Osteomyelitis 78

SECTION K: Bone and Joint Infections 78 Osteomyelitis Kathleen Gutierrez

Osteomyelitis is inflammation of bone. Bacteria are the usual etio- months, providing a vascular connection between the metaphysis logic agents, but fungal osteomyelitis occurs occasionally. Osteo- and the epiphysis.8 As a result, in infants, infection originating in myelitis in children primarily has hematogenous origin, occurring the metaphysis can spread to the epiphysis and joint space. The less commonly as a result of trauma, surgery, or infected contigu- risk of ischemic damage to the growth plate is greater in the young ous soft tissue. Osteomyelitis due to vascular insufficiency is rare infant with osteomyelitis.9 Before puberty, the periosteum is not in children. firmly anchored to underlying bone. Infection in the metaphysis of a bone can spread to perforate the bony cortex, causing sub ACUTE HEMATOGENOUS OSTEOMYELITIS periosteal elevation and extension into surrounding soft tissue. Bony destruction can spread to the diaphysis. By age of 2 years, Pathogenesis the cartilaginous growth plate usually prevents extension of infection to the epiphysis and into the joint space. When the metaphy- Acute hematogenous osteomyelitis (AHO) is primarily a disease sis of the proximal femur or humerus is involved, however, of young children, presumably because of the rich vascular supply infection can extend into the hip or shoulder joint at any age, of their rapidly growing bones.1–3 Infecting organisms enter the because at these sites, the metaphysis is intracapsular. bone through the nutrient artery and then travel to the metaphy- Histologic features of acute osteomyelitis include localized sup- seal capillary loops, where they are deposited, replicate, and puration and abscess formation, with subsequent infarction and initiate an inflammatory response (Figure 78-1). Metaphyseal necrosis of bone. Segments of bone that lose blood supply and localization results from sluggish blood flow, the presence of become separated from viable bone are called sequestra. An involu- endothelial gaps in the tips of growing metaphyseal vessels, and crum is a layer of living bone surrounding dead bone.10 A Brodie lack of phagocytic cells lining the capillaries.3–6 Bacteria prolifer- abscess is a subacute, well-demarcated focal infection, usually in ate, spread through vascular tunnels, and are anchored to areas of the metaphysis but sometimes in the diaphysis of bone. exposed cartilaginous matrix. Large colonies of bacteria sur- rounded by glycocalyx obstruct capillary lumens, impairing Epidemiology phagocytosis and antibiotic penetration.7 Age-related differences in the anatomy of the bone and its blood Approximately half of all cases of AHO occur in the first 5 years supply influence the clinical manifestations of osteomyelitis.2,3 of life.11 Boys are affected twice as frequently as girls, except in the Transphyseal vessels are present in most children younger than 18 first year of life.11,12 One-third of patients have minor trauma to the affected extremity before infection, but the specific importance of this history is unclear, because virtually all young children experience frequent mild trauma.13 The relative risk of developing osteomyelitis appears to be higher in some populations. In one study, Polynesian and Maori children were more likely to develop complicated osteomyelitis with Staphylococcus aureus than other children in the same New Zealand community.14 It is unclear whether genetic or socioeco- nomic or environmental factors accounted for this difference. Microbiology S. aureus is the most common cause of AHO.1,13,15–21 Kingella kingae, Streptococcus pneumoniae,22 and S. pyogenes23 are the organisms isolated in most other cases of AHO in children. K. kingae and S. pneumoniae infections are most common in children less than 3 years of age. S. pneumoniae accounts for a relatively small proportion of infections, especially in the context of widespread immunization with the pneumococcal conjugate vaccine.24,25 K. kingae can be associated with small outbreaks of bone and joint infections in childcare centers.20,26 Coagulase-negative staphylococci (CoNS) (almost exclusively as a complication of medical intervention), enteric gram-negative bacilli, and anaerobic bacteria are uncommon causes of AHO. Bartonella henselae can cause granulomatous infection of bone.27–29 Actinomyces spp. cause facial and cervical osteomyelitis.30 Infection with Serratia spp. and Aspergillus spp. should be considered in children with chronic granulomatous disease.31 Before widespread use of Haemophilus influenzae type b (Hib) conjugate vaccines, 10% to 15% of cases Figure 78-1. Gross specimen showing osteomyelitis of the proximal humerus of osteomyelitis in children younger than 3 years were caused 15,18 in a 6-week-old infant. Note metaphyseal location and bony destruction by this organism. Invasive disease is rare in immunized (arrows). (Courtesy of S.S. Long.) children.32

469 All references are available online at www.expertconsult.com PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION K Bone and Joint Infections

