Chapter 47. Osteomyelitis

Osteomyelitis is an inflammatory condition of bones usually caused by bacterial, or more rarely, fungal infection. Acute hematogenous osteomyelitis (AHO) is the most common form of osteomyelitis in children.1 It occurs as a result of hematogenous deposition of bacteria within bone following symptomatic or asymptomatic bacteremia. The time from onset of symptoms to diagnosis is usually rapid, within 14 days, although certain sites of infection (particularly vertebral and calcaneal) may have a more insidious course and present subacutely.2 Chronic osteomyelitis presents with either chronic, persistent, low-grade symptoms or an exacerbation of symptoms after a period of relative disease quiescence.3 The reported duration of symptoms required to establish a diagnosis of chronic osteomyelitis is quite varied, ranging from 6 weeks to 6 months. The distinction between acute and chronic osteomyelitis is important as it helps define the necessary treatment modalities given that a longer duration of symptoms before treatment may allow for the development of necrotic bone and soft tissues. Nonhematogenous osteomyelitis occurs with direct contamination of bone from trauma, surgery, or spread of infection from an adjacent soft tissue infection.4 This may present as acute or chronic infection. The primary focus of this chapter will be AHO as it is the form of disease that will be seen most commonly in primary care.

The reported incidence of AHO has ranged from 0.1 per 1000 children younger than 12 years to 8.7 per 1000 children younger than 13 years.5–7 In regions where community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) is common, the incidence may be increasing but there are no population-based studies.8 Approximately 50–60% of children with AHO are younger than 5 years with approximately half of those being younger than 2 years.1,5–10 Most studies have documented a male predominance of AHO of approximately 1.5–2:1.1,6,7,9–11

AHO results from the interplay of host and microbial factors.12 The vascular anatomy of bone in infants and children uniquely presdisposes to bacterial infection in the metaphyseal region of long bones or the “metaphyseal-equivalent” portions of irregular or flat bones (e.g., apophyseal growth plates, such as the tibial tubercle, or greater trochanter).13 Bacteria enter the bone through the nutrient artery and travel to the metaphyseal arterioles. These arterioles form sharp loops adjacent to the epiphyseal growth plate and empty into venous sinusoids in the metaphysis of long bones and metaphyseal-equivalent areas. Sluggish blood flow through these sinusoids and endothelial gaps in the tips of growing metaphyseal vessels are thought to predispose to bacterial deposition in these sites.14

Once infection is initiated, pus spreads through vascular canals leading to vascular compression and compromise, ischemia, and bone necrosis. Perforation of the cortex of bone results in periosteal elevation and subperiosteal abscess.12 Capillaries that cross the physis, present in children younger than 18 months, allow spread of metaphyseal infection into the epiphysis15 although older children may also develop epiphyseal infection.15 Septic arthritis of an adjacent joint may result from spread across these transphyseal vessels and/or via direct spread from the subperiosteal space in those joints in which the metaphysis is contained within the joint capsule (hip, knee, shoulder).16

S. aureus is the most common organism isolated from children with culture-confirmed AHO. It accounts for between 40% and 80% of all cases.1,5–11,17–21 CA-MRSA infections have become very common in some regions and are becoming the predominant etiologic agent of AHO.8,22–24S. aureus is uniquely suited to infect bone as it expresses multiple virulence factors that promote attachment to bone in addition to evasion of host defenses.12 It is also able to evade the immune response and antibiotics by forming a biofilm in which the bacteria are embedded25 and by surviving for prolonged periods within osteoblasts, neutrophils, and endothelial cells.26

Streptococcus pyogenes (group A Streptococcus) is the most common streptococcal species isolated from AHO,1,5–8,20,27 occurring more frequently in children with varicella infection.27Streptococcus agalactiae (group B Streptococcus) causes osteomyelitis in neonates and rarely in older children.8,20,28,29Streptococcus pneumoniae is most common among children younger than 2 years and usually causes with septic arthritis alone or with concomitant AHO.8,30Haemophilus influenzae type B1,5,6,9,19,21 has virtually disappeared with routine infant immunization.7,8,10,11,31Salmonella is a pathogen most frequently associated with osteomyelitis in children with sickle cell disease,32 although it may be occasionally isolated in AHO from otherwise healthy children.1,8–10 Other enteric gram-negative organisms, such as Escherichia coli and Enterobacter spp., are encountered in neonates28,29 and children with sickle cell disease.32 Coagulase-negative staphylococci and other low pathogenicity organisms, reported in some case series, are unlikely pathogens except in the setting of nonhematogenous osteomyelitis.

