and separate infectious entities with different signs and symptoms and infecting organisms. Despite advances in therapy, these infections continue to cause significant morbidity from residual damage and chronic or recurring infections. Emphasis on initiating antibiotic therapy as soon as possible is important in reducing long-term complications.

EPIDEMIOLOGY

Osteomyelitis generally is an uncommon disease. One classic publication reported that 247 patients had osteomyelitis in a prominent American teaching hospital during a 4-year period.1 Acute osteomyelitis has an estimated annual incidence of 0.4 per 1,000 children.2 In adults, osteomyelitis caused by contiguous spread, including postoperative, direct puncture, and that associated with adjacent soft tissue infections, comprises 47% of infections. Hematogenous osteomyelitis comprises 19% of infections, and osteomyelitis occurring in patients with significant peripheral vascular disease comprises 34% of infections. A review of osteomyelitis cases based on duration of disease shows that acute disease constitutes 56% of patients and that chronic osteomyelitis, defined as having a previous hospitalization for the same infection, constitutes 44% of patients. Another classification system has defined acute osteomyelitis as <2 weeks duration, subacute as 2 to 4 weeks duration, and chronic as >4 weeks duration.

Infectious or septic arthritis is an inflammatory reaction within the joint space. Distinct from osteomyelitis, septic arthritis is one of the most common causes of new cases of arthritis. The incidence of proven or likely septic arthritis is 4 to 10 cases per 100,000 patient-years per year.3 The incidence of septic arthritis increases to 70 cases per 100,000 patient-years among patients that have rheumatoid arthritis.4

ETIOLOGY

Osteomyelitis

The most common method of classifying osteomyelitis is based on the mode of acquisition of the bone infection. Disease that results from spread through the bloodstream is termed hematogenous osteomyelitis, while that reaching the bone from an adjoining soft tissue infection is termed contiguous osteomyelitis. Patients with peripheral vascular disease are at risk for the development of contiguous osteomyelitis, and they present unique management features. Osteomyelitis that results from direct inoculation, such as from trauma, puncture wounds, or surgery, generally is also classified as inoculation osteomyelitis.

Osteomyelitis also can be classified based on the duration of the disease. Acute osteomyelitis describes infections of recent onset, usually several days to 1 week, whereas chronic infections are those of a longer duration. Some authors describe chronic infections as those with symptoms for more than 1 month before therapy, whereas other authors define chronic infections as relapse of an initial infection. Hematogenous osteomyelitis almost always involves one bone whereas contiguous osteomyelitis can present in multiple bones, especially when vascular insufficiency is an underlying risk factor.

Infectious Arthritis

Infectious arthritis can occur from many different types of microorganisms.5 Most infecting organisms produce an infection in a single joint, termed monoarticular infections; however, infections also can involve two or more joints.6As with osteomyelitis, joint infections also can be classified according to the mechanisms by which the infecting organism reaches the joint. Infectious arthritis can result by spread from an adjacent bone infection, direct contamination of the joint space, or hematogenous dissemination. Hematogenous spread of the disease comprises the majority of infections; spread from osteomyelitis and direct inoculation is much less frequent. Septic arthritis is most prevalent in children and the elderly. Approximately, one-third of people with septic arthritis are children younger than 2 years of age.7

PATHOPHYSIOLOGY

Hematogenous Osteomyelitis

Hematogenous osteomyelitis is typically a disease of the growing bone in children and most cases occur in patients younger than 16 years of age. Table 96–1 summarizes the primary characteristics of osteomyelitis. Less commonly, these infections occur in adults. Osteomyelitis of the vertebrae is also acquired hematogenously and occurs most frequently in patients older than 50 years of age.8

TABLE 96-1 Types of Osteomyelitis, Age Distribution, Common Sites, and Risk Factors

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Unique features of the anatomy and physiology of long bones appear to predispose them to become infected.9 Their vascular structure appears to predispose them for hematogenous infections that begin within the metaphyses (Fig. 96–1). The nutrient arteries of the long bones divide within the medullary canal of the bone into small arterioles. These end in hairpin turns near the growth plate and flow into veins, of much wider diameter, that drain the medullary cavity.1 An infection in hematogenous disease is initiated within the bend of the arterioles where there is considerable slowing of blood flow passing through the hairpin capillary loops. This sludging of blood flow allows bacteria present within the bloodstream to settle and initiate an inflammatory response. They have access to the bone by gaps in the endothelial layer and the absence of a basement membrane. In addition to these structural features, there also appears to be less active phagocytosis within the metaphysis. After the bacteria settle in the bone, avascular necrosis can occur from occlusion of the nutrient vessels and release of bacterial enzymes.

Images

FIGURE 96-1 Cross section of normal bone.

In addition to these anatomic and functional features, there is some evidence that trauma is associated with developing an infection in specific bones. Children who develop hematogenous osteomyelitis may report some type of trauma before the onset of their symptoms and animal data indicate that traumatized bone is more likely to become infected than normal bone.

Once the infection is initiated, exudate begins to form within the bone marrow and the fluid accumulates under increased pressure. The age of the patient largely determines the next stage in the pathophysiology. In children older than 12 to 18 months, the infection that started in the metaphysis of a long bone is prevented from spreading into the epiphysis and the adjacent joint space because of the epiphyseal growth plate that acts as a physical barrier; however, the exudate often dissects from the medulla through the soft cortex to the subperiosteal space as the periosteum in these children is loosely attached to the underlying cortex. The periosteum is thick and not easily ruptured thus containing the pus in the subperiosteal space, sometimes forming a subperiosteal abscess. If there is significant damage to the periosteum, the pus can decompress into a soft-tissue abscess. The cortex obtains most of its blood supply from the periosteum and a subperiosteal abscess can impair the blood flow to the outer portion of the cortical bone resulting in a devitalized piece of dead bone termed a sequestrum. The elevated periosteum remains viable because its blood supply, derived from the overlying muscle, is unaffected. The raised periosteum will continue to produce bone; however, this new bone is now separated from the cortex because the periosteum has been raised from the infection. This new bone that is deposited under the periosteum is termed involucrum.