Community-acquired methicillin-resistant Staphylococcus aureus predictive factors (temperature 38°C, hematocrit <34%, WBC (CA-MRSA) AHO has been increasing dramatically.33–36 Some count >12,000 cells/mm3 and C-reactive protein level >1.3 mg/ CA-MRSA isolates causing osteoarticular infection carry the genes dL) were useful in differentiating MRSA from MSSA osteomyelitis. for Panton–Valentine leukocidin (PVL), a virulence factor or Prospective validation of this scoring system is pending.42a Patients marker for complicated infections.33,37,38 with PVL-positive CA-MRSA are at increased risk for deep-vein thrombosis or septic emboli to the lungs.33,35–37 Compared with Clinical Characteristics and Differential Diagnosis infection due to PVL-negative organisms, infection with PVL- positive S. aureus also appears more likely to result in chronic Most patients with AHO have symptoms for <2 weeks before they osteomyelitis.33 are brought to medical attention, although a small proportion have low-grade fever and intermittent bone pain for several Laboratory Diagnosis weeks.13,17 The most common manifestations are fever, pain at the site of infection, and reluctance to use an affected extremity.18,39 Bacteriologic diagnosis can be confirmed in 50% to 80% of cases Less common complaints are anorexia, malaise, and vomiting. of AHO; the yield is highest when multiple specimens, including Physical findings consist of focal swelling, tenderness, warmth, blood, bone, and joint fluid, are sampled.3,12,13,17,18,39 Cultures and erythema (usually over the metaphysis of a long bone). Rarely, obtained by imaging-guided bone biopsy are more likely to be a draining fistulous tract develops over the affected bone.13 Tender- positive if larger volumes (>2 mL) of purulent material are aspi- ness out of proportion to soft-tissue findings suggests osteomyeli- rated.43 Diagnosis of K. kingae infection is enhanced with intraop- tis rather than soft-tissue infection or cellulitis. Exaggerated erative inoculation of culture material directly into liquid media immobility of the joint and lack of point tenderness over the or onto agar plates or when polymerase chain reaction (PCR) metaphysis suggest pyogenic arthritis. Other causes of bone pain analysis is performed;20,21,44 cultures should be held for at least 7 are fracture, bone infarction secondary to hemoglobinopathy, to 10 days. leukemia, vitamin deficiency, and bony neoplasms such as meta- The erythrocyte sedimentation rate (ESR) is elevated in up to static neuroblastoma and Ewing sarcoma. 90% of cases of osteomyelitis, and the C-reactive protein (CRP) Osteomyelitis most frequently occurs in the long bones (Figure level in 98%.17,18,38,45 The mean ESR is 40 to 60 mm/h, but levels 78-2), although in some series, 10% to 25% of cases involve short >100 mm/h can occur. ESR generally peaks 3 to 5 days after initia- or nontubular bones, including the pelvis, clavicle, calcaneus, tion of therapy and returns to normal in approximately 3 weeks. skull, ribs, and scapula.17,18,40 Multiple bones are involved in about CRP levels peak by the second day (mean, 8.3 mg/dL) and return 5% of cases. to normal (<2.0 mg/dL) after approximately 1 week of therapy.45 Compared with methicillin-sensitive S. aureus (CA-MSSA), Patients infected with PVL-positive versus PVL-negative S. aureus patients with CA-MRSA infections have more protracted courses are more likely to have positive blood cultures and higher ESR and of fever, as well as hospitalization, multiple foci of infection, CRP levels at presentation.38 Higher levels of CRP at diagnosis may pyomyositis, and subperiosteal and intraosseous abscesses.36,38,41,42 predict greater risk of sequelae.46,47 The peripheral white blood cell A recent retrospective study demonstrated that four independent count can be elevated or normal; thrombocytosis can be noted, especially if symptoms have been present for more than 1 week. Radiologic Diagnosis Plain Radiographs Radiographic abnormalities in osteomyelitis reflect inflammation, destruction, and new formation of bone.3,48 The earliest abnormalities, seen within the first 3 days of onset of symptoms, are deep soft-tissue swelling and loss of the normally visible tissue Humerus planes around the affected bone. Osteopenia or osteolytic lesions 12% from destruction of bone usually are not visible until approximately 50% of bone has been demineralized. Lytic lesions, perios teal elevation due to subcortical purulence, and periosteal new Ulna bone formation appear approximately 10 to 20 days after onset of 3% symptoms. Sclerosis of bone is seen when infection has been present for longer than a month. If deep soft-tissue swelling is Radius noted on plain radiograph in a patient with a short history of Pelvis 4% symptoms and with point tenderness over the affected metaphysis, Hands and 9% no further imaging studies are necessary to support the diagnosis feet 13% of osteomyelitis.

Femur Radionuclide Scanning 27% Radionuclide scans are useful in the early diagnosis of osteomyelitis, even when plain radiographs are normal. Technetium- labeled methylene diphosphonate isotope is most frequently used because its uptake by infected bone is enhanced when osteoblastic activity is increased. Tibia Fibula The reported sensitivity of technetium-99 bone scanning is 22% 5% between 80% and 100% (Table 78-1),49–53 (Figures 78-3 and 78-4). The bone scan can be normal in 5% to 20% of children with osteomyelitis in the first few days of illness.52,54–56 Bone scan is less expensive than MRI, and sedation usually is not required. Bone Figure 78-2. Sites of acute osteomyelitis in 657 children in whom a single scan is particularly useful when multifocal bone involvement is 57 bone was involved. Shaded areas constitute sites of approximately 75% of suspected. cases. Miscellaneous sites accounting for 5% are not shown. (Data collated A variety of disorders, including malignancy, deep soft-tissue from references 12, 17, 18, and 39.) infection, cellulitis, pyogenic arthritis, trauma, fracture, and bone

470 Osteomyelitis 78

infarction, can result in positive scan results. Metaphyseal site of TABLE 78-1. Technetium Bone Scans for Osteomyelitis in Children maximal uptake and lack of uptake in bone on both sides of a

a joint support the diagnosis of AHO, rather than pyogenic arthritis. Study Year Patient Age Sensitivity (%) Diaphyseal uptake suggests tumor, trauma, or infarction. Tuson et al.49 1994 6 months–13 years 92 In some cases of osteomyelitis, bone scans show areas of Hamdan et al.50 1987 6 months–14 years 89 decreased technetium uptake (“cold scans”), probably reflecting Howie et al.51 1983 6 weeks–13 years 89 compromised vascular supply to the bone from ischemia or 49,58 Sullivan et al.52 1980 3 weeks–15 years 81b thrombosis; such findings make differentiation of osteomyelitis from infarction associated with sickle-cell disease difficult. Bressler et al.53 1984 6 weeks 100 < Patients with osteomyelitis and decreased uptake on bone scan aSuperscript numbers indicate references. may have more complicated infection, frequently with thrombosis 58 bThe 2 patients younger than 6 weeks of age had normal scans. and ischemic necrosis.

A B C

Figure 78-3. Typical technetium-99 bone scan findings of acute osteomyelitis in a 4-year-old girl who had a 2-day history of fever, ankle pain, and swelling, and refusal to bear weight. Plain radiograph was unremarkable. Triple-phase anterior images of bone scan show increased tracer activity in the region of the right ankle in the angiographic (immediate) phase (A), increased tracer activity in the soft tissues in the region of the ankle in the blood pool (15-minute) phase (B), and localization of tracer in the distal tibial metaphysis (arrow) without periarticular distribution in the delayed (2.5-hour) phase (C). Diagnosis was confirmed at surgery with finding of subperiosteal pus; Streptococcus pyogenes was isolated. (Courtesy of E. Geller and S.S. Long, St. Christopher’s Hospital for Children, Philadelphia, PA.)