Anywhere from 15% to 68% of cases of osteoarticular infections are culture negative when blood culture and bone/joint aspirates are used in combination.1,5–11,33 It is assumed that the majority of these cases are staphylococcal.10Kingella kingae, a fastidious, gram-negative, is also implicated in culture negative infections, particularly septic arthrits.10,20,34,35 Isolation of this fastidious organism is improved with inoculation of specimens into automated blood culture systems and with the use of a Kingella-specific polymerase chain reaction test.34,36 Unusual organisms causing osteomyelitis and associated with negative conventional cultures include Mycobacterium tuberculosis, Blastomyces dermatidis, Coccidioides immitis, Bartonella henselae (agent of cat-scratch disease) and Coxiella burnettii (agent of Q fever). Opportunistic fungi, such as Aspergillus spp., may be seen in immunocompromised patients.

Common clinical findings on presentation with AHO include fever (40–90%1,5,10,11) and focal bone pain and/or tenderness (56–91%1,5,9,11). Patients with fever are more likely to present within a few days of symptom onset.5 If the infection is in a weight-bearing bone, the patient may present with limp. Failure to walk or crawl or pseudoparalysis may be present in young infants who are unable to verbalize focal pain.29 Other signs and symptoms that may be seen are localized swelling, erythema, and warmth and decreased range of motion of an adjacent joint.1,5,11Table 47–1 presents the most common signs and symptoms of AHO.

Children may present with a clinical picture of severe infection or pneumonia as well. It is important to consider musculoskeletal infection in the differential diagnosis of any patient presenting with severe infection, especially in young children who cannot verbalize pain and the primary site of infection in the bone may be overlooked.

AHO disproportionately affects the long bones of the lower extremities (55% of all bones infected). Table 47–2 shows the relative proportions of the bones most frequently involved in osteomyelitis.1,5,8,10,11,37 Multifocal bone infections occur in 4–9% of children with AHO.1,37,38

The differential diagnosis of AHO includes soft tissue infections such as cellulitis, myositis, and fasciitis (Table 47–3). Patients with osteomyelitis of bones with minimal overlying muscle or subcutaneous tissue (e.g., tibia, fibula, distal radius, and ulna) may present with erythema and induration of the skin mimicking cellulitis. Osteomyelitis should be suspected in cases where the degree of pain is disproportionate to the clinical findings of dermal inflammation. Myositis and fasciitis may occur concomitantly with AHO and are generally distinguished with imaging or surgical exploration. Hematologic malignancies may present with fever and bone pain or limp as well. In indolent cases where fever is low grade or absent, the differential diagnosis includes trauma and benign or malignant bone tumors.

AHO must be distinguished from acute inflammatory or infectious arthritis. Joint swelling, erythema, reduced mobility and joint effusion are present in these latter conditions. In 10–20% of patients with AHO, reduced range of motion of an adjacent joint may be caused by septic arthritis of the affected joint.1,8,10

Children with osteoarticular infections caused by CA-MRSA appear to have more severe disease at clinical presentation compared with those with MSSA infection.22,39–45 This enhanced virulence does not appear to be related to its antibiotic resistance pattern and failure to initiate prompt appropriate therapy but because of other genetic features of this organism, the precise mechanisms of which remain elusive.46,47 These children have an increased risk of subperiosteal abscess necessitating repeated surgical procedures,22,43,44 septic thrombophlebitis24,43,48 and severe sepsis with shock and death.23 The risk of overwhelming infection is higher in older children and adolescents.23 In this era of conjugate vaccines, invasive bacterial infections secondary to S. pneumoniae, H. influenzae type B and Neisseria menigitidis are becoming increasingly rare. S. aureus in general and MRSA in particular must be considered as the primary differential diagnosis of sepsis in an otherwise healthy patient. Frequently, the musculoskeletal system will be the primary site of infection in these patients; thus, a bone, joint or deep muscle focus of infection should be sought in any patient presenting with signs and symptoms of sepsis.23