In adults, the periosteum is tightly bound to the cortex that is thick. These anatomic features generally cause the infections to remain intramedullary. As expected, subperiosteal abscess formations are less common in adults. The infection can spread to subperiosteal structures through the Haversian and Volkmann’s canals.

The vascular supply of long bones in neonates also has unique anatomic characteristics that affect their presentation. Bridging blood vessels go across the epiphyseal plate from the metaphysis into the epiphysis thus enabling an infection that started within the metaphyseal area to spread easily to involve the epiphyses and then into the joint.10 Therefore, in infants, not only can the infection spread to involve the periosteum and the shaft as in older children, but the infection also can spread directly to involve the joint.11

In children, hematogenous osteomyelitis typically involves a single bone and has a predilection for involvement of the long bones, such as the femur, tibia, humerus, and fibula.11 In contrast, neonatal infections commonly involve multiple bones. Vertebral infections are common in patients older than 50 years of age.12 Vertebral disease in young children usually involves the disk space and the two vertebral facets adjoining it because of the nature of the vascular supply of the vertebrae at that age. This entity is known as diskitis. Vertebral osteomyelitis involving the body of the vertebra can be seen in children older than 8 years of age.

Chronic osteomyelitis is more likely to occur if large segments of bone become avascular and necrotic. This results in a piece of devitalized bone to which antimicrobial delivery is impaired. As a result, this infection is prone to exacerbations and may lead to weakening of that bone or to the formation of draining sinuses to the skin.

Images The bacteriology of hematogenous osteomyelitis is unique in that one pathogen, Staphylococcus aureus, is responsible for more than 80% of these infections, with group A Streptococci and Streptococcus pneumoniaeaccounting for a few cases. Kingella kingae, an organism that is part of the oral flora is emerging as a pathogen in children less than 3 years of age. Haemophilus influenzae type b (Hib), which used to be an important pathogen, has been almost completely eliminated with the use of the conjugate vaccine and is now a rare pathogen in bone and joint infections.9 Similarly, pneumococcal disease is anticipated to decrease in prevalence as invasive pneumococcal disease is prevented by the use of the conjugate pneumococcal vaccine in infants. While S. aureus is also the major pathogen in neonatal osteomyelitis, disease in this age group can also result from infections with group B streptococcus, and Escherichia coli. They are multifocal in half the cases.

Vertebral osteomyelitis has several unique features and occurs most commonly in adults 50 to 60 years of age. The lumbar and thoracic regions are the locations of most infections. Hematogenous infections are most likely to develop in the vascular areas near the subchondral plate region of the vertebral body. Staphylococci cause approximately 60% of these infections; however, gram-negative organisms now play a significant role.13 These gram-negative organisms, particularly E. coli, most likely originate within the urinary tract. E. coli vertebral infections have been associated with urinary tract infections, positive urine cultures, and bacteremias. Mycobacterium tuberculosis and Coccidioides immitis/posadasii also are known to cause infections in the spine. Skin and respiratory tract infections are other sources of infection known to lead to vertebral infections.

While infections of the spine can involve the vertebrae in 1% to 2% of older children with osteomyelitis, they more commonly involve the disk space of the lumbar vertebrae in children less than 5 years of age.

Osteomyelitis in the IV drug user has unique features.14 More than 50% of such infections involve the vertebral column and less than 20% of infections are located in either the sternoarticular or pelvic girdle. Infections are much less frequent within the extremities. They also have an unusual spectrum of organisms with gram-negative organisms being responsible for 88% of infections. Pseudomonas aeruginosa, either singly or in combination with other organisms, is cultured in 78% of all infections. KlebsiellaEnterobacter, and Serratia species also can be found but less commonly. In addition, staphylococcal and streptococcal organisms are sometimes cultured.

Patients with sickle cell anemia and related hemoglobinopathies also represent a unique population in that two thirds of bone infections in these patients are caused by Salmonella species, while the rest are usually caused by staphylococci and other gram-negative organisms.15 Bowel infarctions from the sickle cell disease can facilitate the entry of salmonellae from the colon into the bloodstream with resultant hematogenous spread to the bone. Osteomyelitis in patients with sickle cell disease may occur in any bone, but it most commonly involves the medullary cavity of long or tubular bones. Because of the difficulty in separating bone pain during a sickle cell crisis from that of an infection, osteomyelitis can be relatively advanced in these patients by the time the diagnosis is made.

Direct Inoculation Osteomyelitis

This category of osteomyelitis includes infections caused by direct entrance of organisms from a source outside the body. Penetrating wounds (e.g., trauma), open fractures, and various invasive orthopedic procedures can result in direct inoculation of organisms into the bone. More than 80% of cases of postoperative osteomyelitis are known to occur following open reductions of fractures. Specifically, these infections occur most commonly after internal fixation of a hip fracture or femoral or tibial shaft fracture. Osteomyelitis resulting from puncture injuries to the feet are associated with gram-negative infection or the bone and cartilage (sometimes classified as osteochondritis), especially infections caused by P. aeruginosa. S. aureus is also a significant pathogen in these patients.

Contiguous-Spread Osteomyelitis

Osteomyelitis secondary to spread from an adjacent soft tissue infection is called contiguous osteomyelitis. It can result from pressure ulcers or from adjacent soft tissue infections and most often involves the distal extremities. Less commonly, infections can spread from infected teeth to involve the mandible or occur secondary to sinus infections by spreading through the mucosal lining of the sinuses into the vascular system surrounding the bone.16,17

In contrast to hematogenous osteomyelitis, which occurs most commonly in children, contiguous-spread osteomyelitis occurs most commonly in patients older than age 50, most likely because of predisposing factors, such as hip fractures or vascular disease, are more common in this age group.