A B C

Figure 78-4. Plain film and technetium-99 bone scan of acute osteomyelitis and pyogenic arthritis in a 7-month-old boy who had a 3-day history of high fever, fussiness and redness, and swelling of the lateral right leg from the thigh to the lower leg, with limitation of motion of the knee. Aspiration of the knee revealed 169,000 white blood cells/mm2 and gram-positive cocci. Plain film shows obscuration of right lateral subcutaneous fat–muscle plane, from the thigh to the lower leg (A). Triple-phase bone scan shows increased tracer activity in the region of the right knee in the angiographic phase (B) and in the periarticular soft tissues in the blood pool phase (C), as well as localization of tracer in the distal femur (arrow) but not in the proximal tibia in the delayed phase (D). Diagnosis of osteomyelitis of the femur was confirmed at surgery. Methicillin-susceptible Staphylococcus aureus was isolated from blood, joint and bone specimens. (Courtesy of E. Geller and S.S. Long, St. Christopher’s Hospital for Children, Philadelphia, PA.)

471 All references are available online at www.expertconsult.com PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION K Bone and Joint Infections

Nuclear scanning using gallium-67 citrate or indium-111- third-generation cephalosporin in addition to antistaphylococcal labeled leukocytes is positive in diseases characterized by increased coverage. A second-generation cephalosporin such as cefuroxime bone turnover and, thus, have limited specificity for osteomyeli- alone is a reasonable alternative if suspicion for MRSA is low.73 tis.59 Indium scanning, which reflects migration of white blood However, with the dramatic reduction of cases of Hib disease in cells into areas of inflammation, can be useful in the diagnosis of the United States, it is reasonable to use only an antistaphylococcal– osteomyelitis associated with trauma, surgery, chronic ulcers, or antistreptococcal antibiotic in the fully immunized and immuno- prosthetic devices,60 but is limited by poor localization of infec- competent child. tion (i.e., bone versus soft tissue), decreased sensitivity in diagnos- Neonates with osteomyelitis should be treated with antibiotics ing infection in the central skeleton, and relatively high radiation active against S. aureus, group B streptococcus (GBS), and gram- exposure. Simultaneous performance of a technetium bone scan negative enteric organisms. Suggested initial empiric parenteral sometimes increases specificity.61 antibiotic therapy for neonates and children with AHO is outlined in Table 78-2. Magnetic Resonance Imaging Antibiotic therapy should be modified according to results of culture and susceptibility testing. Nafcillin, oxacillin, a first- Magnetic resonance imaging (MRI) is a sensitive bone–imaging generation cephalosporin, or clindamycin (if susceptible) are the test.62,63 Its reported sensitivity for detection of osteomyelitis drugs of choice for infections caused by MSSA. Clindamycin is a ranges from 92% to 100%. Normal red and fatty portions of the good definitive choice for susceptible MRSA and MSSA73a but bone marrow have a characteristic appearance on MRI. Fatty should not be used if inducible resistance is detected because of 64 74,75 marrow produces a bright signal on T1-weighted images. Changes reports of treatment failure under this circumstance. in marrow caused by infection and inflammation produce an area There are few antibiotic choices for clindamycin-resistant of low signal intensity within the bright fatty marrow. Areas of low CA-MRSA infection in children. Recently published guidelines signal intensity in infected marrow seen on a T1-weighted image by the Infectious Disease Society of America (IDSA) recommend change to bright signal intensity on a T2-weighted image. These vancomycin plus/minus rifampin for the treatment of MRSA changes are not specific for osteomyelitis and can be seen with osteomyelitis in children. Linezolid is suggested as an alternative malignancy, fracture, and bone infarction. choice.72a Limited data support efficacy of linezolid.76,77 In one MRI can detect signal alterations in soft tissue and is particularly group of pediatric patients, linezolid was as effective as vancomy- useful in differentiating cellulitis from osteomyelitis. MRI also cin in treating infections caused by MRSA, although efficacy in may differentiate acute from chronic osteomyelitis.65 treating bone or joint infections was not specifically evaluated.77 Gadolinium-enhanced MRI can be particularly useful in the Linezolid has excellent oral bioavailability and offers an alterna- diagnosis of soft-tissue, muscle, or bone abscesses associated with tive to prolonged intravenous therapy. However, it is expensive infection.41 The use of contrast agents can increase confidence in and many children object to the taste of the oral suspension. the diagnosis of osteomyelitis in cases which bone and soft-tissue Long-term use has been associated with neutropenia, thrombocy- edema are seen on unenhanced images.66 MRI has been used to topenia, and elevated serum transaminase levels.78 There are rare identify bone marrow infection in cases of Bartonella henselae reports of lactic acidosis and optic neuropathy associated with infection, particularly when plain films and computed tomogra- linezolid therapy.79,80 phy (CT) of the affected bones appear normal.28 Most CA-MRSA isolates are susceptible to trimethoprim- sulfamethoxazole, tetracyclines, and rifampin. Clinical experience TREATMENT with these drugs for osteoarticular infections is limited.81,82 Rifampin should not be used as a single agent because of rapid Antibiotic Choice development of resistance. Although daptomycin and tigecycline have activity against MRSA, neither is approved for use in children. Considerations in choosing a specific antimicrobial regimen The IDSA guidelines suggest that daptomycin may used in chil- include the age of the child, underlying medical conditions, sus- dren in selected circumstances.72a If no organism is isolated, and pected pathogens and their susceptibility pattern, antibiotic phar- the symptoms are resolving, initial empiric therapy should be macodynamics, and the safety and efficacy of the antibiotic. continued. Most cases of culture-negative osteomyelitis respond Most β-lactam antibiotics achieve therapeutic concentrations in to therapy with antistaphylococcal antibiotics.83 bone.67,68 Clindamycin has particularly good bone penetration, Management of children with osteomyelitis should include attaining a high bone-to-serum ratio.67,69–71 Vancomycin has excel- concurrent care by an orthopedic surgeon. Indications for surgery lent penetration into the bones of experimental animals.67 include desirability of specific pathogen diagnosis; prolonged Aminoglycoside agents theoretically have poor bactericidal activ- fever, erythema, pain, and swelling; persistent bacteremia despite ity in bone because of local tissue hypoxia and acidosis. Although adequate antibiotic therapy; soft-tissue or periosteal abscess; for- ciprofloxacin penetrates well into bone, fluoroquinolones are not mation of a sinus tract; and presence of necrotic, nonviable recommended routinely for use in young children.72 bone.16,84–86 Most cases of AHO in any age group are caused by S. aureus. Empiric therapy should include coverage for this organism. Parenterally administered nafcillin, clindamycin, or a first- Duration of Therapy generation cephalosporin historically have been the usual choices for empiric therapy; however, the increase in CA-MRSA infections Duration of antibiotic therapy depends on the cause and extent has made the choice of initial antibiotic therapy challenging. of infection as well as the clinical course. The usual duration Direct sampling of bone for culture is increasingly important. ranges from 3 to 6 weeks and should be individualized on the Clindamycin remains a good choice for empiric therapy in com- basis of severity of illness and clinical response. Historical evi- munities where resistance (both constitutive and inducible) occurs dence suggests that <3 weeks of treatment is associated with higher in fewer than 10% of S. aureus isolates.41 In communities where rates of relapse or recurrence than longer duration of therapy.13 CA-MRSA resistance to clindamycin and methicillin is greater than Plain radiographs obtained at the end of therapy may be useful 10% to 15%, vancomycin is the drug of choice for empiric as a marker of maximal anticipated destruction, a baseline for therapy.72a Clindamycin and vancomycin are active against most further studies, and a guide to possible complications. isolates of S. pyogenes and S. pneumoniae. Neither offers coverage for Peripherally inserted or tunneled central venous catheter (PICC/ K. kingae infection, which is susceptible to most β-lactam antibiot- CVC) often is placed to continue intravenous antibiotics at home. ics. Ampicillin-sulbactam should be considered in addition to Use of PICC or CVC for >2 weeks in children with osteomyelitis clindamycin or vancomycin, especially in young children. can be associated with an increase in catheter-related complica- Empiric therapy for young children who have not been immu- tions,87 including catheter malfunction, thrombosis and catheter- nized against Haemophilus influenzae type b should include a associated bloodstream infections.88