Laboratory Testing

The diagnosis of AHO is made with a combination of clinical findings and supportive laboratory and imaging studies. Laboratory findings that are suggestive of AHO include elevations in acute phase reactants, such as the white blood cell count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). None of these tests is sufficiently specific or sensitive to be used to rule in or out the diagnosis of AHO.1,10,23,37,49,50 The ESR is elevated in 70–90% of patients with a median value of 50–60 mm/h; however, values vary greatly from normal (<10–20 mm/h) to >140 mm/h. CRP values show a similar pattern with close to 100% patients having elevated values spanning a broad range. Children with AHO with an adjacent septic arthritis tend to have higher CRP values.51,52 The greatest utility for the ESR and CRP appears to be in monitoring disease progression and resolution. ESR usually reaches a peak by day 3–5 of admission with a gradual decline to normal by the end of therapy (approximately 3–5 weeks).49–51 The CRP peaks by the second day of admission and normalizes within 7–10 days of effective therapy.49–51

Pathogenic bacteria are isolated from 50–85% of children with AHO.1,8,10,37,38 The blood culture alone is positive in 30–55% of cases.1,8,37,38 Culture of aspirates of bone or subperiosteal abscess and from joint fluid from adjacent infected joints may enhance isolation of pathogens; however, in practice, the willingness of surgeons to obtain a bone aspirate from a patient who does not have a clinical requirement for surgery (i.e., for drainage of a subperiosteal abscess or debridement of necrotic bone) varies among institutions. The rate of isolation of bacteria from subperiosteal pus is high and, thus, should be attempted where possible.8,9

Radiographic Diagnosis

Plain Radiography

The role of plain radiographs in early infection is to exclude other pathologic conditions. A frequently made error is using plain radiographs to exclude the possibility of AHO early in disease. It is extremely important to remember that bone pain or limp in a child with fever is an acute osteoarticular infection until proven otherwise. The earliest findings are soft tissue swelling with blurring of soft tissue planes.53 Bone destruction (osteolysis) may not be seen for 7–10 days after the onset of infection because loss of approximately 50% of bone mineralization is required for changes to be apparent on plain films (Figure 47–1); early treatment with antibiotics may arrest bone loss and typical radiographic changes may never appear.54,55 Periosteal reaction or elevation associated with abscess is seen later as infection extends through and erodes the cortex. One may also see widening of the adjacent joint space because of effusion from a concurrent septic arthritis.

Scintigraphy

Bone scintigraphy may be positive as soon as 24–48 hours after onset of symptoms.54 Technetium-99m-methylene diphosponate localizes in areas of inflammation secondary to hyperemia and early bone resorption. A three-phase bone scan suggested in diagnosing AHO.54,56 The first phase is the angiographic or flow phase which consists of serial images of the suspected area of infection during infusion of the isotope. The second phase, or blood-pool image, is obtained within 5 minutes of injection when isotope has pooled in tissues because of the increased blood flow associated with inflammation. The third phase, or bone phase, is obtained approximately 3 hours later after the isotope has washed out of the soft tissues (Figure 47–2). Osteomyelitis causes a focal increase in uptake in all three phases, whereas, cellulitis results in diffuse increased uptake in the first two phases and either no or diffusely increased uptake in the third. The sensitivity of the three-phase bone scan is 90–95%54,56–58 making this a very useful test in clinical practice. Specificity is lower as bone scintigraphy cannot distinguish among infection, neoplasm, and trauma. False negative (either normal or “cold” spots) bone scans result from limitation of the usual tissue hyperemia secondary to sinsusoidal thrombosis or pressure from pus in the vascular channels59–62 (Figure 47–3); thus, in a patient for whom there is a high index of suspicion for AHO, further imaging should be undertaken in the face of a negative bone scan. Use of other isotopes, such as Gallium-67 or Indium-111-labeled leukocyte, are not routinely recommended.63

Ultrasound

Ultrasound can detect a variety of abnormalities including edema of muscle and subcutaneous tissues which may be maximal near bone, thickening of periosteum and elevation of the periosteum greater than 2 mm including subperiosteal abscess.64 It is sensitive and specific for the diagnosis of AHO (both 90%) and is useful where access to nuclear medicine or magnetic resonance imaging is limited.