Contiguous-spread disease has several important differences compared with hematogenous osteomyelitis. Although S. aureus is still the most common organism isolated, infections with multiple organisms, including gram-negative bacilli, occur frequently. P. aeruginosa, streptococcus, E. coliStaphylococcus epidermidis, and anaerobes can be isolated.

Patients with osteomyelitis in association with severe vascular insufficiency are extremely difficult to manage.18 As anticipated, most of these patients have diabetes mellitus or severe atherosclerosis, and they develop their infections by contiguous spread. Generally, these patients are between the ages of 50 and 70 years. Frequently, patients with vascular disease develop osteomyelitis in their toes and fingers, and there is usually an adjacent area of infection, such as cellulitis or dermal ulcers. Importantly, infections in these patients are almost always polymicrobial and often include staphylococcus and streptococcus or the combination of staphylococcus, streptococcus, and Enterobacteriaceae. Enterococci and anaerobic organisms also can be involved.

Anaerobic organisms also play a role in osteomyelitis. When anaerobes are grown from cultures, they usually are found in association with other organisms, including aerobic bacteria. Predisposing factors in patients who have anaerobic osteomyelitis include vascular disease, bites, contiguous infections, peripheral neuropathy, hematogenous spread, and trauma.19 The anaerobic infections in association with diabetes mellitus almost always occur within the feet. Bacteroides fragilis and Bacteroides melaninogenicus comprise the majority of anaerobic isolates.

Infectious Arthritis

Infectious arthritis usually is acquired by hematogenous spread.6 The synovial tissue is highly vascular and does not have a basement membrane, so organisms in the blood can easily reach the synovial fluid. Table 96–2 summarizes the characteristics of acute infectious arthritis. Some organisms, such as Neisseria gonorrhoeae, are especially likely to infect a joint during bacteremia. Risk factors associated with adult infectious arthritis (more than one factor may be present) are systemic corticosteroid use, preexisting arthritis, arthrocentesis, distant infection, diabetes mellitus, trauma, and other diseases.20

TABLE 96-2 Characteristics of Acute Infectious Arthritis

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Organisms also can gain access to the joint from a deep-penetrating wound injury, intraarticular steroid injections, arthroscopy, prosthetic joint surgery, and spread to the joint from a contiguous focus of osteomyelitis. Trauma also appears to be a risk factor in facilitating microbial entry into the synovial space. Unlike children, adults often have significant systemic diseases that predispose them to infectious arthritis, such as diabetes mellitus, immunosuppressive states (e.g., cancer or liver disease), or preexisting arthritis. IV drug abusers and individuals with intravascular infections such as endocarditis also are prone to develop septic arthritis.

Preexisting abnormal joint architecture, joint trauma, and surgery are other important risk factors because chronic inflammation or trauma makes the joint more susceptible to infection. In addition, individuals with rheumatoid arthritis can be prone to bacterial infection because of an inherent phagocytic defect, as well as concomitant corticosteroid therapy. Women are more prone to develop disseminated gonococcal infections than men. The second and third trimesters of pregnancy and the time of menses appear to be the times of greatest risk for developing gonococcal bacteremia.

After bacteria gain access to the joint, the organisms begin to multiply and produce a purulent exudate within the joint. If this joint effusion is present beyond 7 days, chronic, and sometimes irreversible, damage can occur to the bone and joint as a result of proteolytic enzymes and pressure necrosis. Purulent effusions can promote cartilage destruction by increasing leukocyte enzyme activity. In conjunction with the development of the effusion, almost all patients will develop a hot, swollen, painful joint.

Images S. aureus, the single most common infecting organism, is found in 37% to 65% of cases of nongonococcal bacterial arthritis.7 Streptococcal infections are the second most common and gram-negative organisms are less common. Among the latter, E. coli is the most common; however, P. aeruginosa is the most frequent organism in IV drug abusers. Neonates may have infectious arthritis because of a broad range of organisms, with S. aureus, group B Streptococcus, and gram-negative organisms being most common. S. aureus and streptococcus are the most common pathogens in children younger than 5 years of age. Hib, which used to be the most common pathogen in these children, has essentially been eliminated by immunization with the conjugate Hib vaccine. Pneumococcal arthritis is also decreasing in incidence as a result of conjugate pneumococcal vaccine administration to infants. If a child has not been fully vaccinated or is immunocompromised, Hib may be a cause. Within the adult population, S. aureus is responsible for the vast majority of nongonococcal infections. Gonococcal arthritis is a common manifestation of disseminated gonococcal infection occurring in 42% to 85% of such patients.7Gonococcal arthritis is now uncommon in North America and Europe although it remains an important concern in developing countries. Although rare, osteomyelitis and infectious arthritis can be caused by fungi and in the case of arthritis by viruses such as varicella-zoster, rubella, or parvovirus.21 Arthritis is rarely caused by Salmonella, Corynebacteria, Brucella, Neisseria meningitidesMycoplasma pneumoniae, or Ureaplasma urealyticum. Penetrating injury of the joint can result in an infection due to Pasteurella in dog bites, Capnocytophaga in human bites, and Pantoea when the injury is induced by a thorn.