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TABLE 78-2. Antibiotic Selection for Initial Treatment of Osteomyelitis

Dosage

Patient Age Likely Pathogen Antibiotic Selection mg/kg per day Doses/Day

>3 years Staphylococcus aureus Nafcillin 150 4 or Clindamycinc 30–40 3–4 or Vancomycin 45–60 3–4 <3 years S. aureus Nafcillin 150 4 Haemophilus influenzae type ba or b Kingella kingae Clindamycinc 30–40 3–4 or Vancomycin 45–60 3–4 plus Cefotaxime 100–150 4 or Ceftriaxone 100 2 or Cefuroxime 75–150 3 or Ampicillin-sulbactam 300 4 Neonate S. aureus Nafcillin 100 4 Group B streptococcus or Enteric gram-negative bacteria Vancomycin 30 2 plus Gentamicin 5–7.5 3 OR Nafcillin 100 4 or Vancomycin 30 2 plus Cefotaxime 150 3 aIf patient is fully immunized against Haemophilus influenzae type b, consider using only antistaphylococcal coverage. bIf patient is treated with either clindamycin or vancomycin, consider adding an ampicillin or cephalosporin agent for Kingella kingae. cClindamycin 40 mg/kg/day recommended for treatment of susceptible MRSA osteomyelitis.

Sequential parenteral–oral antibiotic regimens can be Once the change to oral therapy is made, the child should be successful.89–94 Early transition to oral therapy was not associated monitored to ensure continued clinical improvement. The CRP with a higher risk of treatment failure in a recent study.87 The level is expected to return to normal 7 to 10 days after initiation change to oral antibiotics is generally made when fever, pain, and of appropriate therapy, and the ESR normalizes within 3 to 4 signs of local inflammation have resolved and laboratory values, weeks.45,93 especially CRP, are normalizing. The willingness of the child to take oral medication and the likelihood of adherence to the regimen also must be assessed. The oral antibiotic should have SPECIAL CLINICAL SITUATIONS the same spectrum of coverage as the parenteral drug. If a β-lactam agent is used, dosage required is generally two to three times the Neonatal Osteomyelitis usual oral dose (Table 78-3). Osteomyelitis is uncommon in the neonatal period. The incidence is estimated to be approximately 1 to 3 cases for every 1000 TABLE 78-3. Dosage of Antibiotics Commonly Used in the Oral intensive-care nursery admissions.95 Phase of Treatment of Osteomyelitisa Associated risk factors include prematurity, low birthweight, preceding infection, bacteremia, exchange transfusion, and the Dosage presence of an intravenous or umbilical catheter.96–99 Osteomyeli- Antibiotic mg/kg per day Doses/Day tis of the skull secondary to contiguous spread of infection has occurred as a complication of fetal scalp electrode monitoring100–102 Dicloxacillin 75–100 4 and in association with infected cephalohematoma.103,104 Osteomy Cephalexin 100–150 4 elitis of the calcaneus has complicated heel lancet puncture.97,105 Clindamycin 30–40b 3–4 The diagnosis of osteomyelitis in neonates often is delayed 106 aIn general, the dose of β-lactam antibiotics used for osteomyelitis is 2–3 because of nonspecific symptoms. Signs and symptoms include times the usual dose. fever, irritability, swelling or decreased movement of a limb

b (pseudoparalysis), erythema, and tenderness over the affected Clindamycin 40 mg/kg/day is recommended for treatment of susceptible 95–97,107 MRSA osteomyelitis.72a bone. Preterm infants are more likely than term infants to manifest symptoms of septicemia.108