Computed Tomography (CT) and Magnetic Resonance Imaging (MRI)

These studies are sensitive tools in the diagnosis of AHO. The most useful property of CT scanning is the detection of intraosseus gas, sequestra, and involucra (see section “Chronic Osteomyelitis”)65 (Figure 47–4). The greatest utility of MRI is its ability to provide a detailed image of the infected area with superb delineation of the extent of the disease of both bone and adjacent soft tissues. The earliest change seen is edema of bone marrow, demonstrating low-signal intensity (dark) on spin echo T1-weighted images and high-signal intensity (bright) on fast spin echo T2-weighted images65–67 (Figure 47–5). Such findings are not specific for osteomyelitis and can be seen in neoplasia, trauma, or bone infarct. MRI has proved very useful in identifying abscesses in children with pelvic osteomyelitis or those who did not have prompt improvement in symptoms following initiation of therapy.67 A suggested algorithm to guide diagnostic imaging of children with suspected AHO is provided in Figure 47–6.

Surgical Management

Surgery with aspiration of bone and cortical window creation used to be a routine part of care; however, studies have not demonstrated an advantage to routine surgical intervention in addition to antibiotics. Surgical intervention should be reserved for clinically significant subperiosteal or muscle abscess or cases in which the diagnosis is in doubt. Some surgeons will perform bone aspirates for culture.

Medical Management

Several points of controversy persist regarding the antimicrobial management of AHO: Total duration of therapy and the use of oral stepdown to oral therapy following a period of parenteral therapy. The lack of large prospective randomized trials of treatment duration or oral stepdown therapy fuel ongoing debate on these issues.

Duration of Therapy

Early retrospective case series demonstrated a greater risk of relapse in children with staphylococcal osteomyelitis who received fewer than 3 weeks of therapy1; thus, it became accepted that 4–6 weeks of therapy were required to minimize the risk of relapse and development of chronic osteomyelitis. More recent studies have demonstrated that the duration of therapy may be safely reduced by monitoring the CRP and the ESR until both have normalized, usually within 3–4 weeks.51,68 In patients with complicated disease, as is being seen more frequently with CA-MRSA, longer courses of therapy seem prudent and are required to achieve normalization of the ESR.

Oral Stepdown Therapy

Although unacceptably high treatment failure rates were seen initially with shorter courses of parenteral therapy, greater understanding of bone and synovial fluid penetration of antibiotics69 and routine use of higher doses led many to attempt oral therapy again to obviate the need for maintaining prolonged intravenous access.21 For some time, it was recommended that this oral stepdown therapy only be used when monitoring of serum bactericidal titers (SBTs) could be guaranteed. SBTs measure the bactericidal power of the patient's serum against the infecting organism.70 However, treatment failure is rare among patients given high doses of oral antibiotics (2–3 times the usual dose).21,51,68,71,72 Some clinicians will obtain drug levels in place of SBTs to detect the occasional patient in whom oral bioavailability is poor. While many centers continue to use oral stepdown therapy, many others have been using peripherally inserted central catheters which are often easily inserted at the bedside to provide home parenteral therapy. Each route of therapy has its own set of advantages and disadvantages. The primary disadvantage of prolonged intravenous therapy is the risk of complications from a central venous catheter, primarily infection and thrombosis both of which may require emergency department visits or hospital readmission.73 The benefits include lack of reliance on gastric absorption of oral antibiotics and possible better compliance. Oral stepdown therapy does not put patients at risk for central venous catheter infection or upper extremity thrombosis; however, compliance may be more of an issue and there may be the occasional patient who has poor oral bioavailability. A systematic review and meta-analysis of 12 prospective cohort studies, little difference was demonstrated in the cure rate at least 6 months later between short- (≤7 days, pooled cure rate 95.2%) and long-course intravenous therapy (>7 days, pooled cure rate 98.8%)74 (Figure 47–7).