CLINICAL PRESENTATION

The clinical presentation of acute hematogenous osteomyelitis is summarized in Table 96–3. Although neonatal hematogenous osteomyelitis can spread rapidly to involve the joint, often there are few associated systemic symptoms.22 A joint effusion is present in 60% to 70% of neonatal infections. Decreased limb motion or edema over the affected area may be the only signs from which to suspect the diagnosis. Vertebral osteomyelitis produces nonspecific symptoms, such as constant back pain, fever or night sweats, and weight loss.23 The pain typically is present at rest and increases in severity with movement. Serious neurologic complications can occur if the infection extends and compresses the spinal cord. With contiguous-spread osteomyelitis there is often an area of localized tenderness, warmth, edema, and erythema over the infected site. Patients with significant vascular insufficiency usually have local symptoms, such as pain, swelling, and redness. Less commonly, they also can have fever and elevated white blood cell (WBC) count. The presentation of osteomyelitis after surgery or trauma depends on the precipitating cause. If the infection follows surgery or bone trauma, the symptoms usually are noted within 1 month. The most frequent symptom is pain in the area of infection. Less commonly, patients also can develop a fever and elevated WBC count.

TABLE 96-3 Clinical Presentation of Hematogenous Osteomyelitis

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Patients with nongonococcal bacterial arthritis almost always present with a fever, and 50% of patients have an elevated WBC count (see Table 96–2). The average initial synovial WBC count is 10 × 103/mm3(10 × 109/L) or greater in nongonococcal bacterial disease. The most frequent initial sign of disseminated gonococcal infections is the triad of dermatitis, tenosynovitis, and migratory polyarthralgia or polyarthritis.

Nongonococcal bacterial arthritis is almost always monoarticular. The knee is the most commonly involved joint, but infections also can occur in the shoulder, wrist, hip, ankle, interphalangeal joints, and elbow joints. Usually, the initial focus of infection that acted as the source for bacterial or microbial entrance can be identified. Common routes for bacterial entrance include infections of the respiratory tract, skin, and urinary tract; often no specific source can be identified. Blood cultures are important in these patients because they can be positive in 50% of patients.

Another type of infectious arthritis occurs following prosthetic joint surgery. The most common symptom is pain. Local signs of inflammation and fever are common in acute infections while chronic infections present in a more subtle fashion, typically with pain alone and often loosening of the prosthesis. With these infections, the C-reactive protein usually is elevated, although a leukocytosis often is absent. Infections that result from postoperative contamination usually become apparent within 1 year of surgery.

Radiologic and Laboratory Tests

The evaluation of a patient who may have osteomyelitis has several unusual aspects. Radiographs of the involved area should be obtained to rule out other processes such as a fracture; bone changes characteristic of osteomyelitis appear late and are not typically seen until at least 10 to 14 days after the onset of the infection as more than 50% of the bone matrix must be removed before the lesions can be detected radiologically. Magnetic resonance imaging is the most sensitive and commonly used diagnostic imaging modality and offers the advantage of better anatomic definition, especially of abscesses or joint effusions. Radionuclide bone scanning is useful in identifying the focus of osteomyelitis.24,25

Despite the seriousness of osteomyelitis, often there are few laboratory abnormalities. The erythrocyte sedimentation rate (ESR), C-reactive protein, and WBC count may be the only laboratory abnormalities.11 The degree of abnormality of these laboratory findings does not correlate with the disease outcome; however, they are useful for monitoring therapy. C-reactive protein can be elevated because of the presence of inflammation, and it can be substituted for the ESR. C-reactive protein is generally the more sensitive marker of response to therapy and often increases and decreases before the ESR.

When a clinical assessment of osteomyelitis is suspected, it is important to establish a bacteriologic diagnosis by culture of the infected bone. Accurate culture information is especially important as a guide for treatment of osteomyelitis in this era of increasing antimicrobial resistance. Bone aspiration and bone biopsy are valuable in determining an accurate bacteriologic diagnosis. In addition, they help determine whether or not there is an abscess present. If an abscess is identified, it must be drained and the pus is cultured, and a Gram stain is performed. Aspirates of subperiosteal pus or metaphyseal fluid yield a pathogen in 70% of cases. Cultures should be done for both aerobic and anaerobic bacteria. A Gram stain of the aspirate can be useful in initiating appropriate empirical antibiotic therapy.

If a specimen is obtained from a previously undrained or unopened wound abscess, the pathogen usually can be identified. In chronic osteomyelitis, however, identification can be more difficult.26 Open wounds and draining sinuses frequently are contaminated with other organisms and thus provide inaccurate culture information.27 They cannot be relied on to reflect the pathogen unless consecutive deep sinus tract cultures reveal the same pathogens.28Cultures of loculated pus aspirates in the area of orthopedic devices removed from infected bone can be trusted, however, to identify the infecting organism. In diabetic patients that may have osteomyelitis, bone infections are most common in patients with foot ulcers greater than 3 mm and in patients with C-reactive protein levels greater than 3.2 mg/dL (32 mg/L).29The preferable time to obtain culture material in a patient with a chronic draining sinus is at the time of open surgical debridement.

In addition to performing cultures from the involved bone, it also is important to obtain cultures from any site believed to be the source of a bacteremia. Blood cultures should be obtained. Approximately 50% of patients with hematogenous osteomyelitis will have positive blood cultures and may obviate the need for bone aspiration in these patients.

Images When evaluating the possibility of a patient having infectious arthritis, immediate joint aspiration with subsequent analysis of the synovial fluid is extremely important. The presence of purulent fluid usually indicates the presence of a septic joint. The synovial fluid WBC count is usually 50 to 200 × 103/mm3 (50 × 109 to 200 × 109/L) when an infection is present. However, serum WBC, ESR, and C-reactive protein may not be useful acutely in septic arthritis.30 Approximately half the patients with an infected joint have a low synovial glucose level, usually less than 40 mg/dL (2.2 mmol/L). Gram stains of joint fluid demonstrate bacteria in 50% of patients with septic arthritis; however, such stains are positive in only 25% of patients with gonococcal arthritis. Synovial fluid cultures usually are positive in patients with nongonococcal infections. Both blood and joint fluid should be cultured aerobically and anaerobically in a patient suspected of having an infected joint. Blood cultures are positive in one half of patients with nongonococcal infections but in only 20% of those with gonococcal infections. Pharyngeal, rectal, cervical, or urethral smears and cultures, as well as cultures of cutaneous lesions, should be performed if a disseminated gonococcal infection is considered. As with osteomyelitis, most patients will have an elevated C-reactive protein concentration and ESR. Radiographs of infected joints often reveal distension of the joint capsule with soft tissue swelling in the adjacent space. Magnetic resonance imaging can be helpful in identifying an infected joint, especially the hip. In patients who have developed an infected prosthetic joint, loosening of the prosthesis can be seen radiographically.