473 All references are available online at www.expertconsult.com PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION K Bone and Joint Infections

of motion, limb length discrepancy, and gait abnormalities.119 The reported incidence of permanent sequelae varies from 6% to 50%.96,97,108,113 Vertebral Osteomyelitis Vertebral osteomyelitis accounts for approximately 1% to 3% of cases of osteomyelitis in children.13,18,120,121 Boys are affected twice as frequently as girls.122 Infection usually occurs as a result of hematogenous seeding of the vertebral bodies by arterial or venous vessels. Osteomyelitis also can result from extension of soft-tissue infection or as a complication of a surgical procedure.16,123 Clinical manifestations can be indolent and nonspecific, leading to delayed diagnosis. Young infants can have nonspecific signs of septicemia.124 Symptoms in older children include back, chest, abdominal, or leg pain as well as loss of normal curvatures.120,125 Rarely, children manifest dysphagia secondary to a paravertebral or retropharyngeal abscess or acute spinal cord paresis/paralysis Figure 78-5. Plain radiograph of an infant at 2 months of age who had due to paraspinal compression.120,126 Fever is common, and ten- Staphylococcus aureus bloodstream infection during a stay in the neonatal derness over the involved vertebrae is expected. Neurologic deficits intensive care unit in the first month of life. He had multiple sites of infection, are found in 15% to 20% of cases.120,122 including the proximal and distal femur and hip joint. Note widespread S. aureus is isolated in most cases.16,120,122,127 In one review, Sal- destruction of femur, acetabulum, and joint. (Courtesy of S.S. Long, St. monella spp. caused 12% of cases of childhood vertebral osteomy- Christopher’s Hospital for Children, Philadelphia, PA.) elitis.120 Gram-negative bacilli such as Escherichia coli cause vertebral osteomyelitis in adults, particularly those with a history of recent urinary tract infection or instrumentation. Vertebral osteomyelitis in intravenous drug users is commonly caused by Approximately 20% to 50% of neonates with osteomyelitis have Pseudomonas aeruginosa and less commonly by S. aureus, Serratia 128,129 infection of multiple bones,95,96,109and about 75% have suppura- spp., Klebsiella spp., Enterobacter spp., or Candida spp. Tuber- tive arthritis of contiguous joints96 (Figure 78-5). culosis and brucellosis should be considered if symptoms and 130,131 S. aureus (including CA-MRSA110), GBS, and enteric gram- radiographs suggest chronic infection. negative bacilli are the most common causes (Table 78-4); fungi,111 Characteristic findings on plain radiograph consist of narrowing Ureaplasma urealyticum,112 CoNS,113 Neisseria gonorrhoeae,107 and of the involved disk space, lucency of the adjacent vertebral bodies, anaerobic100 bacteria are unusual causes. and, eventually, reactive sclerosis of the bone with fusion of ver- 16,120,127 Infants with GBS bone infection usually have had an uncom- tebral bodies. Vertebral osteomyelitis is differentiated from plicated neonatal course and have infection of a single bone. There diskitis radiographically by the minimal vertebral endplate is a predilection for involvement of long bones on the right, par- involvement associated with diskitis (see Chapter 80, Diskitis). ticularly the right proximal humerus,113,114 which may be related MRI is reported to be highly sensitive (96%) and specific (92%) 132,133 to trauma during vaginal delivery.113 Misdiagnosis of bone infec- for diagnosis of vertebral osteomyelitis. tion as trauma in these mildly ill infants is common. Since the Blood culture results are positive in only about 30% of acute release of the 1996 consensus guidelines for prevention of GBS cases. When blood culture results are negative, strong considera- disease, the incidence of early-onset perinatal GBS disease but not tion should be given to obtaining a biopsy specimen from the 133 late-onset disease has declined in the U.S.115 vertebral body for culture and histologic examination. The white blood cell count commonly is normal; ESR and CRP Children with uncomplicated vertebral osteomyelitis and no often are elevated.116 In most infants, an osteolytic lesion is visible evidence of abscess formation should be treated with at least 4 120 on plain radiograph 10 to 12 days after onset of symptoms (fre- weeks of antibiotic administered parenterally. Surgical decom- quently the time of diagnosis).86,96,97,107,117,118 Radionuclide bone pression or debridement or both are indicated in the presence of scans can be positive53,95,106 but sometimes are less sensitive than spinal epidural abscess, signs of spinal cord compression, or plain radiographs.97 extensive bony destruction. Neonatal osteomyelitis can lead to permanent joint abnormali- Complications of vertebral osteomyelitis include neurologic 134 135 ties or disturbance in skeletal growth secondary to damage to the deficits secondary to epidural abscess, paravertebral abscess, 136 cartilaginous growth plate, including arthritis, decreased range and infected aneurysms of the aorta. Pelvic Osteomyelitis Approximately 6% to 9% of all cases of hematogenous osteomyelitis involve the bones of the pelvis.40,137,138 The ilium and ischium TABLE 78-4. Frequency of Organisms Causing Neonatal 137 Osteomyelitis (n = 128) are most commonly involved; infection of the sacrum, acetabulum, or pubic symphysis is rare.137–140 Risk factors (not always Single Organism % present) include a history of pelvic trauma, intravenous drug use, and genitourinary procedures.137,140 Staphylococcus aureus 60.6 Most patients with pelvic osteomyelitis have fever, gait abnor- β-Hemolytic streptococcus malities, and pain that is often localized to the hip, groin, or Group B 16.5 buttock.137,140–143 Pain with hip movement and point tenderness Group A 3.1 over the affected bone often is observed. Clinical features can Enteric gram-negative bacilli 8.7 mimic those of pyogenic arthritis of the hip;137 however, in pelvic Staphylococcus epidermidis 2.4 osteomyelitis there is more likely to be near-normal range of Nonhemolytic streptococcus 2.4 motion of the hip, absence of referred pain to the knee, specific Streptococcus pneumoniae 0.8 point tenderness over the affected bone (or pain on rocking of 143 Neisseria gonorrhoeae 0.8 the pelvic girdle), and abnormal rectal findings. Responsible pathogens are similar to those that cause osteomyelitis of long Multiple organisms 4.7 bones.