Antibiotic Selection

The choice of empiric therapy is based upon the age of the child and any predisposing conditions (Table 47–4); however, empiric therapy should include coverage for Staph. aureus in all cases. For example, children with sickle cell disease also require coverage for Salmonella, those with varicella also require coverage for group A Streptococcus, and neonates also require coverage for group B Streptococcus and enteric gram-negative bacteria. Therapeutic agents used in MSSA osteomyelitis include the penicillinase-resistant penicillins (nafcillin, oxacillin, cloxacillin), first and second generation cephalosporins (cefazolin, cephalexin, cefuroxime) and clindamycin. For MRSA, clindamycin, vancomycin, and trimethoprim-sulfamethoxazole are used. It is reasonable to empirically treat patients for CA-MRSA when 10–15% of staphylococcal isolates are CA-MRSA, although there is no data to support any particular threshold.75 In those areas where most CA-MRSA isolates are clindamycin susceptible, clindamycin is reasonable empiric coverage. For those areas where more isolates express constitutive or inducible resistance to clindamycin (inducible resistance as determined by the D-test), empiric therapy with vancomycin is recommended. Vancomycin should also be included in empiric therapy in critically ill children with musculoskeletal sepsis. Recommended doses of these antibiotics are found in Table 47–5.

There are little systematic data on the use of newer anti–gram-positive agents in osteomyelitis. Linezolid is an oxazolidinone antibiotic that is approved in children for the therapy of pneumonia and skin and soft tissue infections including those caused by MRSA.76–78 There is limited experience, in adults, in its use in acute and chronic osteomyelitis.79,80 It has the benefit of being available in an oral preparation for stepdown therapy. Daptomycin is another new agent with extremely limited experience in osteomyelitis81,82 and no currently approved indications in children. Given the increasing incidence of CA-MRSA infections, however, there will be greater pressure for use of these agents in children in the future.

The final therapy chosen depends upon the organism isolated. Many cases of AHO are culture-negative (up to 50%) and empiric therapy must be continued. It is generally believed that most patients with culture negative disease have staphylococcal infection and patients with culture negative disease have been demonstrated to be cured with antistaphylococcal therapy (for MSSA or MRSA depending on the prevalence). Treatment of MSSA with first or second generation cephalosporins also provides empiric coverage for Kingella; however, the use of clindamycin and vancomycin for MRSA leaves potential Kingella infections untreated. In children with negative cultures, who have not improved adequately on empiric therapy, therapy should be changed to include coverage for MRSA, Salmonella or Kingella and additional imaging obtained (if not already done) to assess for subperiosteal or deep soft tissue abscess.

Subperiosteal and deep soft tissue abscess8,22 and septic thrombophlebitis24,83,84 are among the most common complications of AHO. Septic shock and necrotizing pneumonia are less common8,23 (Figure 47–8). These complications are being identified more frequently with the emergence of CA-MRSA. Patients with CA-MRSA infection require a thorough evaluation for complications and multisystem infection. Chest tube or surgical drainage of complicated pleural effusion may be required. In addition, patients with septic thrombophlebitis may require anticoagulation and/or thrombolysis depending on the severity of the clot.24,84

Sickle Cell Disease

Children with sickle cell disease are at increased risk of serious bacterial infection including osteomyelitis. Salmonella infection is twice as common as S. aureus in this group of patients compared with otherwise healthy children with AHO.32 Other gram-negative bacilli are overrepresented in this group as well. Painful, bony crises and osteomyelitis may be indistinguishable by history and clinical examination.85 Unfortunately, there is no way to definitively distinguish infarct from osteomyelitis by imaging with plain film, bone scan, or MRI. Some advocate MRI with gadolinium86 while others have used combined technetium bone scanning and sulfur colloid bone marrow scanning to distinguish between these conditions.87 One should have a low threshold for biopsy or bone aspirate in the setting of a slow to resolve pain crisis. Patients require an empiric course of antibiotic therapy (including coverage for Salmonella spp.) when osteomyelitis cannot be ruled out. The optimal duration of therapy in this setting is unknown; a longer course (up to 6 weeks) with oral stepdown therapy is reasonable.