TREATMENT

Desired Outcome

The goals of treatment are resolution of the infection and prevention of long-term sequelae. The ultimate outcome of osteomyelitis depends on the acute or chronic nature of the disease and how rapidly appropriate therapy is initiated. Patients with acute osteomyelitis have the best prognosis. Cure rates exceeding 80% can be expected for patients with acute osteomyelitis who have surgery when indicated and receive appropriate antibiotics for 4 to 6 weeks. When the growth plate is involved in children, discrepancies in the growth of bones or angular bone deformities can result.

In contrast, patients with chronic osteomyelitis have a much poorer prognosis. Dead bone and other necrotic material from the infection act as a bacterial reservoir and make the infection very difficult to eliminate. Adequate surgical debridement to remove all the dead bone and necrotic material, combined with prolonged administration of antibiotics, provides the best chance to obtain a cure.31 The inability to remove all the dead bone can allow residual infection and require suppressive antibiotics to control the infection.

While many patients who develop infectious arthritis recover with no long-term sequelae, 50% are left with decreased joint function or mobility. Gonococcal arthritis usually resolves rapidly with antibiotics and has a lower rate of sequelae. Individuals at greatest risk for long-term sequelae are those who have symptoms present for more than 7 days before starting therapy and those with infections occurring within the hip joint and infections caused by gram-negative organisms. Common long-term residual effects following infectious arthritis are limited joint motion and persistent pain.

General Approach to Treatment

Images Following completion of the steps needed to determine the infecting organism, the most important treatment modality of acute osteomyelitis is the administration of appropriate antibiotics in adequate doses for a sufficient length of time. It is important to stress that early antibiotic therapy can mitigate the need for surgery, subsequent sepsis, chronic infection, disruption of longitudinal bone growth, and angular deformity of the bone.32 A delay in treatment can allow bone necrosis to occur and make eradication of the infection much more difficult. In these patients with chronic osteomyelitis, exacerbations of the infection can result if all necrotic tissue is not removed surgically and all microorganisms eliminated. Chronic suppressive antimicrobial therapy and adjunctive treatment with hyperbaric oxygen or antibiotic-impregnated implants during surgery also has been used.33,34

If a patient with hematogenous osteomyelitis does not respond by having a decrease in fever, local swelling, redness, and pain following the initiation of adequate antibiotic therapy, the patient should undergo surgical debridement of the infected area. It is important to emphasize the priority of starting antibiotics immediately after the cultures have been obtained.

Pharmacologic Therapy

Antibiotic Bone Concentration

Images Antibiotics used in the management of acute osteomyelitis generally are given in high doses (adjusted for weight, renal function, hepatic function, or both) so that adequate antimicrobial concentrations are reached within the infected bone and joint.35 Between 8 and 12 g/day of a penicillinase-resistant penicillin (nafcillin or oxacillin), ampicillin, or cephalosporin or a similar large dose of another parenteral antibiotic is used in the initial management of adults with osteomyelitis.36 These dosing recommendations, however, are empirical; the relationship between a specific dose of a given antibiotic and its resulting concentration within the infected bone is largely unknown. Semisynthetic penicillins, cephalosporins, clindamycin, and the aminoglycosides can be detected in bone homogenates soon after their administration.

Daptomycin may also be an effective empiric therapy for the treatment of osteomyelitis in adults caused by most methicillin-susceptible and methicillin-resistant S. aureus (MRSA), but the data are limited.37Further prospective studies are needed to define the situations in which daptomycin might be best utilized and its optimal dosing.


Clinical Controversy…

The impact of resistant organisms has created some controversy regarding whether empiric therapy should be adjusted. Some clinicians recommend empirical coverage for MRSA when staphylococcal infection is suspected. However, others believe that culture results and susceptibility testing or lack of response to routine staphylococcal antibiotics should instead trigger use of antibiotics directed against MRSA. The frequency of MRSA in a community may help guide which approach is used.

Duration of Antibiotic Therapy

Images The specific duration of antibiotic therapy needed in the management of osteomyelitis is usually 4 to 6 weeks.38,39 Failure rates approaching 20% have been observed in children treated with parenteral antibiotics for 3 weeks or less. One analysis in children with hematogenous osteomyelitis recommended 20 days of antibiotic therapy after initial parenteral therapy as long as the C-reactive protein level normalized within 7 to 10 days.40 Although these data were largely evaluated in children, this duration of therapy recommendation is also used in adults.41 Treatment failures may be due to the presence of infected necrotic bone or infected hardware (wires, plates, screws, and rods) that could not be removed.42

A modification of this recommendation has been used in some patients. Children receiving an appropriate oral antibiotic regimen and adults receiving an oral fluoroquinolone antibiotic, such as ciprofloxacin, have been treated successfully with a 6-week course. Improvement in the patient’s clinical signs and symptoms and normalization of the C-reactive protein level or ESR are important parameters to assess therapy.43 If signs or symptoms are still present at 6 weeks, therapy should be extended. Short course therapy for children who have had a puncture wound of the foot resulting in P. aeruginosa osteochondritis, and who have had surgical debridement of infected material, can be used with parenteral antibiotics for as little as 10 days.