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intravenous drug users.111,154–157 Osteomyelitis caused by Candida BOX 78-1. Bacterial Causes of Osteomyelitis in Children with spp. is reported in intravenous drug users and in prematurely born Sickle-Cell Disease neonates.111,154–158 Aspergillus spp. cause osteomyelitis in children with chronic granulomatous disease, often resulting from contigu- COMMON ous spread of pulmonary infection.159 Blastomyces dermatitidis, Salmonella spp. Coccidioides immitis, Histoplasma capsulatum, and Cryptococcus neo- Staphylococcus aureus formans cause osteomyelitis in indigenous geographic regions and in immunosuppressed hosts.160–163 LESS COMMON Escherichia coli Haemophilus influenzae type b Tuberculous Osteomyelitis Shigella spp. Streptococcus pneumoniae Skeletal lesions occur in approximately 1% of children with tuberculosis.130,164 Bones and joints are infected through hematogenous or lymphatic dissemination of Mycobacterium tuberculosis. Infec- tion can smolder for years before clinical signs are apparent. The Plain radiographs of the pelvis often are normal. Technetium most commonly involved bones are the vertebrae (tuberculous scanning,137,138,141–143 MRI, or CT can suggest the correct diagnosis spondylitis), femur, long bones around knees and ankles, and and may be useful for differentiating osteomyelitis from bacterial small bones of the hands and feet.165 Other sites less frequently infection of the muscles of the pelvic girdle. MRI has the advantage infected are the ribs, mandible, sternum, clavicle, and other long of identifying abscesses associated with pelvic osteomyelitis and bones. Multifocal osteomyelitis is reported in 10% to 15% of is the imaging technique of choice.144 cases.166,167 Patients should be treated for at least 4 weeks with antibiotics Clinical signs and symptoms of skeletal tuberculosis include parenterally.137–140,143 Surgical drainage or debridement should be low-grade fever, weight loss, pain, and soft-tissue swelling at the considered in cases of extraosseous abscess formation or in site of infection. Vertebral involvement begins in the anterior patients whose symptoms do not respond to intravenous anti vertebral body, eventually causing disk space collapse and anterior biotic therapy. wedging of vertebral bodies, and sometimes gibbus deformity. The lower thoracic spine is the usual site of involvement (Pott disease), Children with Sickle Hemoglobinopathies followed by the lumbar spine. The Mantoux tuberculin skin reaction is usually positive. The Children with sickle-cell disease have increased susceptibility to role of interferon-γ release assays in the diagnosis of Pott disease bacterial infections, including osteomyelitis.145 The suspected is currently being evaluated. Plain radiographic findings include pathogenesis is primary microscopic infarction in the intestinal periarticular osteopenia, lytic lesions in the body of the vertebra, mucosa and bone, resulting in bacteremia and focal bone infec- joint space narrowing, and soft-tissue swelling.168 The chest radio- tion. Splenic hypofunction, impaired opsonization, impaired graph often is normal. CT is useful for the evaluation of bone macrophage function, and microembolism as well as tissue infarc- destruction, adjacent soft-tissue abscess formation, and calcifica- tion are likely contributing factors in osteomyelitis.146,147 tion, and in guiding percutaneous biopsy.169,170 MRI is helpful in Salmonella spp. plus other gram-negative enteric bacilli were the determining extent of bone and soft-tissue disease.171 Biopsy speci- cause of >70% of cases of osteomyelitis in children with hemo- mens should be obtained in an attempt to demonstrate the organ- globinopathies in past decades.148–151 S. aureus currently is an ism with stains and culture. important/dominant cause of osteomyelitis in this population. Antituberculous therapy includes 2 months of therapy with four Other organisms causing osteomyelitis in children with sickle drugs, followed by 7 to 10 months of isoniazid and rifampin hemoglobinopathies are listed in Box 78-1. (for susceptible organisms) daily or twice weekly (see Chapter Distinctive features of osteomyelitis in children with sickle-cell 134, Mycobacterium tuberculosis).172 Surgical intervention is disease are frequent involvement of the diaphyses of long bones, indicated in cases of spinal instability and neurologic impairment flat bones, and small bones of the hands and feet as well as multi- secondary to paravertebral abscess formation and for drainage focal, symmetrical bone involvement.146,152 Manifestations of of soft-tissue abscesses. Nontuberculous Mycobacterium spp. osteomyelitis are difficult to differentiate from those of acute vaso- infrequently cause osteomyelitis in immunocompromised occlusive crisis. Fever, bone pain, and leukocytosis are common individuals. to both conditions. Temperature >39°C, toxic appearance, and an absolute band count >500 cells/mm3 are more consistent with infection; however, there is considerable clinical and laboratory Anaerobic Bacterial Osteomyelitis overlap.148 Plain radiograph, technetium scanning, and MRI cannot dif- Anaerobic bacteria are associated with chronic and nonhemato ferentiate infarction from infection.152,153 Therefore, if fever and genously acquired osteomyelitis.173–175 Risk factors include surgery, bone pain have not improved after supportive care has been given trauma, diabetes mellitus, human bites, chronic otitis media or for vaso-occlusive crisis, needle aspiration of the affected area of sinusitis, dental infection, fibrous dysplasia of bone, presence of bone for Gram stain and culture should be performed. a prosthesis, and decubitus ulcers (Figure 78-6). Children are A prolonged course of parenteral antibiotic therapy (6 to 8 more likely than adults to experience anaerobic osteomyelitis of weeks) may be necessary for treatment of osteomyelitis in patients the skull and facial bones.173 Osteomyelitis of ribs follows contigu- with sickle hemoglobinopathy. Oral therapy can be substituted for ous spread from aspiration lung infection; Actinomyces spp. are the parenteral treatment once a pathogen has been confirmed and primary pathogens. Soft-tissue swelling or abscess can be the pre- there is clinical improvement; therapy may need to be very pro- senting abnormality. Similarly, Actinomyces spp. can cause osteo- tracted. Relapses especially when due to Salmonella are not myelitis of the maxilla or mandible, frequently without dental infrequent.146,148 pathology. Infection usually is polymicrobial; gram-positive cocci, Bacter- OSTEOMYELITIS DUE TO UNUSUAL ORGANISMS oides spp., Prevotella spp., and Fusobacterium spp. are the most common anaerobes, and S. aureus is the most commonly associ- Fungal Osteomyelitis ated aerobic isolate.174 Therapy consists of treatment of underlying conditions, surgical debridement of necrotic bone, and appropri- Fungal osteomyelitis is unusual in healthy children, occurring ate antibiotic therapy. Examples of effective antibiotics are clin- occasionally in neonates, immunocompromised patients, and damycin, metronidazole, imipenem, and amoxicillin-clavulanate.