Neonatal Osteomyelitis

Osteomyelitis is an important infection among healthy term infants as well as sick and/or preterm infants requiring intensive care. Among healthy and sick newborns, osteomyelitis is one of the common manifestations of late-onset group B Streptococcus infection.28,88S. aureus, S. pneumoniae and enteric gram-negative bacilli comprise the majority of the remaining cases.28,29 Children with group B Streptococcus osteomyelitis tend to have an uncomplicated clinical course with very little in the way of systemic inflammation.28,88

Osteomyelitis in the NICU setting may be hematogenous89 or by direct inoculation heel puncture.90,91 A multitude of pathogens may cause osteomyelitis in this setting including S. aureus (including CA-MRSA), enteric gram-negatives, coagulase-negative Staphylococcus, group B Streptococcus and Candida spp.29,92–94

Pelvic Osteomyelitis

Approximately 10% of AHO cases involve the bony pelvis with the ilium and ischium the most commonly affected.1,37,95,96 Pelvic osteomyelitis may be misdiagnosed early in the course of infection as a septic hip or intra-abdominal infection/inflammation as a result of the poor localization of signs and symptoms; thus, it should be considered in the differential diagnosis of a febrile child with a limp or range of motion limitations of the hip.94,95 The most useful clinical indicator of the site of infection is point tenderness. Diagnosis of this condition may be made promptly with scintigraphy, MRI or CT (which may be done to assess for intra-abdominal abscess, appendicitis, or deep muscle abscesses).

Vertebral Osteomyelitis and Diskitis

Vertebral osteomyelitis is much less common in children than in adults. It accounts for approximately 2% of all cases of AHO.1,37 Like pelvic osteomyelitis, it may present in an insidious manner without back pain with nonspecific or constitutional symptoms only.97,98 Typically, there will be no abnormality on plain X-ray early in the course of disease. The earliest sign of infection is narrowing of the disk space followed by loss of bone density in the aspect of the vertebral body closest to the cartilaginous plate. One may see involvement of two adjacent vertebrae. Index of suspicion is crucial for obtaining the appropriate imaging (bone scan or MRI). The advantage of MRI is the ability to detect epidural abscess which may complicate vertebral osteomyelitis.

Diskitis is a rare condition but an important differential diagnosis of vertebral osteomyelitis.97,99,100 It is most common in the toddler age group. Diskitis and vertebral osteomyelitis may represent extremes of the same condition with differential clinical presentation between affected age groups secondary to developmental changes in the blood supply to the intervertebral disks and vertebrae. The clinical presentation is typically insidious with generalized fussiness progressing to limp or refusal to walk, crawl, or sit. Older children may complain of back pain. Constitutional symptoms and laboratory signs of inflammation may be mild or absent. Diagnosis is made by demonstrating a narrowed intervertebral disk space on plain X-ray, most commonly in the lumbar region, after about 2–3 weeks of symptoms. There may be associated erosion of adjacent vertebral end plates. MRI will demonstrate abnormalities in the disk and adjacent vertebrae if present and will assess for the presence of alternate diagnoses including spinal tumors and epidural abscess. An infectious etiology is hypothesized but many cultures are sterile and patients may recover without therapy. In children with positive cultures, S. aureus is the most common agent but Kingella and Salmonella are also reported. Diskitis is discussed in more detail in Chapter 49.