Oral Antibiotic Therapy

Images One of the most significant changes in the management of osteomyelitis is the use of oral antibiotics to complete therapy.44 Criteria for the use of oral outpatient antibiotic therapy for osteomyelitis include all of the following:

   1. Confirmed osteomyelitis

   2. Initial clinical response to parenteral antibiotics

   3. Suitable oral agent available

   4. Compliance ensured

Suitable candidates are children with good clinical response to IV therapy and adults without diabetes mellitus or peripheral vascular disease. There have been two primary populations that have benefited from oral treatment. Children responding to initial parenteral therapy may be excellent candidates to receive follow-up oral therapy with an agent such as dicloxacillin, cephalexin, clindamycin, or amoxicillin depending on their culture and susceptibility results.45 Although more controversial, the other population to benefit from oral therapy is adults with an infecting organism susceptible to a fluoroquinolone.46These two populations now no longer routinely require expensive and complicated courses of long-term parenteral antibiotics.

The use of oral antibiotics is well studied in children.47 Typically, injectable antibiotics are used initially and then switched to oral antibiotics when there was a decrease in the signs of inflammation and the C-reactive protein or when the patient was afebrile for 3 days. If pus was obtained on the initial needle aspirate, or if a reduction in fever, local swelling, and tenderness did not occur despite adequate rest, immobilization, and intensive antibiotic therapy, the patients underwent surgical drainage. The patients enrolled in oral antibiotic trials generally had disease of recent onset, identification of a specific infecting organism, enforced compliance, and surgery as indicated. In patients who meet these criteria, oral antibiotics appear to offer a great advantage in the treatment of osteomyelitis.48 Patients not meeting these criteria may have a higher risk of developing chronic osteomyelitis if oral therapy is inappropriate or not strictly adhered to. Limited retrospective data in adults indicated that parenteral therapy for less than 4 weeks followed by oral therapy may be effective.49

Ciprofloxacin is effective in the treatment of osteomyelitis caused by gram-negative bacteria, such as Enterobacter cloacae and Serratia marcescens; however, many strains of streptococci are relatively resistant. Activity of ciprofloxacin against gram-negative bacilli allows patients to be treated orally and avoids the potential toxic complications of 4 to 6 weeks of aminoglycoside therapy.50 Ciprofloxacin and other fluoroquinolones also have demonstrated effectiveness in the treatment of chronic osteomyelitis along with adequate surgical debridement. Another benefit with this agent is that it can be administered on an every-12-hour schedule. An important limitation of this antibiotic class, however, is that fluoroquinolones should not be used in children younger than 16 to 18 years of age or in pregnant women because of the potential to cause cartilage damage. Ciprofloxacin also has poor coverage against anaerobic organisms and staphylococci and emergence of resistant P. aeruginosa can be a problem. Newer fluoroquinolones have additional gram-positive activity; however, additional well-controlled clinical trials are needed to determine most appropriately their role in the treatment of osteomyelitis.50

Concern has been raised about staphylococcal resistance to fluoroquinolones. MRSA infections do not respond well to ciprofloxacin; however, resistance also can be troublesome for methicillin-susceptible strains. It is recommended that when ciprofloxacin is used to treat osteomyelitis with mixed etiologies that include S. aureus, it should be combined with an antistaphylococcal drug such as dicloxacillin, cephalexin, or clindamycin.


Clinical Controversy…

The role of fluoroquinolones may be debated. Some clinicians believe that oral fluoroquinolones should be preferred treatments for osteomyelitis; however, others believe that there have been inadequate studies to date to determine their comparative clinical effectiveness.

Antibiotic Selection

A critical component in the management of osteomyelitis is the selection of appropriate antibiotics. Empirical therapy must be selected on the basis of the most likely infecting organism while the results of culture and susceptibility data are pending. Table 96–4 summarizes empirical therapy recommendations. It is difficult to make evidence-based recommendations on the treatment of these infections as little high-quality clinical evidence exists. Experimental evidence, case series, and published expert opinion are used to suggest preferred treatment options. Dosages expressed in terms of milligrams per kilogram per day generally are given in divided doses every 6 to 8 hours (three to four times a day).

TABLE 96-4 Empirical Treatment of Osteomyelitis

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Because S. aureus, group B streptococci, and E. coli are the most common infecting organisms in newborns, an IV dosage of 150 mg/kg per day (given in four divided doses) of oxacillin or nafcillin plus cefotaxime 150 mg/kg per day (given in three to four divided doses) is appropriate. For children 5 years of age or younger, S. aureus and group A streptococci are the most common infecting organisms. Appropriate therapy in this age group is nafcillin or oxacillin 150 to 200 mg/kg per day IV or cefazolin 100 mg/kg per day. If the patient is immunocompromised or has not been fully vaccinated, empirical therapy is needed to also cover Hib. In this setting, IV cefuroxime 150 mg/kg per day is appropriate empirical therapy. For children older than 5 years, S. aureus is the most likely infecting organism, and either nafcillin or oxacillin 150 to 200 mg/kg per day IV or cefazolin 100 mg/kg per day IV is recommended. If patients are allergic to penicillins or cephalosporins or are infected with MRSA, vancomycin, clindamycin, or linezolid can be used.5153 Children with culture-negative osteomyelitis can be managed as presumed staphylococcal disease with excellent long-term results. Empiric therapy may need to be modified if community-acquired MRSA is prevalent.54 The antimicrobial therapy should then be adjusted based on susceptibility testing results. Children with osteomyelitis usually can be treated successfully with 4 weeks of parenteral therapy or parenteral followed by oral therapy.