475 All references are available online at www.expertconsult.com PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION K Bone and Joint Infections

PUNCTURE WOUND OSTEOCHONDRITIS OF THE FOOT Bacterial osteochondritis is a complication of puncture wounds of the foot, occurring in approximately 1.5% of such injuries.182,186–188 Symptoms of osteochondritis, which appear several days to weeks after the initial injury, include increasing tenderness, erythema, and swelling at the site of the puncture. Infection usually is caused by Pseudomonas aeruginosa,189often as a result of inoculation from the colonized moist soles of tennis shoes.190 S. aureus is the usual pathogen if symptoms began within 3 to 5 days of injury. Obtaining specimens from bone for micro- biologic diagnosis is desirable. Empiric antibiotic therapy should include coverage for P. aeruginosa and S. aureus. Ticarcillin-clavulanate, piperacillin- tazobactam, ceftazidime or cefepime, with or without an aminoglycoside, would be appropriate empiric therapy if MRSA is not likely. With appropriate surgical debridement, short-duration (7 to 10 days) parenteral antibiotic therapy has been effective for P. aeruginosa,189,191 as has 3 to 4 weeks of antibiotic therapy without debridement.190 Treatment with oral ciprofloxacin in conjunction Figure 78-6. Actinomycosis of the mandible in a 9-year-old girl with history of with surgical debridement also is successful192 (see Chapter 292, painless expansion of the jaw over several months. Reconstructed spiral Antimicrobial Agents). computed tomography shows expansion of bone with complex lytic and sclerotic mass (arrow). Surgical biopsy confirmed Actinomyces osteomyelitis and fibrous dysplasia of bone. (Courtesy of L. Kaban and M. Pasternack, CHRONIC RECURRENT MULTIFOCAL Massachusetts General Hospital; and S.S. Long, St. Christopher’s Hospital for OSTEOMYELITIS Children, Philadelphia, PA.) Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disease of children and young adults characterized by recurring episodes of low-grade fever, swelling, and pain over Many anaerobic isolates are susceptible to penicillin. The choice affected bones and by radiologic abnormalities suggestive of of antibiotic depends on the specific organisms isolated and their osteomyelitis.193,194 Females are more frequently affected than potential for β-lactamase production. Therapy is protracted, fre- males.195 The median age of onset of illness is 10 years. CRMO quently exceeding 1 year of oral penicillin or amoxicillin plus sometimes is associated with palmoplantar pustulosis,196psoriasis, probenecid for actinomycosis. arthritis, sacroiliitis, inflammatory bowel disease,197 and Sweet syndrome. Radiographic abnormalities occur most commonly in the meta- NONHEMATOGENOUS OSTEOMYELITIS physis of long bones and are characterized by radiolucent bone lesions with reactive sclerosis and soft-tissue swelling.195,198,199 The Contiguous Infection sternal end of the clavicle, the vertebral bodies, and the smaller bones of the hands and feet often are involved. Radiographic Factors associated with the development of nonhematogenous changes are similar to those seen in acute osteomyelitis, but mul- osteomyelitis include open fractures requiring surgical reduc- tiple, often symmetrical lesions are present in CRMO. Bone scan- tion,176,177 implanted orthopedic devices, decubitus ulcers,173 and ning and MRI are useful in determining the extent and evolution neuropathic ulcers.178,179 Facial osteomyelitis usually is secondary of disease.199–201 An infectious cause of CRMO has not been to untreated mastoiditis, sinusitis, or periodontal abscess.173,177 determined. Osteomyelitis can occur after local soft-tissue infection or direct The course of CRMO consists of prolonged bone pain with inoculation of bone from human and animal bites.180,181 Puncture remissions and relapses over several years; the mean duration of wounds can lead to osteomyelitis of the foot (e.g., stepping on a disease is 6 years.202 In a long-term follow-up study of 23 patients nail or toothpick182) or the patella (e.g., kneeling on a needle). with CRMO, 26% had active disease at a median of 13 years after Indolent presentation is common among children with non diagnosis.197Although the clinical outcome in most patients is hematogenous osteomyelitis. Fever is present in less than half of good, approximately 20% of patients have a prolonged and severe patients.183 Persistent drainage or ulceration of the soft tissue over course. Young age at onset and multiple sites of involvement the affected bone is typical. Plain radiograph shows bony destruc- predict less favorable outcome.203 Treatment with a variety of anti- tion. Peripheral white blood cell count often is normal, and ESR biotics has no apparent effect on the course or outcome. Some and CRP can be normal. experts have advocated the use of corticosteroids or nonsteroidal Nonhematogenous osteomyelitis often is caused by S. aureus, anti-inflammatory agents for relief of symptoms.195,198 Other ther- although coinfection with gram-negative and anaerobic organ- apies utilized in small numbers of patients have included colchi- isms occurs.174 Examination of specimens from an associated sinus cine, INF-γ, IFN-α, and infliximab.197,203,204 tract is unreliable in defining the etiology of osteomyelitis.184 Because multifocal bone lesions in childhood can occur with Biopsy with culture of the affected bone is the best method of neuroblastoma, histiocytosis X, leukemia, and staphylococcal determining appropriate antibiotic therapy. Therapy should be osteomyelitis, histologic examination and culture of bone speci- prolonged if infection is chronic, sometimes with parenteral mens should be performed. Histologic findings in CRMO are non- therapy followed by oral therapy for a total of 4 to 6 months. specific acute and chronic inflammatory changes; in the chronic The rate of recurrence in nonhematogenous osteomyelitis is as phase of the disease, granulomatous changes can be seen.205 high as 40%, even with prolonged courses of antibiotic therapy.183 Aggressive surgical debridement or other interventions are required CHRONIC OSTEOMYELITIS in addition to antibiotic therapy. Implanted devices commonly must be removed for cure. Debridement followed by muscle flap Chronic osteomyelitis develops in fewer than 5% of cases procedure to re-establish the blood supply in decubitus ulcer- of AHO;12,206 it more often follows nonhematogenous associated osteomyelitis frequently is beneficial.185 osteomyelitis.183