Nonhematogenous Osteomyelitis

Osteomyelitis may occur as a result of nonhematogenous infection of bone. This most commonly occurs following trauma, such as compound fractures,101,102 puncture and bite wounds,103 and surgery (orthopedic procedures or sternotomy), with or without prosthetic material.4,104 It may also occur by spread from a contiguous focus of infection, for example infected decubitus4,104 or neuropathic skin ulcers4,104 or facial and skull base osteomyelitis from contiguous sinusitis, mastoiditis, or dental infection.105

Many patients present with indolent low-grade fever and pain.4,104 Some will have more acute presentations with erythema and swelling of the site. There may be purulent drainage from a sinus tract or a poorly healing wound overlying the site of infection. Peripheral white blood cell count and ESR are not reliably elevated. Radiographic appearance is highly variable with chronic infections being more likely to demonstrate abnormalities on plain films. It may be difficult to distinguish overlying soft tissue inflammation from infected bone on technetium bone scanning. CT and MRI are useful for defining the extent of disease and associated soft tissue infection particularly in skull and facial osteomyelitis where infection may have spread intracranially.105

Cultures of sinus tract drainage are unreliable and bone or deep soft tissue biopsy is frequently required to determine the etiologic agent(s).106,107S. aureus is still among the most common pathogens, especially for sites contaminated during surgery, but the microbiology is defined by the location of the disease and its origin.4 Polymicrobial infection is not uncommon. Treatment includes surgical debridement of infected bone and soft tissue along with prolonged antibiotic therapy up to 4–6 months for chronic infections. Most patients receive initial intravenous therapy with stepdown to oral antibiotics if appropriate agents are available.

Osteochondritis of the foot resulting from a puncture wound is a unique clinical syndrome. Infection occurs in a minority of individuals with puncture wounds, usually those occurring through a sneaker.108 Onset of symptoms may be acute to subacute (up to 21 days). Pseudomonas aeruginosa is the most common pathogen in this condition although other gram-negative bacteria, such as E. coli and Proteus have been reported.109–111S. aureus is an occasional pathogen as well. This condition responds well to thorough surgical debridement and drainage of pus. Following this, 2 weeks of appropriate antibiotic therapy has been demonstrated to be sufficient. Parenteral antipseudomonal antibiotics including piperacillin, ticarcillin, and ceftazidime are appropriate initial agents. Step down therapy with ciprofloxacin should be considered.

Unusual Organisms

A variety of unusual bacterial pathogens may cause osteomyelitis. Osteomyelitis is an atypical manifestation of cat-scratch disease, caused by B. henselae.112,113 Sacroiliitis and spondylitis are common complications of brucellosis, a zoonosis acquired by the consumption of unpasteurized animal milk products.114C. burnettii, the agent of Q fever, is a rare cause of granulomatous osteomyelitis.115

Fungi may cause osteomyelitis in immunocompromised and competent hosts. Osteomyelitis caused by Aspergillus spp. is described in patients with chronic granulomatous disease116,117 and hematologic malignancy.118 Individuals with T-cell defects may develop osteomyelitis caused by Cryptococcus neoformans.119,120 Osteomyelitis caused by Candida spp. occurs as a complication of candidemia.121 In immunocompetent individuals, the endemic mycoses, geographically distinct, thermally dimorphic fungi, may cause osteomyelitis, with or without apparent pulmonary disease. This is significantly more common with blastomycosis122,123 and coccidioidomycosis124 than with histoplasmosis.125

Tuberculosis is a major cause of osteoarticular infections worldwide, although it is an uncommon manifestation in children.126 The most frequently encountered musculoskeletal presentations of tuberculosis are vertebral (Pott's disease) and synovial. Solitary and multifocal bone lesions are uncommon in children but may involve almost any bone in the body, but the metaphyses of long bones are the most commonly involved. PPD and chest X-ray should be performed, although a negative PPD should not be used to rule out tuberculosis. Patients will have associated pulmonary disease only 50% of the time.

An unusual organism should be suspected in the setting of a subacute osteomyelitis not responding to antimicrobial therapy for typical pathogens. A high index of suspicion and knowledge of the epidemiology of these pathogens will lead to the diagnosis. Clues to the diagnosis will come from radiographs but pathologic examination of biopsies will be required in most cases. Definitive diagnosis is made by special stains and/or culture of the organism (fungal, tuberculous) or with serology (Bartonella, Brucella, Coxiella, Coccidioides).