An oral regimen can be an alternative to the previous recommendation in many cases of osteomyelitis in children. Children who have undergone surgery, if needed, and have had a good clinical response to IV therapy may be candidates for the alternate oral antibiotic regimen.55 Parenteral antibiotic therapy should be initiated and continued until there has been a resolution in the erythema, swelling, and tenderness and until the patient is afebrile. Dicloxacillin, cloxacillin, and cephalexin (100 mg/kg per day) are effective oral agents. Patients should be monitored with periodic WBC counts, C-reactive protein, and ESR determinations. When oral antibiotics are used, the total duration of oral and injectable therapy is usually at least 4 weeks. As stated previously, because of the risk of cartilage damage, fluoroquinolones should not be used in children. Hematogenous osteomyelitis in adults is caused most frequently by S. aureus and thus is treated appropriately with 8 to 12 g/day of a penicillinase-resistant penicillin such as nafcillin or a first-generation cephalosporin (e.g., cefazolin). Clindamycin 2.4 g/day, or vancomycin 2 g/day (with normal renal function) can be used in adults allergic to penicillin; however, if the infection is located within the vertebrae, E. coli must be considered, and thus, depending on the culture and susceptibility data, a switch to a cephalosporin may be needed. After institution of appropriate antibiotic therapy, the antimicrobial agent should be continued for at least 4 to 6 weeks total (parenteral plus oral).


Clinical Controversy…

H. influenzae vaccination has decreased the frequency of H. influenzae infections. Some clinicians believe that empirical therapy of osteomyelitis and septic arthritis in a child younger than 5 years of age no longer requires Hib coverage; however, others are concerned about children not being fully vaccinated and desire to use an antibiotic with activity against this organism.

Special Populations Osteomyelitis in patients with sickle cell hemoglobinopathies is commonly caused by either Salmonella or S. aureus.15 Thus, empirical antibiotics of first choice include ceftriaxone or cefotaxime. Alternatives are chloramphenicol and ciprofloxacin (in adults).

Bone infections in adults with a history of IV drug abuse require coverage for gram-negative organisms; therefore, empirical treatment with ceftazidime or defepime 2 g IV every 8 hours. If compliance can be ensured, these patients are excellent candidates to receive oral ciprofloxacin 750 mg twice daily. Antibiotic therapy in these patients should be continued for at least 4 to 6 weeks.

As discussed previously, several microorganisms can cause bone infections that occur after surgery or from contiguous spread of an adjacent soft tissue infection. S. aureus is the single most common organism, but multiple organisms can be involved. To provide the required broad-spectrum coverage, nafcillin 2 g IV every 4 hours plus ceftazidime or cefepime 2 g IV every 8 hours should be used as initial therapy. Alternative single agents are ticarcillin–clavulanate potassium 3.1 g IV every 4 hours or piperacillin–tazobactam in adults; however, there is less experience with these agents. Other broad-spectrum alternatives can be cefepime and imipenem. The antibiotic regimen requires reevaluation after culture and susceptibility information is available. Ciprofloxacin can be an appropriate oral alternative for these patients if the susceptibility data are favorable. Frequently, the antibiotics must be continued for 6 weeks to obtain a cure, and surgery often is required to remove any infected or devitalized tissue.

Patients with established vascular insufficiency who subsequently develop osteomyelitis are extremely difficult to manage.56 Impaired blood flow to the extremities impedes the healing process, possibly requiring vascular bypass surgery. Infections in these patients involve a wide range of organisms, including S. aureusStreptococcus, anaerobes, and gram-negative organisms. Bone culture-guided antibiotic therapy has been associated with cure in diabetics with osteomyelitis of the foot.57 Broad-spectrum therapy with a penicillinase-resistant penicillin in combination with ceftazidime is the preferred initial therapy.58 If anaerobes are suspected, an antianaerobic cephalosporin (e.g., cefoxitin) or clindamycin plus ceftazidime can be substituted. Ampicillin may need to be added to the regimen to provide coverage against enterococci. Despite aggressive antibiotic therapy along with surgical debridement, these patients continue to have low cure rates.59,60 Amputation of the involved area may be required to obtain a cure of the infection.61

Home Antibiotic Therapy Because the management of bone and joint infections frequently requires prolonged parenteral antibiotics, newer antibiotic regimens have been used. Administration of antibiotics in the home environment and the use of antibiotics with extended elimination half-lives are commonly used. Although acute osteomyelitis is one of the more common infectious diseases that can be treated with home IV antibiotics, not all patients are acceptable candidates for home administration. Patients must be screened to include only those who are receiving a stable treatment program, those who are interested and are motivated in participating, and those who have good venous access, as well as those who have support from family members or neighbors and have home facilities for storage and refrigeration. Patients with adequate vascular access may be able to use a peripheral IV catheter; however, a central IV catheter may be required if venous access difficulties occur. Certain exclusion criteria also must be considered. Complications of other preexisting diseases such as diabetic retinopathy, intention tremor, disabling inflammation or degenerative joint disease, coagulopathies, or various neurologic disorders can prevent individuals from receiving home antibiotics. A history of alcoholism or of IV drug abuse also is important exclusion criteria. Patients who are fluent in only a foreign language and patients who are illiterate or hard of hearing may have to be excluded if a qualified guardian is unavailable. In addition to meeting these initial screening criteria, patients must successfully complete a thorough training program before hospital discharge. Aseptic technique, proper catheter care, and correct administration techniques must be documented. Once a patient is receiving therapy in the home environment, continued monitoring of their antimicrobial therapy and drug levels when indicated is important. It is vital to ensure compliance with the antimicrobial regimen. Catheter-related complications are common in patients receiving prolonged courses of parenteral antibiotics.62

In addition, the specific antibiotic regimen characteristics must be considered when evaluating a patient for home antibiotics. Some important features are microbiologic culture and susceptibility data, the number of required daily antimicrobial doses, antibiotic stability data, and requirements for unique monitoring for the specific antimicrobial regimen, such as serum creatinine and drug level monitoring with aminoglycosides or vancomycin. Although an organism can be susceptible to several antimicrobial agents, one antibiotic can provide practical benefits over other agents.