476 Chronic osteomyelitis is characterized by alternating periods of Surgical debridement of necrotic bone is primary management. quiescence and recurrent pain, swelling, and sinus tract drainage, Alternative therapeutic approaches include the use of antibiotic- persisting for years despite prolonged antibiotic therapy. Infec- impregnated polymethyl methacrylate beads,207,208 local antibiotic tions are often polymicrobial, and the original metaphyseal infec- delivery via implantable pumps,209 and suction vacuum devices or tion, with skeletal growth, moves to become a lytic lesion in the bone grafts, skin grafts, and muscle flaps to eliminate dead space diaphysis.175,185 and improve vascularity.210–212 Osteomyelitis 78

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477.e1 PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION K Bone and Joint Infections

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190. Fisher MC, Goldsmith JF, Gilligan PH. Sneakers as a source of 201. Dawson JS, Webb JK, Preston BJ. Case report: chronic Pseudomonas aeruginosa in children with osteomyelitis recurrent multifocal osteomyelitis with magnetic resonance following puncture wounds. J Pediatr 1985;106:607. imaging. Clin Radiol 1994;49:133. 191. Jacobs RF, Adelman L, Sack CM, et al. Management of 202. Solheim LF, Paus B, Liverud K, et al. Chronic recurrent Pseudomonas osteochondritis complicating puncture wounds multifocal osteomyelitis. Acta Orthop Scand 1980;51:37. of the foot. Pediatrics 1982;69:432. 203. Catalano-Pons C, Comte A, Wipff J, et al. Clinical outcome in 192. Raz R, Miron D. Oral ciprofloxacin for treatment of infection children with chronic recurrent multifocal osteomyelitis. following nail puncture wounds of the foot. Clin Infect Dis Rheumatology (Oxford) 2008;47(9):1397. 1995;21:194. 204. Gallagher KT, Roberts RL, MacFarlane JA, et al. Treatment of 193. Schultz C, Holterhus PM, Seidel A, et al. Chronic recurrent chronic recurrent multifocal osteomyelitis with interferon multifocal osteomyelitis in children. Pediatr Infect Dis J gamma. J Pediatr 1997;131:470. 1999;18:1008. 205. Bjorksten B, Boquist L. Histopathological aspects of chronic 194. Chun CS. Chronic recurrent multifocal osteomyelitis of the recurrent multifocal osteomyelitis. J Bone Joint Surg Br spine and mandible: case report and review of the literature. 1980;62:376. Pediatrics 2004;113:380. 206. Gillespie WJ, Mayo KM. The management of acute 195. King SM, Laxer RM, Manson D, et al. Chronic recurrent haematogenous osteomyelitis in the antibiotic era: a study of multifocal osteomyelitis: a noninfectious inflammatory the outcome. J Bone Joint Surg Br 1981;63:126. process. Pediatr Infect Dis J 1987;6:907. 207. Mader JT, Shirtliff ME, Bergquist SC, et al. Antimicrobial 196. Bjorksten B, Gustavson KH, Eriksson B, et al. Chronic treatment of chronic osteomyelitis. Clin Orthop recurrent multifocal osteomyelitis and pustulosis 1999;360:47–65. palmoplantaris. J Pediatr 1978;93:227. 208. Henry SL, Hood GA, Seligson D. Long term implantation of 197. Huber AM, Lam P-Y, Duffy CM, et al. Chronic gentamicin polymethyl-methacrylate antibiotic beads. Clin recurrent multifocal osteomyelitis: clinical outcome Orthop 1993;295:47. after more than five years of follow-up. J Pediatr 209. Perry CR, Pearson RL. Local antibiotic delivery in the 2002;141:198. treatment of bone and joint infections. Clin Orthop 198. Probst F, Bjorksten B, Gustavson K-H. Radiological aspect of 1991;263:215. chronic recurrent multifocal osteomyelitis. Ann Radiol 210. Fitzgerald RH, Ruttle PE, Arnold PG, et al. Local muscle flaps 1978;21:115. in the treatment of chronic osteomyelitis. J Bone Joint Surg 199. Mortensson W, Edeburn G, Fries M, et al. Chronic Am 1985;67:175. recurrent multifocal osteomyelitis in children: a 211. Patzakis MJ, Abdollahi K, Sherman R, et al. Treatment of roentgenologic and scintigraphic investigation. Acta Radiol chronic osteomyelitis with muscle flaps. Orthop Clin North 1988;29:565. Am 1993;24:505. 200. Machiels F, Seynaeve P, Lagey C, et al. Chronic recurrent 212. Anthony JP, Mathes SJ, Alpert BS. The muscle flap in the multifocal osteomyelitis with MR correlation: a case report. treatment of lower extremity osteomyelitis: results in patients Pediatr Radiol 1992;22:535. over 5 years of treatment. Plast Reconstr Surg 1991;88:311.

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