Chronic Osteomyelitis

Chronic osteomyelitis occurs when there is vascular compromise as a result of infection in the vascular channels and bone necrosis occurs. The fragments of bone with pus are called sequestra while involucrum is the periosteal new bone that forms around the sequestrum. Bone necrosis may begin as early as 10 days into acute osteomyelitis and sequestrum and involucrum as early as 3 weeks. Infection of surrounding soft tissues ensues with the eventual formation of a sinus tract. These areas form a nidus for ongoing infection as necrotic bone is relatively impervious to antibiotic therapy.3,12,127

The diagnosis of chronic osteomyelitis is made with a typical history and with imaging.2,104,128 Chronic osteomyelitis may occur after a recognized but incompletely treated episode of acute osteomyelitis or may result from the relentless progression of a low-grade, insidious infection with intermittent flares. The clinical presentation may be indistinguishable from benign and malignant bone tumors.129 Radiologic imaging is helpful. Plain radiography, CT, and MRI may reveal the features of sequestrum, involucrum, and/or abscess that indicate the presence of infection.12,104,127–130 Definitive diagnosis rests with biopsy and culture of bone. Sinus tract cultures are unreliable and reveal a different organism from bone approximately 60–70% of the time.106,107,131 Only the presence of S. aureus in a sinus tract culture appears to be reasonably predictive of the bone culture result.107,131

S. aureus is the most common organism isolated from chronic osteomyelitis; however, many other organisms may be identified including streptococci, gram-negatives, including Pseudomonas and anaerobic organisms such as Bacteroides. Polymicrobial infection, especially trauma-related, is not uncommon.3,104,128,131,132

Treatment of chronic osteomyelitis often requires a combination of surgical and medical therapy. Many orthopedic experts advocated extensive debridement of bone and soft tissue, leaving behind only bleeding healthy tissue. The dead space is filled with a muscle flap, bone graft, or antibiotic impregnated polymethyl methacrylate beads.127,129,133,134 This is accompanied by antibiotic therapy targeting the isolated organism (or the organism known to have caused the primary infection) or empiric therapy to cover the most likely organisms in the event of sterile cultures. With the broad array of potential pathogens, reasonable empiric coverage for situation where polymicrobial disease is likely is clindamycin and ciprofloxacin as it provides broad spectrum gram-positive, gram-negative, and anaerobic coverage. The appropriate duration of antimicrobial therapy for chronic osteomyelitis is unknown. Six weeks of antibiotics is felt to be sufficient when surgery has been extensive and necrotic bone fully debrided.3,132 The data in children is limited but medical therapy alone has been used to successfully treat chronic osteomyelitis without radiographic evidence of sequestrum or pus.3,104,130,132,135 Longer courses of treatment, up to 4–6 months, may be used when surgical debridement is limited or absent. It is reasonable to use oral stepdown therapy in this setting, provided appropriate oral agents are available for the isolated organisms.

Chronic Recurrent Multifocal Osteomyelitis (Crmo)

CRMO is an inflammatory bone disease that resembles infectious osteomyelitis but no infectious agent can be identified in cultures of biopsies.136,137 It is characterized by recurrent and remittent pain and swelling in the affected bones. There may be single or multiple, symmetric, or asymmetric sites of involvement at any time. Flares may be associated with fever and elevated acute phase reactants. The most common sites of involvement are the metaphyses of long bones as in AHO; the presence of lesions on the clavicle or vertebral bodies should raise the suspicion of CRMO. Radiographic abnormalities consist of radiolucent lesions with sclerosis consistent with acute and chronic osteomyelitis. The etiology is unknown and pathologic examination reveals acute and chronic inflammatory changes. It is frequently associated with other inflammatory conditions including psoriasis, palmoplantar pustulosis, pyoderma gangrenosum, and inflammatory bowel disease.138,139 There are no randomized controlled trials of treatment modalities but steroids and nonsteroidal antiinflammatories have been used with success to control symptoms. Gamma interferon has been used with favorable outcomes in a few patients.140 While the outcome of CRMO is generally good, some patients have a prolonged disease course with a significant impact on quality of life.141