Infectious Arthritis Images The three most important therapeutic maneuvers in the management of infectious arthritis are appropriate antibiotics, joint drainage, and joint rest. Smears of the synovial fluid can be useful to select appropriate antibiotic therapy initially.7 If bacteria are not observed on the Gram stain in a patient who has a purulent joint effusion, antibiotics still should be initiated because of the low sensitivity of the Gram stain. A delay in initiating antibiotics significantly increases the likelihood for long-term complications.63,64

The specific antibiotic selected depends on the most likely infecting organism.65 In infants younger than 1 month of age, the infecting organisms vary widely, and empirical therapy thus must provide broad-spectrum coverage. A penicillinase-resistant penicillin such as nafcillin or oxacillin plus a third-generation cephalosporin is appropriate. Children younger than 5 years of age who have been immunized for Hib should receive nafcillin, oxacillin, or cefazolin.66

In children older than 5 years of age and in adults, initial therapy with a penicillinase-resistant penicillin or first-generation cephalosporin is appropriate to provide the necessary coverage against S. aureus. Therapy should be changed to clindamycin, vancomycin, or linezolid if the S. aureus is resistant to methicillin.67,68 They can be converted to oral therapy after initial IV therapy.40 As with osteomyelitis, IV drug abusers require coverage for P. aeruginosa, and therefore, combination therapy with an aminoglycoside, fluoroquinolone, or anti-pseudomonal cephalosporin is needed. The antibiotics usually are administered parenterally and achieve sufficient concentrations within the synovial fluid, and thus intraarticular antibiotic injections are unnecessary. Although studies to define clearly the appropriate length of therapy have not been conducted, 2 to 3 weeks of antibiotic therapy generally is adequate in nongonococcal infections.69 Less than 2 weeks of therapy combined with one joint aspiration was effective in closely monitored children with infectious arthritis.70 Joint fluid cultures usually are no longer positive after 7 days of antibiotics.

Disseminated gonococcal infections often respond quickly to antibiotics. Ceftriaxone 1 g/day for 7 to 10 days is the treatment of choice for adults. After culture and susceptibility results are available and the organism is determined to be susceptible, therapy can be switched on the fourth day to cefixime, oral amoxicillin or to doxycycline or tetracycline to complete the 7- to 10-day course. Clinical resolution of signs and symptoms usually is rapid.

Closed-needle aspiration is recommended for all infected joints except the hip.71 Joint drainage can be repeated daily for 5 to 7 days until effusions no longer reaccumulate. Open drainage is required in hip infections because closed-needle aspiration is difficult and inadequate. During the initial phase of the infection, weight bearing, such as walking, on the joint should be avoided. Passive range-of-motion exercises should be initiated when the pain begins to subside to maintain joint mobility.72 Approximately one third of patients with bacterial arthritis have a poor joint outcome, such as severe functional deterioration. Poor joint outcomes are associated with older patients, those with preexisting joint disease, and patients with an infected joint containing synthetic material. Treatment guidelines for septic arthritis of the hip may be helpful in managing these patients.73

PERSONALIZED PHARMACOTHERAPY

Individualized therapy is important in the treatment of osteomyelitis and infectious arthritis. Patient’s quality of life can be significantly diminished if long-term sequelae develop, such as impaired joint motion or draining sinus tracts, or if amputation is required. Patient demographics, infection characteristics (e.g., infecting organism and its susceptibility patterns), treatment cost, and quality-of-life issues all play a major role in evaluating individualized treatment alternatives (oral therapy or home antibiotic treatment) rather than requiring patients to remain hospitalized to receive 4 to 6 weeks of parenteral antibiotics. In addition, adverse events commonly occur with prolonged outpatient parenteral antibiotic therapy. One study in 45 children noted that 85.7% of patients receiving vancomycin had adverse drug events and 42.9% of patients required the drug be discontinued.74 This analysis also noted that cefazolin had the lowest rate of adverse drug events in this population. Monitoring is important to ensure that personalized therapy is effective to both cure the infection as well as minimize the risk for complications.

EVALUATION OF THERAPEUTIC OUTCOMES

Images Patients with bone and joint infections must be monitored closely. Table 96–5 summarizes a pharmaceutical care monitoring protocol. An assessment of a therapy’s success or failure is based on the patient’s clinical findings and laboratory values. The clinical signs of inflammation, such as swelling, tenderness, pain, redness, and fever, should resolve with appropriate therapy. Initially, the clinical signs are assessed daily until improvement and then periodically thereafter. Elevations in WBC count also should decline gradually. The ESR usually is determined weekly. Elevations in the C-reactive protein or ESR may not return to normal until after several weeks of therapy. The WBC count usually is obtained once or twice per week until it returns to the normal range. If by the end of the 4- to 6-week antibiotic course the clinical findings of osteomyelitis are no longer present and the C-reactive protein and ESR are within normal limits, the patient can be considered a clinical cure. Patients can relapse, however, after initially appearing to be cured. No relapse for 1 year generally is considered a complete cure.

TABLE 96-5 Monitoring Protocol

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If a patient fails to resolve the clinical signs and symptoms of inflammation after appropriate empirical antibiotics, surgical debridement may be needed. In addition, the patient might have a resistant or an atypical infecting organism that may require a modification of the antibiotic therapy. It is especially important to identify the infecting organism and its susceptibility pattern. Follow-up cultures at subsequent debridements can be useful to assess the antibiotic therapy.

Despite apparently adequate surgery and antibiotics, some patients can fail therapy and have recurrent relapses in their infection.75 This scenario is more common in the population with chronic osteomyelitis. These patients can require long-term oral suppressive antimicrobial therapy to keep the infection under control.

ABBREVIATIONS

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REFERENCES

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